The 1.85 A structure of an 8R-lipoxygenase suggests a general model for lipoxygenase product specificity.
Lipoxygenases (LOX) play pivotal roles in the biosynthesis of leukotrienes and other biologically active eicosanoids derived from arachidonic acid. A mechanistic understanding of substrate recognition, when lipoxygenases that recognize the same substrate generate different products, can be used to help guide the design of enzyme-specific inhibitors. We report here the 1.85 A resolution structure of an 8R-lipoxygenase from Plexaura homomalla, an enzyme with a sequence approximately 40% identical to that of human 5-LOX. The structure reveals a U-shaped channel, defined by invariant amino acids, that would allow substrate access to the catalytic iron. We demonstrate that mutations within the channel significantly impact enzyme activity and propose a novel model for substrate binding potentially applicable to other members of this enzyme family.
Neau
David B
DB
Department of Biological Sciences, Louisiana State University, Baton Rouge, Louisiana 70803, USA.
Gilbert
Nathaniel C
NC
Bartlett
Sue G
SG
Boeglin
William
W
Brash
Alan R
AR
Newcomer
Marcia E
ME
D000595:Amino Acid Sequence; D000818:Animals; D037421:Anthozoa / Q000201:enzymology*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004789:Enzyme Activation; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000737:chemistry* / Q000235:genetics; D008084:Lipoxygenase / Q000737:chemistry* / Q000235:genetics; D008956:Models, Chemical; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D013237:Stereoisomerism; D013379:Substrate Specificity
D008084:Lipoxygenase; D019746:Intramolecular Oxidoreductases; C021377:hydroperoxide isomerase