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Overview
- Description
- A medication used to treat many types of cancer as well as arthritis and severe psoriasis.
- Description
- A medication used to treat many types of cancer as well as arthritis and severe psoriasis.
- DrugBank ID
- DB00563
- Type
- Small Molecule
- Clinical Trials
- Phase 0
- 18
- Phase 1
- 201
- Phase 2
- 698
- Phase 3
- 455
- Phase 4
- 221
- Mechanism of Action
- Thymidylate synthaseInhibitor
- Reduced folate transporterModulator
- Proton-coupled folate transporterModulator
- + 2 more targets
- Thymidylate synthase
Identification
- Summary
Methotrexate is an antineoplastic agent used the treatment of a wide variety of cancers as well as severe psoriasis, severe rheumatoid arthritis, and juvenile rheumatoid arthritis.
- Brand Names
- Metoject, Nordimet, Otrexup, Rasuvo, Reditrex, Trexall, Xatmep
- Generic Name
- Methotrexate
- DrugBank Accession Number
- DB00563
- Background
Methotrexate is a folate derivative that inhibits several enzymes responsible for nucleotide synthesis.1 This inhibition leads to suppression of inflammation as well as prevention of cell division.1 Because of these effects, methotrexate is often used to treat inflammation caused by arthritis or to control cell division in neoplastic diseases such as breast cancer and non-Hodgkin's lymphoma.1,4,5,6,7
Due to the toxic effects of methotrexate, it is indicated for treatment of some forms of arthritis and severe psoriasis only if first line treatment has failed or patients are intolerant of those treatments.7
Methotrexate was granted FDA approval on 7 December 1953.8
- Type
- Small Molecule
- Groups
- Approved
- Structure
Structure for Methotrexate (DB00563)
- Weight
- Average: 454.4393
Monoisotopic: 454.171315854 - Chemical Formula
- C20H22N8O5
- Synonyms
- 4-amino-10-methylfolic acid
- 4-amino-N(10)-methylpteroylglutamic acid
- Amethopterin
- Methotrexat
- Méthotrexate
- Methotrexate
- Methotrexatum
- Metotrexato
- MTX
- N-[4-[[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]-L-glutamic acid
- External IDs
- CL 14377
- CL-14377
- EMT 25299
- EMT-25299
- NSC-740
- R 9985
- R-9985
Pharmacology
- Indication
Methotrexate oral solution is indicated for pediatric acute lymphoblastic leukemia and pediatric polyarticular juvenile idiopathic arthritis.4 Methotrexate injections for subcutaneous use are indicated for severe active rheumatoid arthritis, polyarticular juvenile idiopathic arthritis and severe, recalcitrant, disabling psoriasis.5,6,10 It has also been approved by the EMA for the treatment of adult patients requiring systemic therapy for moderate-to-severe plaque psoriasis.12
Other formulations are indicated to treat gestational choriocarcinoma, chorioadenoma destruens, hydatiform mole, breast cancer, epidermoid cancer of the head and neck, advanced mycosis fungoides, lung cancer, and advanced non-Hodgkin's lymphoma.7 It is also used in the maintenance of acute lymphocytic leukemia.7 Methotrexate is also given before treatment with leucovorin to prolong relapse-free survival following surgical removal of a tumour in non-metastatic osteosarcoma.7
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Adjunct therapy in treatment of Acute lymphoblastic leukemia (all) •••••••••••• ••••••••••• •••••• ••••••••• Treatment of Acute promyelocytic leukemia ••• ••••• Used in combination to treat Bladder cancer ••• ••••• Adjunct therapy in treatment of Breast cancer •••••••••••• ••••• Used in combination to treat Cns lymphoma ••• ••••• - Associated Therapies
- Contraindications & Blackbox Warnings
Prevent Adverse Drug Events TodayTap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events with our Clinical API- Pharmacodynamics
Methotrexate inhibits enzymes responsible for nucleotide synthesis which prevents cell division and leads to anti-inflammatory actions.1 It has a long duration of action and is generally given to patients once weekly.1,4,5,6 Methotrexate has a narrow therapeutic index.2
- Mechanism of action
Methotrexate enters tissues and is converted to a methotrexate polyglutamate by folylpolyglutamate.1
Methotrexate's mechanism of action is due to its inhibition of enzymes responsible for nucleotide synthesis including dihydrofolate reductase, thymidylate synthase, aminoimidazole caboxamide ribonucleotide transformylase (AICART), and amido phosphoribosyltransferase.1 Inhibtion of nucleotide synthesis prevents cell division.
In rheumatoid arthritis, methotrexate polyglutamates inhibit AICART more than methotrexate.1 This inhibition leads to accumulation of AICART ribonucleotide, which inhibits adenosine deaminase, leading to an accumulation of adenosine triphosphate and adenosine in the extracellular space, stimulating adenosine receptors, leading to anti-inflammatory action.1
Target Actions Organism AThymidylate synthase inhibitorHumans AReduced folate transporter modulatorHumans AProton-coupled folate transporter modulatorHumans ABifunctional purine biosynthesis protein ATIC inhibitorHumans ADihydrofolate reductase inhibitorHumans - Absorption
Methotrexate has a bioavailability of 64-90%, though this decreases at oral doses above 25mg due to saturation of the carrier mediated transport of methotrexate.1. Methotrexate has a Tmax of 1 to 2 hours.1 oral doses of 10-15µg reach serum levels of 0.01-0.1µM.1
- Volume of distribution
The volume of distribution of methotrexate at steady state is approximately 1L/kg.1
- Protein binding
Methotrexate is 46.5-54% bound to plasma proteins.1
- Metabolism
Methotrexate is metabolized by folylpolyglutamate synthase to methotrexate polyglutamate in the liver as well as in tissues.1,7 Gamma-glutamyl hydrolase hydrolyzes the glutamyl chains of methotrexate polyglutamates converting them back to methotrexate.1,7 A small amount of methotrexate is also converted to 7-hydroxymethotrexate.1,7
Hover over products below to view reaction partners
- Route of elimination
Methotrexate is >80% excreted as the unchanged drug and approximately 3% as the 7-hydroxylated metabolite.1 Methotrexate is primarily excreted in the urine with 8.7-26% of an intravenous dose appearing in the bile.1
- Half-life
The half life of low dose methotrexate is 3 to 10 hours in adults.4 The half life for high dose methotrexate is 8 to 15 hours.5 Pediatric patients taking methotrexate for acute lymphoblastic anemia experience a terminal half life of 0.7 to 5.8 hours.4 Pediatric patients taking methotrexate for juvenile idiopathic arthritis experience a half life of 0.9 to 2.3 hours.4
- Clearance
Methotrexate clearance varies widely between patients and decreases with increasing doses.3 Currently, predicting clearance of methotrexate is difficult and exceedingly high serum levels of methotrexate can still occur when all precautions are taken.3
- Adverse Effects
Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!Improve decision support & research outcomes with our structured adverse effects data.- Toxicity
The oral LD50 in rats is 135mg/kg and in mice is 146mg/kg.9
Symptoms of overdose include hematologic and gastrointestinal reactions like leukopenia, thombocytopenia, anemia, pancytopenia, bone marrow suppression, mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration, and gastrointestinal bleeding.7 In the event of an overdose, patients should be treated with glucarpidase and not be given leucovorin for 2 hours before or after glucarpidase.7
- Pathways
Pathway Category Methotrexate Action Pathway Drug action - Pharmacogenomic Effects/ADRs
Interacting Gene/Enzyme Allele name Genotype(s) Defining Change(s) Type(s) Description Details Canalicular multispecific organic anion transporter 1 ABCC2 IVS 23+56 (C;C) / (C;T) T allele ADR Directly Studied Patients with this genotype have increased risk of toxicity with methotrexate. Details Methylenetetrahydrofolate reductase --- (T;T) / (C;T) T allele ADR Directly Studied Patients with this genotype have increased risk of toxicity with methotrexate. Details
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareAbacavir Methotrexate may decrease the excretion rate of Abacavir which could result in a higher serum level. Abametapir The serum concentration of Methotrexate can be increased when it is combined with Abametapir. Abatacept The metabolism of Methotrexate can be increased when combined with Abatacept. Abciximab The risk or severity of bleeding can be increased when Abciximab is combined with Methotrexate. Abemaciclib Abemaciclib may decrease the excretion rate of Methotrexate which could result in a higher serum level. - Food Interactions
- Avoid alcohol.
- Avoid milk and dairy products. Milk and dairy products reduce absorption.
- Exercise caution with St. John's Wort.
- Limit caffeine intake. Caffeine may reduce the effectiveness of methotrexate.
- Take with or without food.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Product Ingredients
Ingredient UNII CAS InChI Key Methotrexate sodium 3IG1E710ZN 7413-34-5 DASQOOZCTWOQPA-GXKRWWSZSA-L - Product Images
- International/Other Brands
- Abitrexate (Teva) / Alltrex (Naprod) / Artrait (TRB) / Atrexel (Schering-Plough) / Bendatrexat (Bendalis) / Carditrex (Cadila) / Dermotrex (East West) / Ebetrex (Ebewe) / Emtexate / Ledertrexate (Biodim) / Maxtrex (Pfizer) / Meisusheng (Hospira) / Mexate (Cadila HC) / Rheumatrex (Wyeth KK) / Trexan (Atafarm) / Zexate (Dabur Pharma)
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Eugia-methotrexate Tablet 2.5 mg Oral Eugia Pharma (Malta) Limited Not applicable Not applicable Canada 
Jylamvo Solution 2 mg/1mL Oral Shorla Oncology Inc. 2023-12-15 Not applicable US 
Jylamvo Solution 2 mg/ml Oral Oresund Pharma Ap S 2020-12-22 Not applicable EU 
M-methotrexate Tablet 2.5 mg Oral Mantra Pharma Inc 2024-04-24 Not applicable Canada Methofill Self-dose Injector Solution 7.5 mg / 0.15 mL Subcutaneous Accord Healthcare, S.L.U. Not applicable Not applicable Canada - Generic Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Ach-methotrexate Tablet 2.5 mg Oral Accord Healthcare, S.L.U. 2021-10-21 Not applicable Canada Apo-methotrexate Tablet 2.5 mg Oral Apotex Corporation 1999-09-17 Not applicable Canada Auro-methotrexate Tablet 2.5 mg Oral Auro Pharma Inc 2023-02-02 Not applicable Canada Jamp-methotrexate Solution 25 mg / mL Intra-arterial; Intramuscular; Intrathecal; Intravenous Jamp Pharma Corporation 2014-03-12 2022-11-14 Canada Methotrexate Tablet 2.5 mg/1 Oral REMEDYREPACK INC. 2023-06-28 Not applicable US - Unapproved/Other Products
Name Ingredients Dosage Route Labeller Marketing Start Marketing End Region Image Methotrexate Methotrexate sodium (25 mg/1mL) Injection, solution Intra-arterial; Intramuscular; Intrathecal; Intravenous Hospira Worldwide, Inc. 2012-03-02 2014-01-31 US METHOTREXATE DBL 50 MG/2ML FLAKON, 1 ADET Methotrexate (50 mg/2ml) Injection, solution Intra-arterial; Intramuscular; Intravenous ORNA İLAÇ TEKSTİL KİMYEVİ MAD. SAN. VE DIŞ TİC. LTD. ŞTİ. 2018-02-20 Not applicable Turkey 
METHOTREXATE DBL 500 MG/20ML FLAKON, 1 ADET Methotrexate (500 mg/20ml) Injection, solution Intramuscular; Intravenous ORNA İLAÇ TEKSTİL KİMYEVİ MAD. SAN. VE DIŞ TİC. LTD. ŞTİ. 2019-08-06 Not applicable Turkey METHOTREXATE DBL 5GR/50 ML FLAKON, 1 ADET Methotrexate (5 gr/50ml) Injection, solution Intramuscular; Intravenous ORNA İLAÇ TEKSTİL KİMYEVİ MAD. SAN. VE DIŞ TİC. LTD. ŞTİ. 2020-07-21 Not applicable Turkey
Categories
- ATC Codes
- L04AX03 — Methotrexate
- L04AX — Other immunosuppressants
- L04A — IMMUNOSUPPRESSANTS
- L04 — IMMUNOSUPPRESSANTS
- L — ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS
- Drug Categories
- Abortifacient Agents
- Abortifacient Agents, Nonsteroidal
- Agents Causing Muscle Toxicity
- Antimetabolites
- Antineoplastic Agents
- Antineoplastic and Immunomodulating Agents
- Antirheumatic Agents
- BCRP/ABCG2 Substrates
- Biological Factors
- Cancer immunotherapy
- Cardiotoxic antineoplastic agents
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 CYP3A4 Substrates with a Narrow Therapeutic Index
- Cytochrome P-450 Substrates
- Dermatologicals
- Drugs causing inadvertant photosensitivity
- Drugs that are Mainly Renally Excreted
- Enzyme Inhibitors
- Folic Acid Analogues
- Folic Acid Antagonists
- Hepatotoxic Agents
- Heterocyclic Compounds, Fused-Ring
- Immunologic Factors
- Immunosuppressive Agents
- Immunotherapy
- Myelosuppressive Agents
- Narrow Therapeutic Index Drugs
- Nephrotoxic agents
- Noxae
- Nucleic Acid Synthesis Inhibitors
- OAT1/SLC22A6 inhibitors
- OAT3/SLC22A8 Inhibitors
- OAT3/SLC22A8 Substrates
- OAT3/SLC22A8 Substrates with a Narrow Therapeutic Index
- OATP1B1/SLCO1B1 Substrates
- OATP1B3 substrates
- P-glycoprotein substrates
- P-glycoprotein substrates with a Narrow Therapeutic Index
- Photosensitizing Agents
- Pigments, Biological
- Pteridines
- Pterins
- Reproductive Control Agents
- Toxic Actions
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as glutamic acid and derivatives. These are compounds containing glutamic acid or a derivative thereof resulting from reaction of glutamic acid at the amino group or the carboxy group, or from the replacement of any hydrogen of glycine by a heteroatom.
