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Title: Crystal Structure of 12-Lipoxygenase Catalytic-Domain-Inhibitor Complex Identifies a Substrate-Binding Channel for Catalysis

Lipoxygenases are critical enzymes in the biosynthesis of families of bioactive lipids including compounds with important roles in the initiation and resolution of inflammation and in associated diseases such as diabetes, cardiovascular disease, and cancer. Crystals diffracting to high resolution (1.9 {angstrom}) were obtained for a complex between the catalytic domain of leukocyte 12-lipoxygenase and the isoform-specific inhibitor, 4-(2-oxapentadeca-4-yne)phenylpropanoic acid (OPP). In the three-dimensional structure of the complex, the inhibitor occupied a new U-shaped channel open at one end to the surface of the protein and extending past the redox-active iron site that is essential for catalysis. In models, the channel accommodated arachidonic acid, defining the binding site for the substrate of the catalyzed reaction. There was a void adjacent to the OPP binding site connecting to the surface of the enzyme and providing a plausible access channel for the other substrate, oxygen.
Authors:
; ; ;  [1] ;  [2]
  1. (Toledo)
  2. (
Publication Date:
OSTI Identifier:
1050087
Resource Type:
Journal Article
Resource Relation:
Journal Name: Structure; Journal Volume: 20; Journal Issue: (9) ; 09, 2012
Research Org:
Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
Sponsoring Org:
NIH
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; ARACHIDONIC ACID; BIOSYNTHESIS; CARDIOVASCULAR DISEASES; CATALYSIS; CRYSTAL STRUCTURE; DISEASES; ENZYMES; INFLAMMATION; IRON; LEUKOCYTES; LIPIDS; NEOPLASMS; OXYGEN; PROTEINS; RESOLUTION; SUBSTRATES