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.
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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
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DOI: https://doi.org/10.1038/354149a0
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