- Kingdom
- Organic compounds
- Super Class
- Organic acids and derivatives
- Class
- Carboxylic acids and derivatives
- Sub Class
- Amino acids, peptides, and analogues
- Direct Parent
- Glutamic acid and derivatives
- Alternative Parents
- N-acyl-alpha amino acids / Hippuric acids / Pteridines and derivatives / Aminobenzamides / Aniline and substituted anilines / Dialkylarylamines / Benzoyl derivatives / Aminopyrimidines and derivatives / Aralkylamines / Pyrazines show 11 more
- Substituents
- Amine / Amino acid / Aminobenzamide / Aminobenzoic acid or derivatives / Aminopyrimidine / Aniline or substituted anilines / Aralkylamine / Aromatic heteropolycyclic compound / Azacycle / Benzamide show 30 more
- Molecular Framework
- Aromatic heteropolycyclic compounds
- External Descriptors
- monocarboxylic acid amide, dicarboxylic acid, pteridines (CHEBI:44185)
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- YL5FZ2Y5U1
- CAS number
- 59-05-2
- InChI Key
- FBOZXECLQNJBKD-ZDUSSCGKSA-N
- InChI
- InChI=1S/C20H22N8O5/c1-28(9-11-8-23-17-15(24-11)16(21)26-20(22)27-17)12-4-2-10(3-5-12)18(31)25-13(19(32)33)6-7-14(29)30/h2-5,8,13H,6-7,9H2,1H3,(H,25,31)(H,29,30)(H,32,33)(H4,21,22,23,26,27)/t13-/m0/s1
- IUPAC Name
- (2S)-2-[(4-{[(4-amino-2-imino-2,3-dihydropteridin-6-yl)methyl](methyl)amino}phenyl)formamido]pentanedioic acid
- SMILES
- CN(CC1=CN=C2N=C(N)N=C(N)C2=N1)C1=CC=C(C=C1)C(=O)N[C@@H](CCC(O)=O)C(O)=O
References
- Synthesis Reference
- US2512572
- General References
- Inoue K, Yuasa H: Molecular basis for pharmacokinetics and pharmacodynamics of methotrexate in rheumatoid arthritis therapy. Drug Metab Pharmacokinet. 2014;29(1):12-9. Epub 2013 Nov 26. [Article]
- Przekop PR Jr, Tulgan H, Przekop AA, Glantz M: Adverse drug reaction to methotrexate: pharmacogenetic origin. J Am Osteopath Assoc. 2006 Dec;106(12):706-7. [Article]
- Muhrez K, Benz-de Bretagne I, Nadal-Desbarats L, Blasco H, Gyan E, Choquet S, Montigny F, Emond P, Barin-Le Guellec C: Endogenous metabolites that are substrates of organic anion transporter's (OATs) predict methotrexate clearance. Pharmacol Res. 2017 Apr;118:121-132. doi: 10.1016/j.phrs.2016.05.021. Epub 2016 May 19. [Article]
- FDA Approved Drug Products: Methotrexate Oral Solution [Link]
- FDA Approved Drug Products: Methotrexate Subcutaneous Injection [Link]
- FDA Approved Drug Products: Methotrexate Prefilled Syringe for Subcutaneous Injection [Link]
- FDA Approved Drug Products: Methotrexate Injection [Link]
- FDA Approved Drug Products: Methotrexate Sodium Oral Tablets [Link]
- Cayman Chemicals: Methotrexate MSDS [Link]
- FDA Approved Drug Products: RediTrex Methotrexate Subcutaneous Injection [Link]
- FDA Approved Drug Products: METHOTREXATE injection, for intravenous, intramuscular, subcutaneous, or intrathecal use [Link]
- EMA Summary of Product Characteristics: Nordimet (methotrexate) solution for injection [Link]
- External Links
- Human Metabolome Database
- HMDB0014703
- KEGG Drug
- D00142
- KEGG Compound
- C01937
- PubChem Compound
- 126941
- PubChem Substance
- 46507678
- ChemSpider
- 112728
- BindingDB
- 66082
- 6851
- ChEBI
- 44185
- ChEMBL
- CHEMBL34259
- ZINC
- ZINC000001529323
- Therapeutic Targets Database
- DNC000933
- PharmGKB
- PA450428
- PDBe Ligand
- MTX
- RxList
- RxList Drug Page
- Drugs.com
- Drugs.com Drug Page
- PDRhealth
- PDRhealth Drug Page
- Wikipedia
- Methotrexate
- PDB Entries
- 1ao8 / 1axw / 1d1g / 1ddr / 1dds / 1df7 / 1dhi / 1dhj / 1dls / 1dra … show 71 more
- FDA label
- Download (518 KB)
- MSDS
- Download (77 KB)
Clinical Trials
- Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample dataNot Available Active Not Recruiting Not Available Brain and Central Nervous System Tumors / Cognitive/Functional Effects / Long-Term Effects Secondary to Cancer Therapy in Children / Ototoxicity 1 somestatus stop reason just information to hide Not Available Active Not Recruiting Other Severe Aplastic Anemia (SAA) 1 somestatus stop reason just information to hide Not Available Active Not Recruiting Treatment Juvenile Idiopathic Arthritis (JIA) 1 somestatus stop reason just information to hide Not Available Completed Not Available Acute Lymphoblastic Leukemia (ALL) 1 somestatus stop reason just information to hide Not Available Completed Not Available Alzheimer's Disease (AD) / Dementia 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Abic ltd
- Pharmacia and upjohn co
- Hospira inc
- App pharmaceuticals llc
- Abraxis pharmaceutical products
- Bedford laboratories div ben venue laboratories inc
- Norbrook laboratories ltd
- Pharmachemie usa inc
- Bioniche pharma usa llc
- Ebewe pharma ges mbh nfg kg
- Pharmachemie bv
- Bristol laboratories inc div bristol myers co
- Bristol myers co
- Bristol myers squibb
- Barr laboratories inc
- Dava pharmaceuticals inc
- Duramed pharmaceuticals inc sub barr laboratories inc
- Mylan pharmaceuticals inc
- Roxane laboratories inc
- Packagers
- Apotheca Inc.
- APP Pharmaceuticals
- A-S Medication Solutions LLC
- Barr Pharmaceuticals
- Baxter International Inc.
- Bedford Labs
- Ben Venue Laboratories Inc.
- Bigmar Bioren Pharmaceuticals Sa
- Bryant Ranch Prepack
- DAVA Pharmaceuticals
- Dispensing Solutions
- Diversified Healthcare Services Inc.
- Duramed
- Ebewe Pharma
- Excella GmbH
- Gallipot
- Generamedix Inc.
- Hospira Inc.
- Intas Pharmaceuticals Ltd.
- Lake Erie Medical and Surgical Supply
- Major Pharmaceuticals
- Murfreesboro Pharmaceutical Nursing Supply
- Mylan
- Nucare Pharmaceuticals Inc.
- PD-Rx Pharmaceuticals Inc.
- Pharmedix
- Physicians Total Care Inc.
- Qualitest
- Rebel Distributors Corp.
- Remedy Repack
- Roxane Labs
- Spectrum Pharmaceuticals
- UDL Laboratories
- Wyeth Pharmaceuticals
- Dosage Forms
Form Route Strength Injection Subcutaneous 10 mg/mL Injection Subcutaneous 20 mg/2.0mL Injection Subcutaneous Injection, solution Subcutaneous 7.5 mg/0.75ml Solution Subcutaneous 25.000 mg Injection, solution Parenteral 50 MG Injection Intra-arterial; Intramuscular; Intravenous 1 g/10ml Injection Intra-arterial; Intramuscular; Intravenous 50 mg/2ml Injection Intravenous 500 mg/20ml Injection Intravenous 50 mg/2ml Injection Intravenous 1 g/10ml Tablet Oral Solution Parenteral Injection, solution Parenteral Injection, solution, concentrate Parenteral Injection, solution Parenteral 20 mg/ml Solution Parenteral 500 mg Injection Injection Parenteral 25 mg Solution 100 mg/1ml Solution Parenteral 50.0 mg Injection, solution Intramuscular; Intrathecal; Intravenous 1000 MG Injection, solution Intramuscular; Intrathecal; Intravenous 50 MG Solution Oral 2 mg/1mL Solution Oral 2 mg/ml Injection, solution 10 mg/0.4ml Injection, solution 12.5 mg/0.5ml Injection, solution 15 mg/0.6ml Injection, solution 17.5 mg/0.7ml Injection, solution 20 mg/0.8ml Injection, solution 22.5 mg/0.9ml Injection, solution 25 mg/ml Injection, solution 7.5 mg/0.3ml Injection Intramuscular; Intravenous 15 mg/3ml Injection, solution Parenteral 10 MG Injection, solution Parenteral 12.5 MG Injection, solution Parenteral 15 MG Injection, solution Parenteral 17.5 MG Injection, solution Parenteral 20 MG Injection, solution Parenteral 22.5 MG Injection, solution Parenteral 25 MG Injection, solution Parenteral 27.5 MG Injection, solution Parenteral 30 MG Injection, solution Parenteral 7.5 MG Injection, solution Subcutaneous Injection Parenteral Injection, solution Parenteral 1000 MG/40ML Injection, solution Parenteral 500 MG/20ML Injection, solution Parenteral 50 MG/2ML Injection, solution, concentrate Intravenous Solution Parenteral 1 G/10ML Solution Parenteral 5 G/50ML Injection, solution Parenteral 10 MG/0.4ML Injection, solution Parenteral 15 MG/0.6ML Injection, solution Parenteral 20 MG/0.8ML Injection, solution Parenteral 25 MG/1.0ML Injection, solution Parenteral 7.5 MG/0.3ML Injection 50 MG/5ML Injection, solution, concentrate Intramuscular; Intravenous 50 mg/5ml Injection, solution, concentrate Intramuscular; Intravenous 500 mg/5ml Injection, solution Intramuscular; Intravenous; Intravenous bolus; Subcutaneous Injection Parenteral 25 mg/ml Injection Parenteral 50 mg/2ml Injection, solution Parenteral 1000 MG Injection, solution Parenteral 5000 MG Injection, solution Parenteral 500 MG Solution Parenteral 1000 mg/10ml Injection, solution Parenteral 5 mg/2ml Solution Parenteral 500 mg/20ml Solution Parenteral 5000 mg/50ml Injection 25 mg Injection 25 mg/ml Injection Intra-arterial; Intramuscular; Intrathecal; Intravenous 25 mg/1mL Injection, powder, for solution Intrathecal 1 G Injection, powder, for solution Parenteral 5 MG Injection, powder, for solution Parenteral 50 MG Injection, powder, for solution Parenteral 500 MG Injection, powder, lyophilized, for solution Intra-arterial; Intramuscular; Intrathecal; Intravenous 1 g/20mL Injection, powder, lyophilized, for solution Intra-arterial; Intramuscular; Intrathecal; Intravenous 1 g/1 Injection, solution Intra-arterial; Intramuscular; Intrathecal; Intravenous 1 g/40mL Injection, solution Intra-arterial; Intramuscular; Intrathecal; Intravenous 25 mg/1mL Injection, solution Intra-arterial; Intramuscular; Intravenous 10 mg/1mL Injection, solution Intra-arterial; Intramuscular; Intravenous 25 mg/1mL Injection, solution Intramuscular; Intrathecal; Intravenous; Subcutaneous 25 mg/1mL Injection, solution Intramuscular; Intravenous; Subcutaneous 25 mg/1mL Injection, solution Intravenous 100 mg/1mL Injection, solution Parenteral 1 G/10ML Injection, solution Parenteral 10 MG/1.33ML Injection, solution Parenteral 15 MG/2ML Injection, solution Parenteral 20 MG/2.66ML Injection, solution Parenteral 5 G/50ML Injection, solution Subcutaneous 10 mg/0.4mL Injection, solution Subcutaneous 15 mg/0.6mL Injection, solution Subcutaneous 17.5 mg/0.7mL Injection, solution Subcutaneous 20 mg/0.8mL Injection, solution Subcutaneous 22.5 mg/0.9mL Injection, solution Subcutaneous 25 mg/1mL Solution Intra-arterial; Intramuscular; Intrathecal; Intravenous 25 mg/1mL Solution Intra-arterial; Intramuscular; Intravenous 25 mg / mL Injection, solution, concentrate Intra-arterial; Intramuscular; Intrathecal; Intravenous 50 mg/5ml Tablet, coated Oral 2.5 mg Solution Parenteral 5 mg Injection, solution Intra-arterial; Intramuscular; Intravenous 50 mg/2ml Injection, solution Intramuscular; Intravenous 500 mg/20ml Injection, solution Intramuscular; Intravenous 5 gr/50ml Liquid Intravenous 10 mg / mL Liquid Intravenous 2.5 mg / mL Liquid Intravenous 25 mg / mL Tablet Oral 2.5 mg Solution Intra-arterial; Intramuscular; Intrathecal; Intravenous 25 mg / mL Injection Intramuscular; Intravenous 100 mg/ml Injection Intramuscular; Intrathecal; Intravenous 50 mg/2ml Solution Intra-arterial; Intramuscular; Intrathecal; Intravenous 10 mg / mL Solution Intravenous 25 mg / mL Solution Intramuscular; Intravenous 10 mg / 0.4 mL Solution Intramuscular; Intravenous 15 mg / 0.6 mL Solution Intramuscular; Intravenous 20 mg / 0.8 mL Solution Intramuscular; Intravenous 25 mg / mL Solution Intramuscular; Intravenous 7.5 mg / 0.3 mL Injection, solution Intra-arterial; Intramuscular; Intrathecal; Iontophoresis 25 mg/1mL Tablet Oral 2.5 mg/1 Powder, for solution Intramuscular; Intrathecal; Intravenous 20 mg / vial Liquid Intramuscular; Intrathecal; Intravenous 25 mg / mL Liquid Intramuscular; Intrathecal; Intravenous 50 mg / vial Liquid Intra-arterial; Intramuscular; Intrathecal; Intravenous 25 mg / mL Solution Intra-arterial; Intramuscular; Intrathecal; Intravenous; Intraventricular 25 mg / mL Tablet Oral 2.500 mg Tablet Oral 10 mg Powder, for solution Intra-arterial; Intramuscular; Intrathecal; Intravenous 20 mg / vial Solution Intra-arterial; Intramuscular; Intrathecal; Intravenous 1000 mg Solution Intra-arterial; Intramuscular; Intrathecal; Intravenous 10 mg Solution Intra-arterial; Intramuscular; Intravesical 50 mg Injection Subcutaneous 10 mg/1ml Injection Subcutaneous 15 mg/1.5ml Injection Subcutaneous 20 mg/2ml Injection Subcutaneous 25 mg/2.5ml Injection, solution 10 mg/0.25ml Injection, solution 12.5 mg/03125ml Injection, solution 15 mg/0375ml Injection, solution 17.5 mg/04375ml Injection, solution 20 mg/0500ml Injection, solution 22.5 mg/05625ml Injection, solution 25 mg/0625ml Injection, solution 27.5 mg/0.6875ml Injection, solution 30 mg/0.75ml Injection, solution 7.5 mg/0.1875ml Injection, solution 50 mg/0.6ml Solution Intra-arterial; Intramuscular; Intravenous 10 mg / mL Solution Intra-arterial; Intramuscular; Intravenous 15 mg / 1.5 mL Solution Intra-arterial; Intramuscular; Intravenous 20 mg / 2 mL Solution Intra-arterial; Intramuscular; Intravenous 25 mg / 2.5 mL Solution Intra-arterial; Intramuscular; Intravenous 7.5 mg / 0.75 mL Solution Parenteral 16.450 mg Injection, solution Intramuscular; Intravenous; Subcutaneous 10 mg/1ml Injection, solution Intramuscular; Intravenous; Subcutaneous 15 mg/1.5ml Injection, solution Intramuscular; Intravenous; Subcutaneous 20 mg/2ml Injection, solution Intramuscular; Intravenous; Subcutaneous 25 mg/2.5ml Solution Subcutaneous 10 mg / 0.2 mL Solution