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Mutations of Triad Determinants Changes the Substrate Alignment at the Catalytic Center of Human ALOX5.

Abstract：

:For the specificity of ALOX15 orthologs of different mammals, the geometry of the amino acids Phe353, Ile418, Met419, and Ile593 ("triad determinants") is important, and mutagenesis of these residues altered the reaction specificity of these enzymes. Here we expressed wild-type human ALOX5 and its F359W/A424I/N425M/A603I mutant in Sf9 insect cells and characterized the catalytic differences of the two enzyme variants. We found that wild-type ALOX5 converted arachidonic acid mainly to 5(S)-hydroperoxyeicosatetraenoic acid (HpETE). In contrast, 15(S)- and 8(S)-H(p)ETE were formed by the mutant enzyme. In addition to arachidonic acid, wild-type ALOX5 accepted eicosapentaenoic acid (EPA) as substrate, but C18 fatty acids were not oxygenated. The quadruple mutant also accepted linoleic acid and α- and γ-linolenic acid as substrate. Structural analysis of the oxygenation products and kinetic studies with stereospecifically labeled 11(S)- and 11(R)-deutero-linoleic acid suggested alternative ways of substrate orientation at the active site. In silico docking studies, molecular dynamics simulations, and quantum mechanics/molecular mechanics (QM/MM) calculations confirmed this hypothesis. These data indicate that "triad determinant" mutagenesis alters the catalytic properties of ALOX5 abolishing its leukotriene synthase activity but improving its biosynthetic capacity for pro-resolving lipoxins.

journal_name

ACS Chem Biol

journal_title

ACS chemical biology

authors

Ivanov I,Golovanov AB,Ferretti C,Canyelles-Niño M,Heydeck D,Stehling S,Lluch JM,González-Lafont À,Kühn H

doi

10.1021/acschembio.9b00674

subject

Has Abstract

pub_date

2019-12-20 00:00:00

pages

2768-2782

issue

12

eissn

1554-8929

issn

1554-8937

journal_volume

14

pub_type

杂志文章

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