The 1.85 Å Structure of an 8R-Lipoxygenase Suggests a General Model for Lipoxygenase Product Specificity

• Published in: Biochemistry (Easton) Vol. 48; no. 33; pp. 7906 - 7915
• Main Authors: Neau, David B, Gilbert, Nathaniel C, Bartlett, Sue G, Boeglin, William, Brash, Alan R, Newcomer, Marcia E
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 25.08.2009
• Subjects: Amino Acid Sequence; Animals; Anthozoa - enzymology; Binding Sites; Crystallography, X-Ray; Enzyme Activation; Humans; Intramolecular Oxidoreductases - chemistry; Intramolecular Oxidoreductases - genetics; Lipoxygenase - chemistry; Lipoxygenase - genetics; Models, Chemical; Models, Molecular; Molecular Sequence Data; Mutagenesis, Site-Directed; Stereoisomerism; Substrate Specificity
• ISSN: 0006-2960; 1520-4995
• DOI: 10.1021/bi900084m

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 Å resolution structure of an 8R-lipoxygenase from Plexaura homomalla, an enzyme with a sequence ∼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.