Subcutaneous 12.5 mg / 0.25 mL Solution Subcutaneous 15 mg / 0.3 mL Solution Subcutaneous 17.5 mg / 0.35 mL Solution Subcutaneous 20 mg / 0.4 mL Solution Subcutaneous 22.5 mg / 0.45 mL Solution Subcutaneous 25 mg / 0.5 mL Solution Subcutaneous 7.5 mg / 0.15 mL Solution Subcutaneous 10 mg Solution Subcutaneous 15 mg Solution Subcutaneous 20 mg Solution Subcutaneous 25 mg Solution Intravenous; Subcutaneous 7.5 mg Tablet Oral 7.5 mg Injection, solution Parenteral 50 MG/ML Injection, solution Parenteral 100 MG/ML Injection, solution Parenteral 25 MG/ML Solution Intravenous 50.000 mg Solution Intra-arterial; Intramuscular; Intrathecal; Intravenous 100 mg Injection, powder, lyophilized, for solution Intravenous 50 mg Injection, powder, lyophilized, for solution Intravenous 500 mg Injection, powder, lyophilized, for solution Intra-arterial; Intramuscular; Intrathecal; Intravenous 500 mg Solution Intra-arterial; Intramuscular; Intrathecal; Intravenous 500 mg Injection, solution Intra-arterial; Intramuscular; Intrathecal; Intravenous 25 MG/ML Injection, solution, concentrate Intra-arterial; Intramuscular; Intravenous 100 MG/ML Injection, solution 10 MG Injection, solution 12.5 MG Injection, solution 15 MG Injection, solution 17.5 MG Injection, solution 2.5 MG Injection, solution 20 MG Injection, solution 22.5 MG Injection, solution 25 MG Injection, solution 27.5 MG Injection, solution 30 MG Injection, solution 7.5 MG Injection, solution Parenteral 2.5 MG Solution Parenteral 25 mg Injection Parenteral 100 mg Solution Parenteral 200 mg Solution Intramuscular; Intrathecal; Intravenous 500 mg Injection, solution 5 MG Solution Intramuscular; Intrathecal; Intravenous 50 mg Injection, solution Injection, solution 1 G/10ML Injection, solution 100 MG/4ML Injection, solution 5 MG/2ML Injection, solution 50 MG/2ML Injection, solution 500 MG/20ML Solution Intramuscular; Intravenous 5000 mg Injection, powder, lyophilized, for solution Intramuscular; Intrathecal; Intravenous 500 mg Solution Intramuscular; Intrathecal; Intravenous 25 mg Injection Intramuscular; Intravenous Injection, solution Parenteral 10 mg/4ml Tablet Oral 15 MG Tablet Oral 5 MG Injection, solution Parenteral 7.5 MG/ML Solution Intramuscular; Intrathecal; Intravenous; Subcutaneous 25 mg Injection, solution Subcutaneous 10 MG Injection, solution Subcutaneous 12.5 MG Injection, solution Subcutaneous 15 MG Injection, solution Subcutaneous 17.5 MG Injection, solution Subcutaneous 20 MG Injection, solution Subcutaneous 22.5 MG Injection, solution Subcutaneous 25 MG Injection, solution Subcutaneous 7.5 MG Solution Subcutaneous 10 mg / 0.4 mL Solution Subcutaneous 12.5 mg / 0.5 mL Solution Subcutaneous 15 mg / 0.6 mL Solution Subcutaneous 17.5 mg / 0.7 mL Solution Subcutaneous 20 mg / 0.8 mL Solution Subcutaneous 22.5 mg / 0.9 mL Solution Subcutaneous 25 mg / mL Solution Subcutaneous 7.5 mg / 0.3 mL Injection, solution Subcutaneous 12.5 mg/0.4mL Injection, solution Subcutaneous 15 mg/0.4mL Injection, solution Subcutaneous 17.5 mg/0.4mL Injection, solution Subcutaneous 20 mg/0.4mL Injection, solution Subcutaneous 22.5 mg/0.4mL Injection, solution Subcutaneous 25 mg/0.4mL Injection, solution Subcutaneous 7.5 mg/0.4mL Injection, solution Subcutaneous 10 mg/0.2mL Injection, solution Subcutaneous 12.5 mg/0.25mL Injection, solution Subcutaneous 15 mg/0.3mL Injection, solution Subcutaneous 17.5 mg/0.35mL Injection, solution Subcutaneous 22.5 mg/0.45mL Injection, solution Subcutaneous 25 mg/0.5mL Injection, solution Subcutaneous 27.5 mg/0.55mL Injection, solution Subcutaneous 30 mg/0.6mL Injection, solution Subcutaneous 7.5 mg/0.15mL Injection, solution Subcutaneous 12.5 mg/0.5mL Injection, solution Subcutaneous 7.5 mg/0.3mL Injection, solution Parenteral; Subcutaneous 50 MG/ML Injection, solution Subcutaneous 50 MG/ML Tablet Oral 2.5 mg / tab Solution Parenteral 50.00 mg Solution Parenteral 50.000 mg Tablet, film coated Oral 10 mg/1 Tablet, film coated Oral 15 mg/1 Tablet, film coated Oral 5 mg/1 Tablet, film coated Oral 7.5 mg/1 Solution 100 mg/ml Solution 25 mg/ml Solution Intravenous 2.500 mg Solution Parenteral 50 mg Solution Intravenous 54.800 mg Solution Oral 2.5 mg/1mL Injection, solution 15 mg/3ml Injection, solution Intravenous 500 mg/20ml Injection Intramuscular; Intravenous 500 MG/20ML Solution Parenteral 15 mg Injection Intramuscular; Intravenous 50 mg/2ml Solution Intravenous 500.000 mg Solution Subcutaneous 8.226 mg Solution 25 mg/1ml - Prices
Unit description Cost Unit Methotrexate powder 261.33USD g Rheumatrex 8 2.5 mg tablet Disp Pack 169.98USD disp Rheumatrex 24 2.5 mg tablet Disp Pack 129.06USD disp Rheumatrex 20 2.5 mg tablet Disp Pack 107.59USD disp Rheumatrex 12 2.5 mg tablet Disp Pack 63.65USD disp Methotrexate Sodium 25 mg/ml (pf) Solution 40ml Vial 58.99USD vial Trexall 15 mg tablet 25.98USD tablet Methotrexate Sodium 25 mg/ml (pf) Solution 10ml Vial 24.99USD vial Trexall 10 mg tablet 17.67USD tablet Methotrexate Sodium 25 mg/ml Solution 1 Vial = 2ml 15.11USD vial Methotrexate Sodium 25 mg/ml (pf) Solution 2ml Vial 14.99USD vial Trexall 7.5 mg tablet 12.99USD tablet Rheumatrex 2.5 mg tablet 11.23USD tablet Trexall 5 mg tablet 8.66USD tablet Methotrexate Sod. (Preserved) 25 mg/ml 8.38USD ml Methotrexate Sod.(Unpreserved) 25 mg/ml 4.56USD ml Methotrexate 2.5 mg tablet 2.71USD tablet Methotrexate 10 mg Tablet 2.58USD tablet Ratio-Methotrexate Sodium 2.5 mg Tablet 0.66USD tablet Apo-Methotrexate 2.5 mg Tablet 0.66USD tablet DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US8480631 No 2013-07-09 2030-03-19 US USRE44847 No 2014-04-15 2019-08-10 US US8579865 No 2013-11-12 2030-03-19 US US8945063 No 2015-02-03 2030-03-19 US USRE44846 No 2014-04-15 2019-08-10 US US8021335 No 2011-09-20 2026-10-04 US US6746429 No 2004-06-08 2020-04-12 US US8562564 No 2013-10-22 2026-01-24 US US7744582 No 2010-06-29 2019-08-10 US US7776015 No 2010-08-17 2019-08-10 US US8664231 No 2014-03-04 2029-06-01 US US9533102 No 2017-01-03 2026-01-24 US US9629959 No 2017-04-25 2026-01-24 US US9421333 No 2016-08-23 2030-03-19 US US9259427 No 2016-02-16 2033-01-02 US US9855215 No 2018-01-02 2033-01-02 US US10231927 No 2019-03-19 2033-01-02 US US10610485 No 2020-04-07 2033-01-02 US US8814834 No 2014-08-26 2031-05-27 US US9867949 No 2018-01-16 2029-03-10 US US10709844 No 2020-07-14 2029-03-10 US US11116724 No 2021-09-14 2033-01-02 US US11446441 No 2006-01-24 2026-01-24 US US11497753 No 2010-03-19 2030-03-19 US US11684723 No 2009-03-10 2029-03-10 US US11129833 No 2021-09-28 2035-10-28 US US11771701 No 2014-10-29 2034-10-29 US US11969503 No 2013-01-02 2033-01-02 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source melting point (°C) 195 °C http://www.chemspider.com/Chemical-Structure.112728.html?rid=5b5d388b-5afb-4024-803b-99539fa66a77 logP -1.85 HANSCH,C ET AL. (1995) Caco2 permeability -5.92 ADME Research, USCD pKa 4.7 SANGSTER (1994) - Predicted Properties
Property Value Source Water Solubility 0.0819 mg/mL ALOGPS logP -0.05 ALOGPS logP -2.3 Chemaxon logS -3.7 ALOGPS pKa (Strongest Acidic) 2.95 Chemaxon pKa (Strongest Basic) 14.55 Chemaxon Physiological Charge -2 Chemaxon Hydrogen Acceptor Count 12 Chemaxon Hydrogen Donor Count 6 Chemaxon Polar Surface Area 205.92 Å2 Chemaxon Rotatable Bond Count 9 Chemaxon Refractivity 137.57 m3·mol-1 Chemaxon Polarizability 45.43 Å3 Chemaxon Number of Rings 3 Chemaxon Bioavailability 0 Chemaxon Rule of Five No Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
Property Value Probability Human Intestinal Absorption + 0.8261 Blood Brain Barrier - 0.9467 Caco-2 permeable - 0.7754 P-glycoprotein substrate Substrate 0.8172 P-glycoprotein inhibitor I Non-inhibitor 0.7752 P-glycoprotein inhibitor II Non-inhibitor 0.9879 Renal organic cation transporter Non-inhibitor 0.8886 CYP450 2C9 substrate Non-substrate 0.85 CYP450 2D6 substrate Non-substrate 0.7968 CYP450 3A4 substrate Substrate 0.5177 CYP450 1A2 substrate Non-inhibitor 0.9045 CYP450 2C9 inhibitor Non-inhibitor 0.907 CYP450 2D6 inhibitor Non-inhibitor 0.9231 CYP450 2C19 inhibitor Non-inhibitor 0.9025 CYP450 3A4 inhibitor Non-inhibitor 0.8333 CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.9739 Ames test Non AMES toxic 0.9132 Carcinogenicity Non-carcinogens 0.9517 Biodegradation Not ready biodegradable 0.9741 Rat acute toxicity 3.4955 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.9564 hERG inhibition (predictor II) Non-inhibitor 0.6958
Spectra
- Mass Spec (NIST)
- Download (10.1 KB)
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 231.2446027 predictedDarkChem Lite v0.1.0 [M-H]- 238.6607027 predictedDarkChem Lite v0.1.0 [M-H]- 197.56255 predictedDeepCCS 1.0 (2019) [M+H]+ 231.1687027 predictedDarkChem Lite v0.1.0 [M+H]+ 237.4665027 predictedDarkChem Lite v0.1.0 [M+H]+ 199.95813 predictedDeepCCS 1.0 (2019) [M+Na]+ 231.0697027 predictedDarkChem Lite v0.1.0 [M+Na]+ 237.7759027 predictedDarkChem Lite v0.1.0 [M+Na]+ 205.89827 predictedDeepCCS 1.0 (2019)
Targets
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- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Catalyzes the reductive methylation of 2'-deoxyuridine 5'-monophosphate (dUMP) to thymidine 5'-monophosphate (dTMP), using the cosubstrate, 5,10- methylenetetrahydrofolate (CH2H4folate) as a 1-carbon donor and reductant and contributes to the de novo mitochondrial thymidylate biosynthesis pathway
- Specific Function
- folic acid binding
- Gene Name
- TYMS
- Uniprot ID
- P04818
- Uniprot Name
- Thymidylate synthase
- Molecular Weight
- 35715.65 Da
References
- Inoue K, Yuasa H: Molecular basis for pharmacokinetics and pharmacodynamics of methotrexate in rheumatoid arthritis therapy. Drug Metab Pharmacokinet. 2014;29(1):12-9. Epub 2013 Nov 26. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Modulator
- General Function
- Antiporter that mediates the import of reduced folates or a subset of cyclic dinucleotides, driven by the export of organic anions (PubMed:10787414, PubMed:15337749, PubMed:16115875, PubMed:22554803, PubMed:31126740, PubMed:31511694, PubMed:32276275, PubMed:7826387, PubMed:9041240). Mechanistically, acts as a secondary active transporter, which exports intracellular organic anions down their concentration gradients to facilitate the uptake of its substrates (PubMed:22554803, PubMed:31126740, PubMed:31511694). Has high affinity for N5-methyltetrahydrofolate, the predominant circulating form of folate (PubMed:10787414, PubMed:14609557, PubMed:22554803). Also able to mediate the import of antifolate drug methotrexate (PubMed:22554803, PubMed:7615551, PubMed:7641195, PubMed:9767079). Also acts as an importer of immunoreactive cyclic dinucleotides, such as cyclic GMP-AMP (2'-3'-cGAMP), an immune messenger produced in response to DNA virus in the cytosol, and its linkage isomer 3'-3'-cGAMP, thus playing a role in triggering larger immune responses (PubMed:31126740, PubMed:31511694, PubMed:36745868). 5-amino-4-imidazolecarboxamide riboside (AICAR), when phosphorylated to AICAR monophosphate, can serve as an organic anion for antiporter activity (PubMed:22554803)
- Specific Function
- 2',3'-cyclic GMP-AMP binding
- Gene Name
- SLC19A1
- Uniprot ID
- P41440
- Uniprot Name
- Reduced folate transporter
- Molecular Weight
- 64867.62 Da
References
- Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Modulator
- General Function
- Proton-coupled folate symporter that mediates folate absorption using an H(+) gradient as a driving force (PubMed:17129779, PubMed:17446347, PubMed:17475902, PubMed:19389703, PubMed:19762432, PubMed:25504888, PubMed:29344585, PubMed:30858177, PubMed:31494288, PubMed:31792273, PubMed:32893190, PubMed:34619546). Involved in the intestinal absorption of folates at the brush-border membrane of the proximal jejunum, and the transport from blood to cerebrospinal fluid across the choroid plexus (PubMed:17129779, PubMed:17446347, PubMed:17475902, PubMed:19389703, PubMed:25504888, PubMed:29344585, PubMed:30858177, PubMed:31494288, PubMed:32893190). Functions at acidic pH via alternate outward- and inward-open conformation states (PubMed:32893190, PubMed:34040256). Protonation of residues in the outward open state primes the protein for transport (PubMed:34040256). Binding of folate promotes breaking of salt bridge network and subsequent closure of the extracellular gate, leading to the inward-open state and release of protons and folate (PubMed:34040256). Also able to transport antifolate drugs, such as methotrexate and pemetrexed, which are established treatments for cancer and autoimmune diseases (PubMed:18524888, PubMed:19762432, PubMed:22345511, PubMed:25608532, PubMed:28802835, PubMed:29326243, PubMed:34040256, PubMed:34619546). Involved in FOLR1-mediated endocytosis by serving as a route of export of folates from acidified endosomes (PubMed:19074442). Also acts as a lower-affinity, pH-independent heme carrier protein and constitutes the main importer of heme in the intestine (PubMed:17156779). Imports heme in the retina and retinal pigment epithelium, in neurons of the hippocampus, in hepatocytes and in the renal epithelial cells (PubMed:32621820). Hence, participates in the trafficking of heme and increases intracellular iron content (PubMed:32621820)
