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A study of the product profile and substrate specificity of prostaglandin endoperoxide H synthases
Author(s) -
Song Inseok
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.502.12
Subject(s) - chemistry , cyclooxygenase , isozyme , arachidonic acid , prostaglandin h2 , prostaglandin , biochemistry , atp synthase , thromboxane a synthase , substrate (aquarium) , thromboxane a2 , peroxidase , thromboxane , enzyme , stereochemistry , platelet , biology , receptor , ecology , immunology
Prostaglandin endoperxide H synthase (PGHS), which catalyzes the first and committed step in prostaglandin synthesis, exhibits both a cyclooxygenase and a peroxidase activity. Initially two molecules of O 2 are incorporated into arachidonic acid to form the hydroperoxy endoperoxide PGG 2 , which is reduced to form the hydroxyl endoperoxide PGH 2 . There are two isozymes (PGHS‐1 and ‐2), encoded by different genes. Both are structurally and catalytically similar, but show different expression pattern. PGHS‐1 is constitutively expressed, but PGHS‐2 expression is transient and inducible in response to several mitogenic and pro‐inflammatory stimuli. Besides their different expression mode, coupling of each isozyme with the downstream prostanoid synthases is distinctive. For instance, thromboxane A 2 is synthesized by functional coupling between PGHS‐1 and thromboxane synthase in platelet cells, which do not express PGHS‐2. Depending on the efficiency of their coupling, not only the designated prostaglandin is formed, but a combination of other prostaglandins can be produced. The product profile was shown to be even more complicated in the presence of reduced glutathione at physiological concentrations, which altered drastically arachidonic acid metabolism. Secondly, the peroxidase active site of PGHS, which is located across from the cyclooxygenase site and hydrophobic dome‐shaped, was investigated to dissect the essential residues for PGG 2 specificity.