Abstract
THE three mammalian lipoxygenases are named according to the carbon position (5,12 or 15) at which they catalyse the oxygenation of arachidonic acid1; they are implicated in inflammatory disorders, for example 15-1ipoxy gen ase is induced in atherosclerosis2 and can oxidize low-density lipoprotein to its atherogenic form3'4. To identify what determines this positional specificity, we have exchanged conserved differences in the isoforms of 12- and 15-lipoxygenases. Substitution of methionine with valine at position 418 of human 15-lipoxygenase results in an enzyme that performs 12- and 15-lipoxygenation equally. This effect can be mimicked by incubating wild-type 15-lipoxygenase with a synthetically altered substrate which has its doubly allylic methylene carbons shifted by one carbon relative to arachidonic acid. Other mutations at the neighbouring amino acids 416 and 417 give an enzyme which performs 12- and 15-lipoxygenation in a ratio of 15:1. These results indicate that this region might position the substrate in the active site.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Samuelson, B. et al. Science 237, 1171–1176 (1987).
Yla-Herttuala, S. et al. Proc. natn. Acad. Sci. U.S.A. 87, 6959–6963 (1990).
Sparrow, C. P. et al. J. Lipid Res. 29, 745–753 (1988).
Steinberg, D. et al. New Engl. J. Med. 320, 915–924 (1989).
Yoshimoto, T. et al. Proc. natn. Acad. Sci. USA. 87, 2142–2146 (1990).
Funk, C. D. et al. Proc. natn. Acad. Sci. U.S.A. 87, 5638–5642 (1990).
De Marzo, N. et al. Am. J. Physiol. (in the press).
Sigal, E. et al. Biochem. biophys. Res. Commun. 157, 457–464 (1988).
Fleming, J. et al. Gene 79, 181–188 (1989).
Ponder, J. W. & Richards, F. M. J. molec. Biol. 193, 775–791 (1987).
Kuhn, H. et al. J. biol. Chem. 265, 16300–16305 (1990).
Hamberg, M. & Samuelsson, B. J. biol. Chem. 242, 5329–5335 (1967).
Sloane, D. L. et al. Biomed. biochim. Acta 49, S11–S16 (1990).
Pistorius, E. K. & Axelrod, B. J. biol. Chem. 249, 3183–3186 (1974).
Shibata, D. et al. J. biol. Chem. 263, 6816–6821 (1988).
Nguyen, T. et al. J. biol. Chem. (in the press).
Bryant, R. W. et al. J. biol. Chem. 257, 6050–6055 (1982).
Craik, C. S. et al. Science 228, 291–297 (1985).
Fersht, A. R. et al. Nature 314, 235–238 (1985).
Wells, J. A. et al. Proc. natn. Acad. Sci. U.S.A. 84, 5167–5171 (1987).
Wilks, H. M. et al. Science 242, 1541–1544 (1988).
Kunkel, T. A. Proc. natn. Acad. Sci. U.S.A. 82, 488–492 (1985).
Sanger, F. et al. Proc. natn. Acad. Sci. U.S.A. 74, 5463–5467 (1977).
Sigal, E. et al. J. biol. Chem. 265, 5113–5120 (1990).
Matsumoto, T. et al. Proc. natn. Acad. Sci. U.S.A. 85, 26–30 (1988).
Dixon, R. A. F. et al. Proc. natn. Acad. Sci. U.S.A. 85, 416–420 (1988).
Balcarek, J. M. et al. J. biol. Chem. 263, 13937–13941 (1988).
Navaratnam, S. et al. Biochim. biophys. Acta 956, 70–76 (1988).
Dunham, W. R. et al. Eur. J. Biochem. 190, 611–617 (1990).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Sloane, D., Leung, R., Craik, C. et al. A primary determinant for lipoxygenase positional specificity. Nature 354, 149–152 (1991). https://doi.org/10.1038/354149a0
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/354149a0
This article is cited by
-
Transgenic mice overexpressing human ALOX15 under the control of the aP2 promoter are partly protected in the complete Freund’s adjuvant-induced paw inflammation model
Inflammation Research (2023)
-
Genome-wide identification, classification and expression of lipoxygenase gene family in pepper
Plant Molecular Biology (2018)
-
Lipoxygenase 2 from Cyanothece sp. controls dioxygen insertion by steric shielding and substrate fixation
Scientific Reports (2017)
-
Comparison of headspace-oxylipin-volatilomes of some Eastern Himalayan mosses extracted by sample enrichment probe and analysed by gas chromatography-mass spectrometry
Protoplasma (2017)
-
Molecular Cloning, Structural Characterization, and Ripening-Related Expression of Lipoxygenase Genes from Three Persimmon Cultivars Differing in Postharvest Ripening Rate
Plant Molecular Biology Reporter (2016)