- Specific Function
- folic acid binding
- Gene Name
- SLC46A1
- Uniprot ID
- Q96NT5
- Uniprot Name
- Proton-coupled folate transporter
- Molecular Weight
- 49770.04 Da
References
- Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Bifunctional enzyme that catalyzes the last two steps of purine biosynthesis (PubMed:11948179, PubMed:14756554). Acts as a transformylase that incorporates a formyl group to the AMP analog AICAR (5-amino-1-(5-phospho-beta-D-ribosyl)imidazole-4-carboxamide) to produce the intermediate formyl-AICAR (FAICAR) (PubMed:10985775, PubMed:11948179, PubMed:9378707). Can use both 10-formyldihydrofolate and 10-formyltetrahydrofolate as the formyl donor in this reaction (PubMed:10985775). Also catalyzes the cyclization of FAICAR to IMP (PubMed:11948179, PubMed:14756554). Is able to convert thio-AICAR to 6-mercaptopurine ribonucleotide, an inhibitor of purine biosynthesis used in the treatment of human leukemias (PubMed:10985775). Promotes insulin receptor/INSR autophosphorylation and is involved in INSR internalization (PubMed:25687571)
- Specific Function
- cadherin binding
- Gene Name
- ATIC
- Uniprot ID
- P31939
- Uniprot Name
- Bifunctional purine biosynthesis protein ATIC
- Molecular Weight
- 64615.255 Da
References
- Inoue K, Yuasa H: Molecular basis for pharmacokinetics and pharmacodynamics of methotrexate in rheumatoid arthritis therapy. Drug Metab Pharmacokinet. 2014;29(1):12-9. Epub 2013 Nov 26. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Key enzyme in folate metabolism. Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis. Binds its own mRNA and that of DHFR2
- Specific Function
- dihydrofolate reductase activity
- Gene Name
- DHFR
- Uniprot ID
- P00374
- Uniprot Name
- Dihydrofolate reductase
- Molecular Weight
- 21452.61 Da
References
- Al-Rashood ST, Aboldahab IA, Nagi MN, Abouzeid LA, Abdel-Aziz AA, Abdel-Hamide SG, Youssef KM, Al-Obaid AM, El-Subbagh HI: Synthesis, dihydrofolate reductase inhibition, antitumor testing, and molecular modeling study of some new 4(3H)-quinazolinone analogs. Bioorg Med Chem. 2006 Dec 15;14(24):8608-21. Epub 2006 Sep 12. [Article]
- Assaraf YG: Molecular basis of antifolate resistance. Cancer Metastasis Rev. 2007 Mar;26(1):153-81. [Article]
- Bennett B, Langan P, Coates L, Mustyakimov M, Schoenborn B, Howell EE, Dealwis C: Neutron diffraction studies of Escherichia coli dihydrofolate reductase complexed with methotrexate. Proc Natl Acad Sci U S A. 2006 Dec 5;103(49):18493-8. Epub 2006 Nov 27. [Article]
- Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
- Totani K, Matsuo I, Ihara Y, Ito Y: High-mannose-type glycan modifications of dihydrofolate reductase using glycan-methotrexate conjugates. Bioorg Med Chem. 2006 Aug 1;14(15):5220-9. Epub 2006 May 2. [Article]
- Uga H, Kuramori C, Ohta A, Tsuboi Y, Tanaka H, Hatakeyama M, Yamaguchi Y, Takahashi T, Kizaki M, Handa H: A new mechanism of methotrexate action revealed by target screening with affinity beads. Mol Pharmacol. 2006 Nov;70(5):1832-9. Epub 2006 Aug 25. [Article]
- Inoue K, Yuasa H: Molecular basis for pharmacokinetics and pharmacodynamics of methotrexate in rheumatoid arthritis therapy. Drug Metab Pharmacokinet. 2014;29(1):12-9. Epub 2013 Nov 26. [Article]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Key enzyme in folate metabolism. Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis. Binds its own mRNA and that of DHFR2
- Specific Function
- dihydrofolate reductase activity
- Gene Name
- DHFR
- Uniprot ID
- P00374
- Uniprot Name
- Dihydrofolate reductase
- Molecular Weight
- 21452.61 Da
References
- Hider SL, Bruce IN, Thomson W: The pharmacogenetics of methotrexate. Rheumatology (Oxford). 2007 Oct;46(10):1520-4. Epub 2007 Jun 24. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Oxidase with broad substrate specificity, oxidizing aromatic azaheterocycles, such as N1-methylnicotinamide, N-methylphthalazinium and phthalazine, as well as aldehydes, such as benzaldehyde, retinal, pyridoxal, and vanillin. Plays a key role in the metabolism of xenobiotics and drugs containing aromatic azaheterocyclic substituents. Participates in the bioactivation of prodrugs such as famciclovir, catalyzing the oxidation step from 6-deoxypenciclovir to penciclovir, which is a potent antiviral agent. Is probably involved in the regulation of reactive oxygen species homeostasis. May be a prominent source of superoxide generation via the one-electron reduction of molecular oxygen. May also catalyze nitric oxide (NO) production via the reduction of nitrite to NO with NADH or aldehyde as electron donor. May play a role in adipogenesis
- Specific Function
- 2 iron, 2 sulfur cluster binding
- Gene Name
- AOX1
- Uniprot ID
- Q06278
- Uniprot Name
- Aldehyde oxidase
- Molecular Weight
- 147916.735 Da
References
- Zientek M, Jiang Y, Youdim K, Obach RS: In vitro-in vivo correlation for intrinsic clearance for drugs metabolized by human aldehyde oxidase. Drug Metab Dispos. 2010 Aug;38(8):1322-7. doi: 10.1124/dmd.110.033555. Epub 2010 May 5. [Article]
- Baggott JE, Morgan SL: Methotrexate catabolism to 7-hydroxymethotrexate in rheumatoid arthritis alters drug efficacy and retention and is reduced by folic acid supplementation. Arthritis Rheum. 2009 Aug;60(8):2257-61. doi: 10.1002/art.24685. [Article]
- Jordan CG, Rashidi MR, Laljee H, Clarke SE, Brown JE, Beedham C: Aldehyde oxidase-catalysed oxidation of methotrexate in the liver of guinea-pig, rabbit and man. J Pharm Pharmacol. 1999 Apr;51(4):411-8. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a cosubstrate for homocysteine remethylation to methionine (PubMed:29891918). Represents a key regulatory connection between the folate and methionine cycles (Probable)
- Specific Function
- FAD binding
- Gene Name
- MTHFR
- Uniprot ID
- P42898
- Uniprot Name
- Methylenetetrahydrofolate reductase (NADPH)
- Molecular Weight
- 74595.895 Da
References
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Catalyzes the oxidative decarboxylation of 6-phosphogluconate to ribulose 5-phosphate and CO(2), with concomitant reduction of NADP to NADPH
- Specific Function
- NADP binding
- Gene Name
- PGD
- Uniprot ID
- P52209
- Uniprot Name
- 6-phosphogluconate dehydrogenase, decarboxylating
- Molecular Weight
- 53139.56 Da
References
- Akkemik E, Budak H, Ciftci M: Effects of some drugs on human erythrocyte 6-phosphogluconate dehydrogenase: an in vitro study. J Enzyme Inhib Med Chem. 2010 Aug;25(4):476-9. doi: 10.3109/14756360903257900. [Article]
- Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE: The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Catalyzes conversion of folates to polyglutamate derivatives allowing concentration of folate compounds in the cell and the intracellular retention of these cofactors, which are important substrates for most of the folate-dependent enzymes that are involved in one-carbon transfer reactions involved in purine, pyrimidine and amino acid synthesis. Unsubstituted reduced folates are the preferred substrates. Metabolizes methotrexate (MTX) to polyglutamates
- Specific Function
- ATP binding
- Gene Name
- FPGS
- Uniprot ID
- Q05932
- Uniprot Name
- Folylpolyglutamate synthase, mitochondrial
- Molecular Weight
- 64608.53 Da
References
- Hider SL, Bruce IN, Thomson W: The pharmacogenetics of methotrexate. Rheumatology (Oxford). 2007 Oct;46(10):1520-4. Epub 2007 Jun 24. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Catalyzes the reductive methylation of 2'-deoxyuridine 5'-monophosphate (dUMP) to thymidine 5'-monophosphate (dTMP), using the cosubstrate, 5,10- methylenetetrahydrofolate (CH2H4folate) as a 1-carbon donor and reductant and contributes to the de novo mitochondrial thymidylate biosynthesis pathway
- Specific Function
- folic acid binding
- Gene Name
- TYMS
- Uniprot ID
- P04818
- Uniprot Name
- Thymidylate synthase
- Molecular Weight
- 35715.65 Da
References
- Hider SL, Bruce IN, Thomson W: The pharmacogenetics of methotrexate. Rheumatology (Oxford). 2007 Oct;46(10):1520-4. Epub 2007 Jun 24. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Bifunctional enzyme that catalyzes the last two steps of purine biosynthesis (PubMed:11948179, PubMed:14756554). Acts as a transformylase that incorporates a formyl group to the AMP analog AICAR (5-amino-1-(5-phospho-beta-D-ribosyl)imidazole-4-carboxamide) to produce the intermediate formyl-AICAR (FAICAR) (PubMed:10985775, PubMed:11948179, PubMed:9378707). Can use both 10-formyldihydrofolate and 10-formyltetrahydrofolate as the formyl donor in this reaction (PubMed:10985775). Also catalyzes the cyclization of FAICAR to IMP (PubMed:11948179, PubMed:14756554). Is able to convert thio-AICAR to 6-mercaptopurine ribonucleotide, an inhibitor of purine biosynthesis used in the treatment of human leukemias (PubMed:10985775). Promotes insulin receptor/INSR autophosphorylation and is involved in INSR internalization (PubMed:25687571)
- Specific Function
- cadherin binding
- Gene Name
- ATIC
- Uniprot ID
- P31939
- Uniprot Name
- Bifunctional purine biosynthesis protein ATIC
- Molecular Weight
- 64615.255 Da
References
- Hider SL, Bruce IN, Thomson W: The pharmacogenetics of methotrexate. Rheumatology (Oxford). 2007 Oct;46(10):1520-4. Epub 2007 Jun 24. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Hydrolyzes the polyglutamate sidechains of pteroylpolyglutamates. Progressively removes gamma-glutamyl residues from pteroylpoly-gamma-glutamate to yield pteroyl-alpha-glutamate (folic acid) and free glutamate (PubMed:11005824, PubMed:8816764). May play an important role in the bioavailability of dietary pteroylpolyglutamates and in the metabolism of pteroylpolyglutamates and antifolates
- Specific Function
- exopeptidase activity
- Gene Name
- GGH
- Uniprot ID
- Q92820
- Uniprot Name
- Gamma-glutamyl hydrolase
- Molecular Weight
- 35964.045 Da
References
- Hider SL, Bruce IN, Thomson W: The pharmacogenetics of methotrexate. Rheumatology (Oxford). 2007 Oct;46(10):1520-4. Epub 2007 Jun 24. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of sterols, steroid hormones, retinoids and fatty acids (PubMed:10681376, PubMed:11093772, PubMed:11555828, PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:19965576, PubMed:20702771, PubMed:21490593, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:21490593, PubMed:21576599, PubMed:2732228). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2, as well as D-ring hydroxylated E1 and E2 at the C-16 position (PubMed:11555828, PubMed:12865317, PubMed:14559847). Plays a role in the metabolism of androgens, particularly in oxidative deactivation of testosterone (PubMed:15373842, PubMed:15764715, PubMed:22773874, PubMed:2732228). Metabolizes testosterone to less biologically active 2beta- and 6beta-hydroxytestosterones (PubMed:15373842, PubMed:15764715, PubMed:2732228). Contributes to the formation of hydroxycholesterols (oxysterols), particularly A-ring hydroxylated cholesterol at the C-4beta position, and side chain hydroxylated cholesterol at the C-25 position, likely contributing to cholesterol degradation and bile acid biosynthesis (PubMed:21576599). Catalyzes bisallylic hydroxylation of polyunsaturated fatty acids (PUFA) (PubMed:9435160). Catalyzes the epoxidation of double bonds of PUFA with a preference for the last double bond (PubMed:19965576). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:20702771). Plays a role in the metabolism of retinoids. Displays high catalytic activity for oxidation of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes atRA toward 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Responsible for oxidative metabolism of xenobiotics. Acts as a 2-exo-monooxygenase for plant lipid 1,8-cineole (eucalyptol) (PubMed:11159812). Metabolizes the majority of the administered drugs. Catalyzes sulfoxidation of the anthelmintics albendazole and fenbendazole (PubMed:10759686). Hydroxylates antimalarial drug quinine (PubMed:8968357). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850). Also involved in vitamin D catabolism and calcium homeostasis. Catalyzes the inactivation of the active hormone calcitriol (1-alpha,25-dihydroxyvitamin D(3)) (PubMed:29461981)
- Specific Function
- 1,8-cineole 2-exo-monooxygenase activity
- Gene Name
- CYP3A4
- Uniprot ID
- P08684
- Uniprot Name
- Cytochrome P450 3A4
- Molecular Weight
- 57342.67 Da
References
- Vecht CJ, Wagner GL, Wilms EB: Interactions between antiepileptic and chemotherapeutic drugs. Lancet Neurol. 2003 Jul;2(7):404-9. [Article]
- Kind
- Protein
- Organism
- Pseudomonas sp. (strain RS-16)
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Catalyzes the hydrolysis of reduced and non-reduced folates to pteroates and L-glutamate. This enzyme has a broad specificity.
- Specific Function
- carboxypeptidase activity
- Gene Name
- cpg2
- Uniprot ID
- P06621
- Uniprot Name
- Carboxypeptidase G2
- Molecular Weight
- 43931.68 Da
References
- Green JM: Glucarpidase to combat toxic levels of methotrexate in patients. Ther Clin Risk Manag. 2012;8:403-13. doi: 10.2147/TCRM.S30135. Epub 2012 Nov 22. [Article]
Carriers
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Binder
- General Function
- Binds water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs (Probable). Its main function is the regulation of the colloidal osmotic pressure of blood (Probable). Major zinc transporter in plasma, typically binds about 80% of all plasma zinc (PubMed:19021548). Major calcium and magnesium transporter in plasma, binds approximately 45% of circulating calcium and magnesium in plasma (By similarity). Potentially has more than two calcium-binding sites and might additionally bind calcium in a non-specific manner (By similarity). The shared binding site between zinc and calcium at residue Asp-273 suggests a crosstalk between zinc and calcium transport in the blood (By similarity). The rank order of affinity is zinc > calcium > magnesium (By similarity). Binds to the bacterial siderophore enterobactin and inhibits enterobactin-mediated iron uptake of E.coli from ferric transferrin, and may thereby limit the utilization of iron and growth of enteric bacteria such as E.coli (PubMed:6234017). Does not prevent iron uptake by the bacterial siderophore aerobactin (PubMed:6234017)
- Specific Function
- antioxidant activity
- Gene Name
- ALB
- Uniprot ID
- P02768
- Uniprot Name
- Albumin
- Molecular Weight
- 69365.94 Da
References
- Warnecke A, Fichtner I, Sass G, Kratz F: Synthesis, cleavage profile, and antitumor efficacy of an albumin-binding prodrug of methotrexate that is cleaved by plasmin and cathepsin B. Arch Pharm (Weinheim). 2007 Aug;340(8):389-95. [Article]
- Xie WJ, Feng YP, Cao SL, Zhao YF: [Study of the interaction between methotrexate and bovine serum albumin by spectrometry]. Guang Pu Xue Yu Guang Pu Fen Xi. 2006 Oct;26(10):1876-9. [Article]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInhibitor
- General Function
- ATP-dependent transporter of the ATP-binding cassette (ABC) family that binds and hydrolyzes ATP to enable active transport of various substrates including many drugs, toxicants and endogenous compound across cell membranes (PubMed:10359813, PubMed:11581266, PubMed:15083066). Transports glucuronide conjugates such as bilirubin diglucuronide, estradiol-17-beta-o-glucuronide and GSH conjugates such as leukotriene C4 (LTC4) (PubMed:11581266, PubMed:15083066). Transports also various bile salts (taurocholate, glycocholate, taurochenodeoxycholate-3-sulfate, taurolithocholate- 3-sulfate) (By similarity). Does not contribute substantially to bile salt physiology but provides an alternative route for the export of bile acids and glucuronides from cholestatic hepatocytes (By similarity). May contribute to regulate the transport of organic compounds in testes across the blood-testis-barrier (Probable). Can confer resistance to various anticancer drugs, methotrexate, tenoposide and etoposide, by decreasing accumulation of these drugs in cells (PubMed:10359813, PubMed:11581266)
- Specific Function
- ABC-type bile acid transporter activity
- Gene Name
- ABCC3
- Uniprot ID
- O15438
- Uniprot Name
- ATP-binding cassette sub-family C member 3
- Molecular Weight
- 169341.14 Da
References
- Akita H, Suzuki H, Hirohashi T, Takikawa H, Sugiyama Y: Transport activity of human MRP3 expressed in Sf9 cells: comparative studies with rat MRP3. Pharm Res. 2002 Jan;19(1):34-41. [Article]
- Oleschuk CJ, Deeley RG, Cole SP: Substitution of Trp1242 of TM17 alters substrate specificity of human multidrug resistance protein 3. Am J Physiol Gastrointest Liver Physiol. 2003 Feb;284(2):G280-9. Epub 2002 Oct 9. [Article]
- Hirohashi T, Suzuki H, Sugiyama Y: Characterization of the transport properties of cloned rat multidrug resistance-associated protein 3 (MRP3). J Biol Chem. 1999 May 21;274(21):15181-5. [Article]
- Zeng H, Liu G, Rea PA, Kruh GD: Transport of amphipathic anions by human multidrug resistance protein 3. Cancer Res. 2000 Sep 1;60(17):4779-84. [Article]
- Zeng H, Chen ZS, Belinsky MG, Rea PA, Kruh GD: Transport of methotrexate (MTX) and folates by multidrug resistance protein (MRP) 3 and MRP1: effect of polyglutamylation on MTX transport. Cancer Res. 2001 Oct 1;61(19):7225-32. [Article]
- Paumi CM, Wright M, Townsend AJ, Morrow CS: Multidrug resistance protein (MRP) 1 and MRP3 attenuate cytotoxic and transactivating effects of the cyclopentenone prostaglandin, 15-deoxy-Delta(12,14)prostaglandin J2 in MCF7 breast cancer cells. Biochemistry. 2003 May 13;42(18):5429-37. [Article]
- Li T, Ito K, Horie T: Transport of fluorescein methotrexate by multidrug resistance-associated protein 3 in IEC-6 cells. Am J Physiol Gastrointest Liver Physiol. 2003 Sep;285(3):G602-10. [Article]
- Zehnpfennig B, Urbatsch IL, Galla HJ: Functional reconstitution of human ABCC3 into proteoliposomes reveals a transport mechanism with positive cooperativity. Biochemistry. 2009 May 26;48(20):4423-30. doi: 10.1021/bi9001908. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInhibitor
- General Function
- ATP-dependent transporter of the ATP-binding cassette (ABC) family that actively extrudes physiological compounds and xenobiotics from cells. Transports a range of endogenous molecules that have a key role in cellular communication and signaling, including cyclic nucleotides such as cyclic AMP (cAMP) and cyclic GMP (cGMP), bile acids, steroid conjugates, urate, and prostaglandins (PubMed:11856762, PubMed:12523936, PubMed:12835412, PubMed:12883481, PubMed:15364914, PubMed:15454390, PubMed:16282361, PubMed:17959747, PubMed:18300232, PubMed:26721430). Mediates the ATP-dependent efflux of glutathione conjugates such as leukotriene C4 (LTC4) and leukotriene B4 (LTB4) too. The presence of GSH is necessary for the ATP-dependent transport of LTB4, whereas GSH is not required for the transport of LTC4 (PubMed:17959747). Mediates the cotransport of bile acids with reduced glutathione (GSH) (PubMed:12523936, PubMed:12883481, PubMed:16282361). Transports a wide range of drugs and their metabolites, including anticancer, antiviral and antibiotics molecules (PubMed:11856762, PubMed:12105214, PubMed:15454390, PubMed:17344354, PubMed:18300232). Confers resistance to anticancer agents such as methotrexate (PubMed:11106685)
- Specific Function
- 15-hydroxyprostaglandin dehydrogenase (NAD+) activity
- Gene Name
- ABCC4
- Uniprot ID
- O15439
- Uniprot Name
- ATP-binding cassette sub-family C member 4
- Molecular Weight
- 149525.33 Da
References
- Chen ZS, Lee K, Kruh GD: Transport of cyclic nucleotides and estradiol 17-beta-D-glucuronide by multidrug resistance protein 4. Resistance to 6-mercaptopurine and 6-thioguanine. J Biol Chem. 2001 Sep 7;276(36):33747-54. Epub 2001 Jul 10. [Article]
- Rius M, Nies AT, Hummel-Eisenbeiss J, Jedlitschky G, Keppler D: Cotransport of reduced glutathione with bile salts by MRP4 (ABCC4) localized to the basolateral hepatocyte membrane. Hepatology. 2003 Aug;38(2):374-84. [Article]
- Bai J, Lai L, Yeo HC, Goh BC, Tan TM: Multidrug resistance protein 4 (MRP4/ABCC4) mediates efflux of bimane-glutathione. Int J Biochem Cell Biol. 2004 Feb;36(2):247-57. [Article]
- van Aubel RA, Smeets PH, Peters JG, Bindels RJ, Russel FG: The MRP4/ABCC4 gene encodes a novel apical organic anion transporter in human kidney proximal tubules: putative efflux pump for urinary cAMP and cGMP. J Am Soc Nephrol. 2002 Mar;13(3):595-603. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInhibitor
- General Function
- Mediates export of organic anions and drugs from the cytoplasm (PubMed:10064732, PubMed:11114332, PubMed:16230346, PubMed:7961706, PubMed:9281595). Mediates ATP-dependent transport of glutathione and glutathione conjugates, leukotriene C4, estradiol-17-beta-o-glucuronide, methotrexate, antiviral drugs and other xenobiotics (PubMed:10064732, PubMed:11114332, PubMed:16230346, PubMed:7961706, PubMed:9281595). Confers resistance to anticancer drugs by decreasing accumulation of drug in cells, and by mediating ATP- and GSH-dependent drug export (PubMed:9281595). Hydrolyzes ATP with low efficiency (PubMed:16230346). Catalyzes the export of sphingosine 1-phosphate from mast cells independently of their degranulation (PubMed:17050692). Participates in inflammatory response by allowing export of leukotriene C4 from leukotriene C4-synthezing cells (By similarity). Mediates ATP-dependent, GSH-independent cyclic GMP-AMP (cGAMP) export (PubMed:36070769). Thus, by limiting intracellular cGAMP concentrations negatively regulates the cGAS-STING pathway (PubMed:36070769)
- Specific Function
- ABC-type glutathione S-conjugate transporter activity
- Gene Name
- ABCC1
- Uniprot ID
- P33527
- Uniprot Name
- Multidrug resistance-associated protein 1
- Molecular Weight
- 171589.5 Da
References
- Heijn M, Hooijberg JH, Scheffer GL, Szabo G, Westerhoff HV, Lankelma J: Anthracyclines modulate multidrug resistance protein (MRP) mediated organic anion transport. Biochim Biophys Acta. 1997 May 22;1326(1):12-22. [Article]
- Zeng H, Chen ZS, Belinsky MG, Rea PA, Kruh GD: Transport of methotrexate (MTX) and folates by multidrug resistance protein (MRP) 3 and MRP1: effect of polyglutamylation on MTX transport. Cancer Res. 2001 Oct 1;61(19):7225-32. [Article]
- Paumi CM, Wright M, Townsend AJ, Morrow CS: Multidrug resistance protein (MRP) 1 and MRP3 attenuate cytotoxic and transactivating effects of the cyclopentenone prostaglandin, 15-deoxy-Delta(12,14)prostaglandin J2 in MCF7 breast cancer cells. Biochemistry. 2003 May 13;42(18):5429-37. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInhibitor
- General Function
- Secondary active transporter that functions as a Na(+)-independent organic anion (OA)/dicarboxylate antiporter where the uptake of one molecule of OA into the cell is coupled with an efflux of one molecule of intracellular dicarboxylate such as 2-oxoglutarate or glutarate (PubMed:11669456, PubMed:11907186, PubMed:14675047, PubMed:22108572, PubMed:23832370, PubMed:28534121, PubMed:9950961). Mediates the uptake of OA across the basolateral side of proximal tubule epithelial cells, thereby contributing to the renal elimination of endogenous OA from the systemic circulation into the urine (PubMed:9887087). Functions as a biopterin transporters involved in the uptake and the secretion of coenzymes tetrahydrobiopterin (BH4), dihydrobiopterin (BH2) and sepiapterin to urine, thereby determining baseline levels of blood biopterins (PubMed:28534121). Transports prostaglandin E2 (PGE2) and prostaglandin F2-alpha (PGF2-alpha) and may contribute to their renal excretion (PubMed:11907186). Also mediates the uptake of cyclic nucleotides such as cAMP and cGMP (PubMed:26377792). Involved in the transport of neuroactive tryptophan metabolites kynurenate (KYNA) and xanthurenate (XA) and may contribute to their secretion from the brain (PubMed:22108572, PubMed:23832370). May transport glutamate (PubMed:26377792). Also involved in the disposition of uremic toxins and potentially toxic xenobiotics by the renal organic anion secretory pathway, helping reduce their undesired toxicological effects on the body (PubMed:11669456, PubMed:14675047). Uremic toxins include the indoxyl sulfate (IS), hippurate/N-benzoylglycine (HA), indole acetate (IA), 3-carboxy-4- methyl-5-propyl-2-furanpropionate (CMPF) and urate (PubMed:14675047, PubMed:26377792). Xenobiotics include the mycotoxin ochratoxin (OTA) (PubMed:11669456). May also contribute to the transport of organic compounds in testes across the blood-testis-barrier (PubMed:35307651)
- Specific Function
- alpha-ketoglutarate transmembrane transporter activity
- Gene Name
- SLC22A6
- Uniprot ID
- Q4U2R8
- Uniprot Name
- Solute carrier family 22 member 6
- Molecular Weight
- 61815.78 Da
References
- Lu R, Chan BS, Schuster VL: Cloning of the human kidney PAH transporter: narrow substrate specificity and regulation by protein kinase C. Am J Physiol. 1999 Feb;276(2 Pt 2):F295-303. [Article]
- Kuze K, Graves P, Leahy A, Wilson P, Stuhlmann H, You G: Heterologous expression and functional characterization of a mouse renal organic anion transporter in mammalian cells. J Biol Chem. 1999 Jan 15;274(3):1519-24. [Article]
- Uwai Y, Okuda M, Takami K, Hashimoto Y, Inui K: Functional characterization of the rat multispecific organic anion transporter OAT1 mediating basolateral uptake of anionic drugs in the kidney. FEBS Lett. 1998 Nov 6;438(3):321-4. [Article]
- Takeda M, Khamdang S, Narikawa S, Kimura H, Hosoyamada M, Cha SH, Sekine T, Endou H: Characterization of methotrexate transport and its drug interactions with human organic anion transporters. J Pharmacol Exp Ther. 2002 Aug;302(2):666-71. [Article]
- Sekine T, Watanabe N, Hosoyamada M, Kanai Y, Endou H: Expression cloning and characterization of a novel multispecific organic anion transporter. J Biol Chem. 1997 Jul 25;272(30):18526-9. [Article]
- Uwai Y, Iwamoto K: Transport of aminopterin by human organic anion transporters hOAT1 and hOAT3: Comparison with methotrexate. Drug Metab Pharmacokinet. 2010;25(2):163-9. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- ATP-dependent transporter of the ATP-binding cassette (ABC) family that actively extrudes physiological compounds, and xenobiotics from cells. Lipophilic anion transporter that mediates ATP-dependent transport of glucuronide conjugates such as estradiol-17-beta-o-glucuronide and GSH conjugates such as leukotriene C4 (LTC4) (PubMed:12527806, PubMed:15256465). May contribute to regulate the transport of organic compounds in testes across the blood-testis-barrier (Probable). Mediates multidrug resistance (MDR) in cancer cells by preventing the intracellular accumulation of certain antitumor drugs, such as, docetaxel and paclitaxel (PubMed:15256465, PubMed:23087055). Does not transport glycocholic acid, taurocholic acid, MTX, folic acid, cAMP, or cGMP (PubMed:12527806)
- Specific Function
- ABC-type glutathione S-conjugate transporter activity
- Gene Name
- ABCC10
- Uniprot ID
- Q5T3U5
- Uniprot Name
- ATP-binding cassette sub-family C member 10
- Molecular Weight
- 161627.375 Da
References
- Chen ZS, Hopper-Borge E, Belinsky MG, Shchaveleva I, Kotova E, Kruh GD: Characterization of the transport properties of human multidrug resistance protein 7 (MRP7, ABCC10). Mol Pharmacol. 2003 Feb;63(2):351-8. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInhibitor
- General Function
- Functions as an organic anion/dicarboxylate exchanger that couples organic anion uptake indirectly to the sodium gradient (PubMed:14586168, PubMed:15644426, PubMed:15846473, PubMed:16455804, PubMed:31553721). Transports organic anions such as estrone 3-sulfate (E1S) and urate in exchange for dicarboxylates such as glutarate or ketoglutarate (2-oxoglutarate) (PubMed:14586168, PubMed:15846473, PubMed:15864504, PubMed:22108572, PubMed:23832370). Plays an important role in the excretion of endogenous and exogenous organic anions, especially from the kidney and the brain (PubMed:11306713, PubMed:14586168, PubMed:15846473). E1S transport is pH- and chloride-dependent and may also involve E1S/cGMP exchange (PubMed:26377792). Responsible for the transport of prostaglandin E2 (PGE2) and prostaglandin F2(alpha) (PGF2(alpha)) in the basolateral side of the renal tubule (PubMed:11907186). Involved in the transport of neuroactive tryptophan metabolites kynurenate and xanthurenate (PubMed:22108572, PubMed:23832370). Functions as a biopterin transporters involved in the uptake and the secretion of coenzymes tetrahydrobiopterin (BH4), dihydrobiopterin (BH2) and sepiapterin to urine, thereby determining baseline levels of blood biopterins (PubMed:28534121). May be involved in the basolateral transport of steviol, a metabolite of the popular sugar substitute stevioside (PubMed:15644426). May participate in the detoxification/ renal excretion of drugs and xenobiotics, such as the histamine H(2)-receptor antagonists fexofenadine and cimetidine, the antibiotic benzylpenicillin (PCG), the anionic herbicide 2,4-dichloro-phenoxyacetate (2,4-D), the diagnostic agent p-aminohippurate (PAH), the antiviral acyclovir (ACV), and the mycotoxin ochratoxin (OTA), by transporting these exogenous organic anions across the cell membrane in exchange for dicarboxylates such as 2-oxoglutarate (PubMed:11669456, PubMed:15846473, PubMed:16455804). Contributes to the renal uptake of potent uremic toxins (indoxyl sulfate (IS), indole acetate (IA), hippurate/N-benzoylglycine (HA) and 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF)), pravastatin, PCG, E1S and dehydroepiandrosterone sulfate (DHEAS), and is partly involved in the renal uptake of temocaprilat (an angiotensin-converting enzyme (ACE) inhibitor) (PubMed:14675047). May contribute to the release of cortisol in the adrenals (PubMed:15864504). Involved in one of the detoxification systems on the choroid plexus (CP), removes substrates such as E1S or taurocholate (TC), PCG, 2,4-D and PAH, from the cerebrospinal fluid (CSF) to the blood for eventual excretion in urine and bile (By similarity). Also contributes to the uptake of several other organic compounds such as the prostanoids prostaglandin E(2) and prostaglandin F(2-alpha), L-carnitine, and the therapeutic drugs allopurinol, 6-mercaptopurine (6-MP) and 5-fluorouracil (5-FU) (By similarity). Mediates the transport of PAH, PCG, and the statins pravastatin and pitavastatin, from the cerebrum into the blood circulation across the blood-brain barrier (BBB). In summary, plays a role in the efflux of drugs and xenobiotics, helping reduce their undesired toxicological effects on the body (By similarity)
- Specific Function
- organic anion transmembrane transporter activity
- Gene Name
- SLC22A8
- Uniprot ID
- Q8TCC7
- Uniprot Name
- Organic anion transporter 3
- Molecular Weight
- 59855.585 Da
References
- Ohtsuki S, Kikkawa T, Mori S, Hori S, Takanaga H, Otagiri M, Terasaki T: Mouse reduced in osteosclerosis transporter functions as an organic anion transporter 3 and is localized at abluminal membrane of blood-brain barrier. J Pharmacol Exp Ther. 2004 Jun;309(3):1273-81. Epub 2004 Feb 4. [Article]
- Kusuhara H, Sekine T, Utsunomiya-Tate N, Tsuda M, Kojima R, Cha SH, Sugiyama Y, Kanai Y, Endou H: Molecular cloning and characterization of a new multispecific organic anion transporter from rat brain. J Biol Chem. 1999 May 7;274(19):13675-80. [Article]
- Cha SH, Sekine T, Fukushima JI, Kanai Y, Kobayashi Y, Goya T, Endou H: Identification and characterization of human organic anion transporter 3 expressing predominantly in the kidney. Mol Pharmacol. 2001 May;59(5):1277-86. [Article]
- Takeda M, Khamdang S, Narikawa S, Kimura H, Hosoyamada M, Cha SH, Sekine T, Endou H: Characterization of methotrexate transport and its drug interactions with human organic anion transporters. J Pharmacol Exp Ther. 2002 Aug;302(2):666-71. [Article]
- Uwai Y, Iwamoto K: Transport of aminopterin by human organic anion transporters hOAT1 and hOAT3: Comparison with methotrexate. Drug Metab Pharmacokinet. 2010;25(2):163-9. [Article]
- VanWert AL, Sweet DH: Impaired clearance of methotrexate in organic anion transporter 3 (Slc22a8) knockout mice: a gender specific impact of reduced folates. Pharm Res. 2008 Feb;25(2):453-62. doi: 10.1007/s11095-007-9407-0. Epub 2007 Jul 28. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInhibitor
- General Function
- ATP-dependent transporter of the ATP-binding cassette (ABC) family that binds and hydrolyzes ATP to enable active transport of various substrates including many drugs, toxicants and endogenous compound across cell membranes. Transports a wide variety of conjugated organic anions such as sulfate-, glucuronide- and glutathione (GSH)-conjugates of endo- and xenobiotics substrates (PubMed:10220572, PubMed:10421658, PubMed:11500505, PubMed:16332456). Mediates hepatobiliary excretion of mono- and bis-glucuronidated bilirubin molecules and therefore play an important role in bilirubin detoxification (PubMed:10421658). Mediates also hepatobiliary excretion of others glucuronide conjugates such as 17beta-estradiol 17-glucosiduronic acid and leukotriene C4 (PubMed:11500505). Transports sulfated bile salt such as taurolithocholate sulfate (PubMed:16332456). Transports various anticancer drugs, such as anthracycline, vinca alkaloid and methotrexate and HIV-drugs such as protease inhibitors (PubMed:10220572, PubMed:11500505, PubMed:12441801). Confers resistance to several anti-cancer drugs including cisplatin, doxorubicin, epirubicin, methotrexate, etoposide and vincristine (PubMed:10220572, PubMed:11500505)
- Specific Function
- ABC-type glutathione S-conjugate transporter activity
- Gene Name
- ABCC2
- Uniprot ID
- Q92887
- Uniprot Name
- ATP-binding cassette sub-family C member 2
- Molecular Weight
- 174205.64 Da
References
- Han YH, Kato Y, Haramura M, Ohta M, Matsuoka H, Sugiyama Y: Physicochemical parameters responsible for the affinity of methotrexate analogs for rat canalicular multispecific organic anion transporter (cMOAT/MRP2). Pharm Res. 2001 May;18(5):579-86. [Article]
- Masuda M, I'izuka Y, Yamazaki M, Nishigaki R, Kato Y, Ni'inuma K, Suzuki H, Sugiyama Y: Methotrexate is excreted into the bile by canalicular multispecific organic anion transporter in rats. Cancer Res. 1997 Aug 15;57(16):3506-10. [Article]
- Hooijberg JH, Broxterman HJ, Kool M, Assaraf YG, Peters GJ, Noordhuis P, Scheper RJ, Borst P, Pinedo HM, Jansen G: Antifolate resistance mediated by the multidrug resistance proteins MRP1 and MRP2. Cancer Res. 1999 Jun 1;59(11):2532-5. [Article]
- Bakos E, Evers R, Sinko E, Varadi A, Borst P, Sarkadi B: Interactions of the human multidrug resistance proteins MRP1 and MRP2 with organic anions. Mol Pharmacol. 2000 Apr;57(4):760-8. [Article]
- Chen C, Scott D, Hanson E, Franco J, Berryman E, Volberg M, Liu X: Impact of Mrp2 on the biliary excretion and intestinal absorption of furosemide, probenecid, and methotrexate using Eisai hyperbilirubinemic rats. Pharm Res. 2003 Jan;20(1):31-7. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Translocates drugs and phospholipids across the membrane (PubMed:2897240, PubMed:35970996, PubMed:8898203, PubMed:9038218). Catalyzes the flop of phospholipids from the cytoplasmic to the exoplasmic leaflet of the apical membrane. Participates mainly to the flop of phosphatidylcholine, phosphatidylethanolamine, beta-D-glucosylceramides and sphingomyelins (PubMed:8898203). Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells (PubMed:2897240, PubMed:35970996, PubMed:9038218)
- Specific Function
- ABC-type xenobiotic transporter activity
- Gene Name
- ABCB1
- Uniprot ID
- P08183
- Uniprot Name
- ATP-dependent translocase ABCB1
- Molecular Weight
- 141477.255 Da
References
- Norris MD, De Graaf D, Haber M, Kavallaris M, Madafiglio J, Gilbert J, Kwan E, Stewart BW, Mechetner EB, Gudkov AV, Roninson IB: Involvement of MDR1 P-glycoprotein in multifactorial resistance to methotrexate. Int J Cancer. 1996 Mar 1;65(5):613-9. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Na(+)-independent transporter that mediates the cellular uptake of a broad range of organic anions such as the endogenous bile salts cholate and deoxycholate, either in their unconjugated or conjugated forms (taurocholate and glycocholate), at the plasmam membrane (PubMed:19129463, PubMed:7557095). Responsible for intestinal absorption of bile acids (By similarity). Transports dehydroepiandrosterone 3-sulfate (DHEAS), a major circulating steroid secreted by the adrenal cortex, as well as estrone 3-sulfate and 17beta-estradiol 17-O-(beta-D-glucuronate) (PubMed:11159893, PubMed:12568656, PubMed:19129463, PubMed:23918469, PubMed:25560245, PubMed:9539145). Mediates apical uptake of all-trans-retinol (atROL) across human retinal pigment epithelium, which is essential to maintaining the integrity of the visual cycle and thus vision (PubMed:25560245). Involved in the uptake of clinically used drugs (PubMed:17301733, PubMed:20686826, PubMed:27777271). Capable of thyroid hormone transport (both T3 or 3,3',5'-triiodo-L-thyronine, and T4 or L-tyroxine) (PubMed:19129463, PubMed:20358049). Also transports prostaglandin E2 (PubMed:19129463). Plays roles in blood-brain and -cerebrospinal fluid barrier transport of organic anions and signal mediators, and in hormone uptake by neural cells (By similarity). May also play a role in the reuptake of neuropeptides such as substance P/TAC1 and vasoactive intestinal peptide/VIP released from retinal neurons (PubMed:25132355). May play an important role in plasma and tissue distribution of the structurally diverse chemotherapeutic drugs methotrexate and paclitaxel (PubMed:23243220). Shows a pH-sensitive substrate specificity which may be ascribed to the protonation state of the binding site and leads to a stimulation of substrate transport in an acidic microenvironment (PubMed:19129463). Hydrogencarbonate/HCO3(-) acts as the probable counteranion that exchanges for organic anions (PubMed:19129463). May contribute to regulate the transport of organic compounds in testis across the blood-testis-barrier (Probable)
- Specific Function
- bile acid transmembrane transporter activity
- Gene Name
- SLCO1A2
- Uniprot ID
- P46721
- Uniprot Name
- Solute carrier organic anion transporter family member 1A2
- Molecular Weight
- 74144.105 Da
References
- Cattori V, van Montfoort JE, Stieger B, Landmann L, Meijer DK, Winterhalter KH, Meier PJ, Hagenbuch B: Localization of organic anion transporting polypeptide 4 (Oatp4) in rat liver and comparison of its substrate specificity with Oatp1, Oatp2 and Oatp3. Pflugers Arch. 2001 Nov;443(2):188-95. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Bidirectional proton-coupled monocarboxylate transporter (PubMed:12946269, PubMed:32946811, PubMed:33333023). Catalyzes the rapid transport across the plasma membrane of many monocarboxylates such as lactate, pyruvate, acetate and the ketone bodies acetoacetate and beta-hydroxybutyrate, and thus contributes to the maintenance of intracellular pH (PubMed:12946269, PubMed:33333023). The transport direction is determined by the proton motive force and the concentration gradient of the substrate monocarboxylate. MCT1 is a major lactate exporter (By similarity). Plays a role in cellular responses to a high-fat diet by modulating the cellular levels of lactate and pyruvate that contribute to the regulation of central metabolic pathways and insulin secretion, with concomitant effects on plasma insulin levels and blood glucose homeostasis (By similarity). Facilitates the protonated monocarboxylate form of succinate export, that its transient protonation upon muscle cell acidification in exercising muscle and ischemic heart (PubMed:32946811). Functions via alternate outward- and inward-open conformation states. Protonation and deprotonation of 309-Asp is essential for the conformational transition (PubMed:33333023)
- Specific Function
- carboxylic acid transmembrane transporter activity
- Gene Name
- SLC16A1
- Uniprot ID
- P53985
- Uniprot Name
- Monocarboxylate transporter 1
- Molecular Weight
- 53943.685 Da
References
- Tamai I, Sai Y, Ono A, Kido Y, Yabuuchi H, Takanaga H, Satoh E, Ogihara T, Amano O, Izeki S, Tsuji A: Immunohistochemical and functional characterization of pH-dependent intestinal absorption of weak organic acids by the monocarboxylic acid transporter MCT1. J Pharm Pharmacol. 1999 Oct;51(10):1113-21. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- ATP-dependent transporter of the ATP-binding cassette (ABC) family that actively extrudes physiological compounds and xenobiotics from cells. Plays a role in physiological processes involving bile acids, conjugated steroids and cyclic nucleotides, including cAMP and cGMP (PubMed:12764137, PubMed:15537867). Mediates the ATP-dependent efflux of a range of physiological lipophilic anions, including the glutathione S-conjugates leukotriene C4 and dinitrophenyl S-glutathione, steroid sulfates, such as dehydroepiandrosterone 3-sulfate (DHEAS) and estrone 3-sulfate, glucuronides such as estradiol 17-beta-D-glucuronide (E(2)17betaG), the monoanionic bile acids glycocholate and taurocholate, and methotrexate (PubMed:15537867, PubMed:16359813, PubMed:25896536). Plays a role in the transport of earwax components (PubMed:16444273, PubMed:19383836). Participates in the secretion of odorants and their precursors from the apocrine sweat glands, including the secretion of glutamine conjugates, as well as the Cys-Gly-(S) conjugates of 3-methyl-3-sulfanyl-hexanol (PubMed:19710689). Involved in the cellular extrusion of nucleotide analogs, hence confering resistance to various drugs, including clinically relevant drugs such as 5-fluorouracil (5-FU) and methotrexate (PubMed:12764137, PubMed:15537867, PubMed:25896536)
- Specific Function
- ABC-type bile acid transporter activity
- Gene Name
- ABCC11
- Uniprot ID
- Q96J66
- Uniprot Name
- ATP-binding cassette sub-family C member 11
- Molecular Weight
- 154299.625 Da
References
- Chen ZS, Guo Y, Belinsky MG, Kotova E, Kruh GD: Transport of bile acids, sulfated steroids, estradiol 17-beta-D-glucuronide, and leukotriene C4 by human multidrug resistance protein 8 (ABCC11). Mol Pharmacol. 2005 Feb;67(2):545-57. Epub 2004 Nov 10. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Mediates the Na(+)-independent uptake of organic anions (PubMed:10779507, PubMed:15159445, PubMed:17412826). Shows broad substrate specificity, can transport both organic anions such as bile acid taurocholate (cholyltaurine) and conjugated steroids (17-beta-glucuronosyl estradiol, dehydroepiandrosterone sulfate (DHEAS), and estrone 3-sulfate), as well as eicosanoid leukotriene C4, prostaglandin E2 and L-thyroxine (T4) (PubMed:10779507, PubMed:11159893, PubMed:12568656, PubMed:15159445, PubMed:17412826, PubMed:19129463). Hydrogencarbonate/HCO3(-) acts as the probable counteranion that exchanges for organic anions (PubMed:19129463). Shows a pH-sensitive substrate specificity towards sulfated steroids, taurocholate and T4 which may be ascribed to the protonation state of the binding site and leads to a stimulation of substrate transport in an acidic microenvironment (PubMed:19129463). Involved in the clearance of bile acids and organic anions from the liver (PubMed:22232210). Can take up bilirubin glucuronides from plasma into the liver, contributing to the detoxification-enhancing liver-blood shuttling loop (PubMed:22232210). Transports coproporphyrin I and III, by-products of heme synthesis, and may be involved in their hepatic disposition (PubMed:26383540). May contribute to regulate the transport of organic compounds in testes across the blood-testis-barrier (Probable). Can transport HMG-CoA reductase inhibitors (also known as statins) such as pitavastatin, a clinically important class of hypolipidemic drugs (PubMed:15159445). May play an important role in plasma and tissue distribution of the structurally diverse chemotherapeutic drugs methotrexate and paclitaxel (PubMed:23243220). May also transport antihypertension agents, such as the angiotensin-converting enzyme (ACE) inhibitor prodrug enalapril, and the highly selective angiotensin II AT1-receptor antagonist valsartan, in the liver (PubMed:16624871, PubMed:16627748)
- Specific Function
- bile acid transmembrane transporter activity
- Gene Name
- SLCO1B3
- Uniprot ID
- Q9NPD5
- Uniprot Name
- Solute carrier organic anion transporter family member 1B3
- Molecular Weight
- 77402.175 Da
References
- Abe T, Unno M, Onogawa T, Tokui T, Kondo TN, Nakagomi R, Adachi H, Fujiwara K, Okabe M, Suzuki T, Nunoki K, Sato E, Kakyo M, Nishio T, Sugita J, Asano N, Tanemoto M, Seki M, Date F, Ono K, Kondo Y, Shiiba K, Suzuki M, Ohtani H, Shimosegawa T, Iinuma K, Nagura H, Ito S, Matsuno S: LST-2, a human liver-specific organic anion transporter, determines methotrexate sensitivity in gastrointestinal cancers. Gastroenterology. 2001 Jun;120(7):1689-99. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Antiporter that mediates the transport of conjugated steroids and other specific organic anions at the basal membrane of syncytiotrophoblast and at the apical membrane of proximal tubule epithelial cells, in exchange for anionic compounds (PubMed:10660625, PubMed:11907186, PubMed:15037815, PubMed:15102942, PubMed:15291761, PubMed:15576633, PubMed:17229912, PubMed:18501590, PubMed:26277985, PubMed:28027879). May be responsible for placental absorption of fetal-derived steroid sulfates such as estrone sulfate (E1S) and the steroid hormone precursor dehydroepiandrosterone sulfate (DHEA-S), as well as clearing waste products and xenobiotics from the fetus (PubMed:12409283). Maybe also be involved in placental urate homeostasis (PubMed:17229912). Facilitates the renal reabsorption of organic anions such as urate and derived steroid sulfates (PubMed:15037815, PubMed:17229912). Organic anion glutarate acts as conteranion for E1S renal uptake (PubMed:15037815, PubMed:17229912). Possible transport mode may also include DHEA-S/E1S exchange (PubMed:28027879). Also interacts with inorganic anions such as chloride and hydroxyl ions, therefore possible transport modes may include E1S/Cl(-), E1S/OH(-), urate/Cl(-) and urate/OH(-) (PubMed:17229912). Also mediates the transport of prostaglandin E2 (PGE2) and prostaglandin F2-alpha (PGF2-alpha) and may be involved in their renal excretion (PubMed:11907186). Also able to uptake anionic drugs, diuretics, bile salts and ochratoxin A (PubMed:10660625, PubMed:26277985). Mediates the unidirectional efflux of glutamate and aspartate (PubMed:28027879). Glutamate efflux down its transmembrane gradient may drive SLC22A11/OAT4-mediated placental uptake of E1S (PubMed:26277985)
- Specific Function
- organic anion transmembrane transporter activity
- Gene Name
- SLC22A11
- Uniprot ID
- Q9NSA0
- Uniprot Name
- Solute carrier family 22 member 11
- Molecular Weight
- 59970.945 Da
References
- Takeda M, Khamdang S, Narikawa S, Kimura H, Hosoyamada M, Cha SH, Sekine T, Endou H: Characterization of methotrexate transport and its drug interactions with human organic anion transporters. J Pharmacol Exp Ther. 2002 Aug;302(2):666-71. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Mediates the Na(+)-independent high affinity transport of organic anions such as the thyroid hormones L-thyroxine (T4), L-thyroxine sulfate (T4S), and 3,3',5'-triiodo-L-thyronine (reverse T3, rT3) at the plasma membrane (PubMed:12351693, PubMed:18566113, PubMed:19129463). Regulates T4 levels in different brain regions by transporting T4, and also by serving as an export pump for T4S, which is a source of T4 after hydrolysis by local sulfatases (PubMed:18566113). Increases the access of these substrates to the intracellular sites where they are metabolized by the deiodinases (PubMed:18566113). Other potential substrates, such as triiodothyronine (T3), 17-beta-glucuronosyl estradiol (17beta-estradiol 17-O-(beta-D-glucuronate)), estrone-3-sulfate (E1S) and sulfobromophthalein (BSP) are transported with much lower efficiency (PubMed:12351693, PubMed:19129463). Transports T4 and E1S in a pH-insensitive manner (PubMed:19129463). Facilitates the transport of thyroid hormones across the blood-brain barrier and into glia and neuronal cells in the brain (PubMed:30296914)
- Specific Function
- bile acid transmembrane transporter activity
- Gene Name
- SLCO1C1
- Uniprot ID
- Q9NYB5
- Uniprot Name
- Solute carrier organic anion transporter family member 1C1
- Molecular Weight
- 78695.625 Da
References
- Pizzagalli F, Hagenbuch B, Stieger B, Klenk U, Folkers G, Meier PJ: Identification of a novel human organic anion transporting polypeptide as a high affinity thyroxine transporter. Mol Endocrinol. 2002 Oct;16(10):2283-96. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Putative organic anion antiporter with apparent broad substrate specificity. Recognizes various substrates including thyroid hormone L-thyroxine, prostanoids such as prostaglandin E1 and E2, bile acids such as taurocholate, glycolate and glycochenodeoxycholate and peptide hormones such as L-arginine vasopressin, likely operating in a tissue-specific manner (PubMed:10873595, PubMed:14631946, PubMed:16971491, PubMed:19129463, PubMed:30063921). The transport mechanism, its electrogenicity and potential tissue-specific counterions remain to be elucidated (Probable)
- Specific Function
- organic anion transmembrane transporter activity
- Gene Name
- SLCO3A1
- Uniprot ID
- Q9UIG8
- Uniprot Name
- Solute carrier organic anion transporter family member 3A1
- Molecular Weight
- 76552.135 Da
References
- Adachi H, Suzuki T, Abe M, Asano N, Mizutamari H, Tanemoto M, Nishio T, Onogawa T, Toyohara T, Kasai S, Satoh F, Suzuki M, Tokui T, Unno M, Shimosegawa T, Matsuno S, Ito S, Abe T: Molecular characterization of human and rat organic anion transporter OATP-D. Am J Physiol Renal Physiol. 2003 Dec;285(6):F1188-97. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Broad substrate specificity ATP-dependent transporter of the ATP-binding cassette (ABC) family that actively extrudes a wide variety of physiological compounds, dietary toxins and xenobiotics from cells (PubMed:11306452, PubMed:12958161, PubMed:19506252, PubMed:20705604, PubMed:28554189, PubMed:30405239, PubMed:31003562). Involved in porphyrin homeostasis, mediating the export of protoporphyrin IX (PPIX) from both mitochondria to cytosol and cytosol to extracellular space, it also functions in the cellular export of heme (PubMed:20705604, PubMed:23189181). Also mediates the efflux of sphingosine-1-P from cells (PubMed:20110355). Acts as a urate exporter functioning in both renal and extrarenal urate excretion (PubMed:19506252, PubMed:20368174, PubMed:22132962, PubMed:31003562, PubMed:36749388). In kidney, it also functions as a physiological exporter of the uremic toxin indoxyl sulfate (By similarity). Also involved in the excretion of steroids like estrone 3-sulfate/E1S, 3beta-sulfooxy-androst-5-en-17-one/DHEAS, and other sulfate conjugates (PubMed:12682043, PubMed:28554189, PubMed:30405239). Mediates the secretion of the riboflavin and biotin vitamins into milk (By similarity). Extrudes pheophorbide a, a phototoxic porphyrin catabolite of chlorophyll, reducing its bioavailability (By similarity). Plays an important role in the exclusion of xenobiotics from the brain (Probable). It confers to cells a resistance to multiple drugs and other xenobiotics including mitoxantrone, pheophorbide, camptothecin, methotrexate, azidothymidine, and the anthracyclines daunorubicin and doxorubicin, through the control of their efflux (PubMed:11306452, PubMed:12477054, PubMed:15670731, PubMed:18056989, PubMed:31254042). In placenta, it limits the penetration of drugs from the maternal plasma into the fetus (By similarity). May play a role in early stem cell self-renewal by blocking differentiation (By similarity)
- Specific Function
- ABC-type xenobiotic transporter activity
- Gene Name
- ABCG2
- Uniprot ID
- Q9UNQ0
- Uniprot Name
- Broad substrate specificity ATP-binding cassette transporter ABCG2
- Molecular Weight
- 72313.47 Da
References
- Suzuki M, Suzuki H, Sugimoto Y, Sugiyama Y: ABCG2 transports sulfated conjugates of steroids and xenobiotics. J Biol Chem. 2003 Jun 20;278(25):22644-9. Epub 2003 Apr 7. [Article]
- Breedveld P, Zelcer N, Pluim D, Sonmezer O, Tibben MM, Beijnen JH, Schinkel AH, van Tellingen O, Borst P, Schellens JH: Mechanism of the pharmacokinetic interaction between methotrexate and benzimidazoles: potential role for breast cancer resistance protein in clinical drug-drug interactions. Cancer Res. 2004 Aug 15;64(16):5804-11. [Article]
- Mitomo H, Kato R, Ito A, Kasamatsu S, Ikegami Y, Kii I, Kudo A, Kobatake E, Sumino Y, Ishikawa T: A functional study on polymorphism of the ATP-binding cassette transporter ABCG2: critical role of arginine-482 in methotrexate transport. Biochem J. 2003 Aug 1;373(Pt 3):767-74. [Article]
- Chen ZS, Robey RW, Belinsky MG, Shchaveleva I, Ren XQ, Sugimoto Y, Ross DD, Bates SE, Kruh GD: Transport of methotrexate, methotrexate polyglutamates, and 17beta-estradiol 17-(beta-D-glucuronide) by ABCG2: effects of acquired mutations at R482 on methotrexate transport. Cancer Res. 2003 Jul 15;63(14):4048-54. [Article]
- Volk EL, Schneider E: Wild-type breast cancer resistance protein (BCRP/ABCG2) is a methotrexate polyglutamate transporter. Cancer Res. 2003 Sep 1;63(17):5538-43. [Article]
- Suzuki K, Doki K, Homma M, Tamaki H, Hori S, Ohtani H, Sawada Y, Kohda Y: Co-administration of proton pump inhibitors delays elimination of plasma methotrexate in high-dose methotrexate therapy. Br J Clin Pharmacol. 2009 Jan;67(1):44-9. doi: 10.1111/j.1365-2125.2008.03303.x. Epub 2008 Nov 17. [Article]
- Hou YX, Li CZ, Palaniyandi K, Magtibay PM, Homolya L, Sarkadi B, Chang XB: Effects of putative catalytic base mutation E211Q on ABCG2-mediated methotrexate transport. Biochemistry. 2009 Sep 29;48(38):9122-31. doi: 10.1021/bi900675v. [Article]
- Tiwari AK, Sodani K, Wang SR, Kuang YH, Ashby CR Jr, Chen X, Chen ZS: Nilotinib (AMN107, Tasigna) reverses multidrug resistance by inhibiting the activity of the ABCB1/Pgp and ABCG2/BCRP/MXR transporters. Biochem Pharmacol. 2009 Jul 15;78(2):153-61. doi: 10.1016/j.bcp.2009.04.002. Epub 2009 Apr 11. [Article]
- Dai CL, Liang YJ, Wang YS, Tiwari AK, Yan YY, Wang F, Chen ZS, Tong XZ, Fu LW: Sensitization of ABCG2-overexpressing cells to conventional chemotherapeutic agent by sunitinib was associated with inhibiting the function of ABCG2. Cancer Lett. 2009 Jun 28;279(1):74-83. doi: 10.1016/j.canlet.2009.01.027. Epub 2009 Feb 18. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Functions as a Na(+)-independent bidirectional multispecific transporter (PubMed:11327718, PubMed:18216183, PubMed:21446918, PubMed:28945155). Contributes to the renal and hepatic elimination of endogenous organic compounds from the systemic circulation into the urine and bile, respectively (PubMed:11327718, PubMed:25904762). Capable of transporting a wide range of purine and pyrimidine nucleobases, nucleosides and nucleotides, with cGMP, 2'deoxyguanosine and GMP being the preferred substrates (PubMed:11327718, PubMed:18216183, PubMed:26377792, PubMed:28945155). Functions as a pH- and chloride-independent cGMP bidirectional facilitative transporter that can regulate both intracellular and extracellular levels of cGMP and may be involved in cGMP signaling pathways (PubMed:18216183, PubMed:26377792). Mediates orotate/glutamate bidirectional exchange and most likely display a physiological role in hepatic release of glutamate into the blood (PubMed:21446918). Involved in renal secretion and possible reabsorption of creatinine (PubMed:25904762, PubMed:28945155). Able to uptake prostaglandin E2 (PGE2) and may contribute to PGE2 renal excretion (Probable). Also transports alpha-ketoglutarate and urate (PubMed:11327718, PubMed:26377792). Apart from the orotate/glutamate exchange, the counterions for the uptake of other SLC22A7/OAT2 substrates remain to be identified (PubMed:26377792)
- Specific Function
- alpha-ketoglutarate transmembrane transporter activity
- Gene Name
- SLC22A7
- Uniprot ID
- Q9Y694
- Uniprot Name
- Solute carrier family 22 member 7
- Molecular Weight
- 60025.025 Da
References
- Sun W, Wu RR, van Poelje PD, Erion MD: Isolation of a family of organic anion transporters from human liver and kidney. Biochem Biophys Res Commun. 2001 May 4;283(2):417-22. [Article]
- Sekine T, Cha SH, Tsuda M, Apiwattanakul N, Nakajima N, Kanai Y, Endou H: Identification of multispecific organic anion transporter 2 expressed predominantly in the liver. FEBS Lett. 1998 Jun 12;429(2):179-82. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInhibitor
- General Function
- Proton-coupled folate symporter that mediates folate absorption using an H(+) gradient as a driving force (PubMed:17129779, PubMed:17446347, PubMed:17475902, PubMed:19389703, PubMed:19762432, PubMed:25504888, PubMed:29344585, PubMed:30858177, PubMed:31494288, PubMed:31792273, PubMed:32893190, PubMed:34619546). Involved in the intestinal absorption of folates at the brush-border membrane of the proximal jejunum, and the transport from blood to cerebrospinal fluid across the choroid plexus (PubMed:17129779, PubMed:17446347, PubMed:17475902, PubMed:19389703, PubMed:25504888, PubMed:29344585, PubMed:30858177, PubMed:31494288, PubMed:32893190). Functions at acidic pH via alternate outward- and inward-open conformation states (PubMed:32893190, PubMed:34040256). Protonation of residues in the outward open state primes the protein for transport (PubMed:34040256). Binding of folate promotes breaking of salt bridge network and subsequent closure of the extracellular gate, leading to the inward-open state and release of protons and folate (PubMed:34040256). Also able to transport antifolate drugs, such as methotrexate and pemetrexed, which are established treatments for cancer and autoimmune diseases (PubMed:18524888, PubMed:19762432, PubMed:22345511, PubMed:25608532, PubMed:28802835, PubMed:29326243, PubMed:34040256, PubMed:34619546). Involved in FOLR1-mediated endocytosis by serving as a route of export of folates from acidified endosomes (PubMed:19074442). Also acts as a lower-affinity, pH-independent heme carrier protein and constitutes the main importer of heme in the intestine (PubMed:17156779). Imports heme in the retina and retinal pigment epithelium, in neurons of the hippocampus, in hepatocytes and in the renal epithelial cells (PubMed:32621820). Hence, participates in the trafficking of heme and increases intracellular iron content (PubMed:32621820)
- Specific Function
- folic acid binding
- Gene Name
- SLC46A1
- Uniprot ID
- Q96NT5
- Uniprot Name
- Proton-coupled folate transporter
- Molecular Weight
- 49770.04 Da
References
- Nakai Y, Inoue K, Abe N, Hatakeyama M, Ohta KY, Otagiri M, Hayashi Y, Yuasa H: Functional characterization of human proton-coupled folate transporter/heme carrier protein 1 heterologously expressed in mammalian cells as a folate transporter. J Pharmacol Exp Ther. 2007 Aug;322(2):469-76. Epub 2007 May 2. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Mediates the Na(+)-independent uptake of organic anions (PubMed:10358072, PubMed:15159445, PubMed:17412826). Shows broad substrate specificity, can transport both organic anions such as bile acid taurocholate (cholyltaurine) and conjugated steroids (dehydroepiandrosterone 3-sulfate, 17-beta-glucuronosyl estradiol, and estrone 3-sulfate), as well as eicosanoids (prostaglandin E2, thromboxane B2, leukotriene C4, and leukotriene E4), and thyroid hormones (T4/L-thyroxine, and T3/3,3',5'-triiodo-L-thyronine) (PubMed:10358072, PubMed:10601278, PubMed:10873595, PubMed:11159893, PubMed:12196548, PubMed:12568656, PubMed:15159445, PubMed:15970799, PubMed:16627748, PubMed:17412826, PubMed:19129463, PubMed:26979622). Can take up bilirubin glucuronides from plasma into the liver, contributing to the detoxification-enhancing liver-blood shuttling loop (PubMed:22232210). Involved in the clearance of endogenous and exogenous substrates from the liver (PubMed:10358072, PubMed:10601278). Transports coproporphyrin I and III, by-products of heme synthesis, and may be involved in their hepatic disposition (PubMed:26383540). May contribute to regulate the transport of organic compounds in testes across the blood-testis-barrier (Probable). Can transport HMG-CoA reductase inhibitors (also known as statins), such as pravastatin and pitavastatin, a clinically important class of hypolipidemic drugs (PubMed:10601278, PubMed:15159445, PubMed:15970799). May play an important role in plasma and tissue distribution of the structurally diverse chemotherapeutic drug methotrexate (PubMed:23243220). May also transport antihypertension agents, such as the angiotensin-converting enzyme (ACE) inhibitor prodrug enalapril, and the highly selective angiotensin II AT1-receptor antagonist valsartan, in the liver (PubMed:16624871, PubMed:16627748). Shows a pH-sensitive substrate specificity towards prostaglandin E2 and T4 which may be ascribed to the protonation state of the binding site and leads to a stimulation of substrate transport in an acidic microenvironment (PubMed:19129463). Hydrogencarbonate/HCO3(-) acts as the probable counteranion that exchanges for organic anions (PubMed:19129463)
- Specific Function
- bile acid transmembrane transporter activity
- Gene Name
- SLCO1B1
- Uniprot ID
- Q9Y6L6
- Uniprot Name
- Solute carrier organic anion transporter family member 1B1
- Molecular Weight
- 76447.99 Da
References
- Abe T, Unno M, Onogawa T, Tokui T, Kondo TN, Nakagomi R, Adachi H, Fujiwara K, Okabe M, Suzuki T, Nunoki K, Sato E, Kakyo M, Nishio T, Sugita J, Asano N, Tanemoto M, Seki M, Date F, Ono K, Kondo Y, Shiiba K, Suzuki M, Ohtani H, Shimosegawa T, Iinuma K, Nagura H, Ito S, Matsuno S: LST-2, a human liver-specific organic anion transporter, determines methotrexate sensitivity in gastrointestinal cancers. Gastroenterology. 2001 Jun;120(7):1689-99. [Article]
- van de Steeg E, van der Kruijssen CM, Wagenaar E, Burggraaff JE, Mesman E, Kenworthy KE, Schinkel AH: Methotrexate pharmacokinetics in transgenic mice with liver-specific expression of human organic anion-transporting polypeptide 1B1 (SLCO1B1). Drug Metab Dispos. 2009 Feb;37(2):277-81. doi: 10.1124/dmd.108.024315. Epub 2008 Nov 20. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- General Function
- Mediates the transport of organic anions such as steroids (estrone 3-sulfate, chenodeoxycholate, glycocholate) and thyroid hormones (3,3',5-triiodo-L-thyronine (T3), L-thyroxine (T4)), in the kidney (PubMed:14993604, PubMed:19129463, PubMed:20610891). Capable of transporting cAMP and pharmacological substances such as digoxin, ouabain and methotrexate (PubMed:14993604). Transport is independent of sodium, chloride ion, and ATP (PubMed:14993604). Transport activity is stimulated by an acidic extracellular environment due to increased substrate affinity to the transporter (PubMed:19129463). The driving force for this transport activity is currently not known (By similarity). The role of hydrogencarbonate (HCO3(-), bicarbonate) as the probable counteranion that exchanges for organic anions is still not well defined (PubMed:19129463). Functions as an uptake transporter at the apical membrane, suggesting a role in renal reabsorption (By similarity). Involved in the renal secretion of the uremic toxin ADMA (N(omega),N(omega)-dimethyl-L-arginine or asymmetrical dimethylarginine), which is associated to cardiovascular events and mortality, and the structurally related amino acids L-arginine and L-homoarginine (a cardioprotective biomarker) (PubMed:30865704). Can act bidirectionally, suggesting a dual protective role of this transport protein; exporting L-homoarginine after being synthesized in proximal tubule cells, and mediating uptake of ADMA from the blood into proximal tubule cells where it is degraded by the enzyme dimethylarginine dimethylaminohydrolase 1 (DDAH1) (PubMed:30865704, PubMed:32642843). May be involved in sperm maturation by enabling directed movement of organic anions and compounds within or between cells (By similarity). This ion-transporting process is important to maintain the strict epididymal homeostasis necessary for sperm maturation (By similarity). May have a role in secretory functions since seminal vesicle epithelial cells are assumed to secrete proteins involved in decapacitation by modifying surface proteins to facilitate the acquisition of the ability to fertilize the egg (By similarity)
- Specific Function
- organic anion transmembrane transporter activity
- Gene Name
- SLCO4C1
- Uniprot ID
- Q6ZQN7
- Uniprot Name
- Solute carrier organic anion transporter family member 4C1
- Molecular Weight
- 78947.525 Da
References
- Mikkaichi T, Suzuki T, Onogawa T, Tanemoto M, Mizutamari H, Okada M, Chaki T, Masuda S, Tokui T, Eto N, Abe M, Satoh F, Unno M, Hishinuma T, Inui K, Ito S, Goto J, Abe T: Isolation and characterization of a digoxin transporter and its rat homologue expressed in the kidney. Proc Natl Acad Sci U S A. 2004 Mar 9;101(10):3569-74. Epub 2004 Mar 1. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Antiporter that mediates the import of reduced folates or a subset of cyclic dinucleotides, driven by the export of organic anions (PubMed:10787414, PubMed:15337749, PubMed:16115875, PubMed:22554803, PubMed:31126740, PubMed:31511694, PubMed:32276275, PubMed:7826387, PubMed:9041240). Mechanistically, acts as a secondary active transporter, which exports intracellular organic anions down their concentration gradients to facilitate the uptake of its substrates (PubMed:22554803, PubMed:31126740, PubMed:31511694). Has high affinity for N5-methyltetrahydrofolate, the predominant circulating form of folate (PubMed:10787414, PubMed:14609557, PubMed:22554803). Also able to mediate the import of antifolate drug methotrexate (PubMed:22554803, PubMed:7615551, PubMed:7641195, PubMed:9767079). Also acts as an importer of immunoreactive cyclic dinucleotides, such as cyclic GMP-AMP (2'-3'-cGAMP), an immune messenger produced in response to DNA virus in the cytosol, and its linkage isomer 3'-3'-cGAMP, thus playing a role in triggering larger immune responses (PubMed:31126740, PubMed:31511694, PubMed:36745868). 5-amino-4-imidazolecarboxamide riboside (AICAR), when phosphorylated to AICAR monophosphate, can serve as an organic anion for antiporter activity (PubMed:22554803)
- Specific Function
- 2',3'-cyclic GMP-AMP binding
- Gene Name
- SLC19A1
- Uniprot ID
- P41440
- Uniprot Name
- Reduced folate transporter
- Molecular Weight
- 64867.62 Da
References
- Qiu A, Jansen M, Sakaris A, Min SH, Chattopadhyay S, Tsai E, Sandoval C, Zhao R, Akabas MH, Goldman ID: Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption. Cell. 2006 Dec 1;127(5):917-28. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Binds to folate and reduced folic acid derivatives and mediates delivery of 5-methyltetrahydrofolate and folate analogs into the interior of cells (PubMed:19074442, PubMed:23851396, PubMed:23934049, PubMed:2527252, PubMed:8033114, PubMed:8567728). Has high affinity for folate and folic acid analogs at neutral pH (PubMed:23851396, PubMed:23934049, PubMed:2527252, PubMed:8033114, PubMed:8567728). Exposure to slightly acidic pH after receptor endocytosis triggers a conformation change that strongly reduces its affinity for folates and mediates their release (PubMed:8567728). Required for normal embryonic development and normal cell proliferation (By similarity)
- Specific Function
- folic acid binding
- Gene Name
- FOLR1
- Uniprot ID
- P15328
- Uniprot Name
- Folate receptor alpha
- Molecular Weight
- 29818.94 Da
References
- Sharma S, Das M, Kumar A, Marwaha V, Shankar S, Aneja R, Grover R, Arya V, Dhir V, Gupta R, Kumar U, Juyal RC, B K T: Interaction of genes from influx-metabolism-efflux pathway and their influence on methotrexate efficacy in rheumatoid arthritis patients among Indians. Pharmacogenet Genomics. 2008 Dec;18(12):1041-9. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Binds to folate and reduced folic acid derivatives and mediates delivery of 5-methyltetrahydrofolate and folate analogs into the interior of cells. Has high affinity for folate and folic acid analogs at neutral pH. Exposure to slightly acidic pH after receptor endocytosis triggers a conformation change that strongly reduces its affinity for folates and mediates their release
- Specific Function
- folic acid binding
- Gene Name
- FOLR2
- Uniprot ID
- P14207
- Uniprot Name
- Folate receptor beta
- Molecular Weight
- 29279.31 Da
References
- Inoue K, Yuasa H: Molecular basis for pharmacokinetics and pharmacodynamics of methotrexate in rheumatoid arthritis therapy. Drug Metab Pharmacokinet. 2014;29(1):12-9. Epub 2013 Nov 26. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Electrogenic proton-coupled amino-acid transporter that transports oligopeptides of 2 to 4 amino acids with a preference for dipeptides. Transports neutral and monovalently charged peptides with a proton to peptide stoichiometry of 1:1 or 2:1 (By similarity) (PubMed:15521010, PubMed:18367661, PubMed:19685173, PubMed:26320580, PubMed:7896779, PubMed:8914574, PubMed:9835627). Primarily responsible for the absorption of dietary di- and tripeptides from the small intestinal lumen (By similarity). Mediates transepithelial transport of muramyl and N-formylated bacterial dipeptides contributing to recognition of pathogenic bacteria by the mucosal immune system (PubMed:15521010, PubMed:9835627)
- Specific Function
- dipeptide transmembrane transporter activity
- Gene Name
- SLC15A1
- Uniprot ID
- P46059
- Uniprot Name
- Solute carrier family 15 member 1
- Molecular Weight
- 78805.265 Da
References
- Inoue K, Yuasa H: Molecular basis for pharmacokinetics and pharmacodynamics of methotrexate in rheumatoid arthritis therapy. Drug Metab Pharmacokinet. 2014;29(1):12-9. Epub 2013 Nov 26. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Electrogenic proton/amino acid symporter with selectivity for small apolar L-amino acids, their D-enantiomers and selected amino acid derivatives such as 4-aminobutanoate/GABA (PubMed:12527723, PubMed:12809675, PubMed:19549785). May be involved in the efflux from the lysosomal compartment of neutral amino acids resulting from proteolysis (By similarity). May play a role in specifying sites for exocytosis in neurons (By similarity)
- Specific Function
- alanine transmembrane transporter activity
- Gene Name
- SLC36A1
- Uniprot ID
- Q7Z2H8
- Uniprot Name
- Proton-coupled amino acid transporter 1
- Molecular Weight
- 53075.045 Da
References
- Inoue K, Yuasa H: Molecular basis for pharmacokinetics and pharmacodynamics of methotrexate in rheumatoid arthritis therapy. Drug Metab Pharmacokinet. 2014;29(1):12-9. Epub 2013 Nov 26. [Article]
Drug created at June 13, 2005 13:24 / Updated at November 07, 2024 23:49