OVINE PGHS-1 COMPLEXED WITH SALICYL HYDROXAMIC ACID
[PGH1_SHEEP] May play an important role in regulating or promoting cell proliferation in some normal and neoplastically transformed cells.
Publication Abstract from PubMed
Aspirin is unique among clinically used nonsteroidal antiinflammatory drugs in that it irreversibly inactivates prostaglandin (PG) H2 synthase (PGHS) via acetylation of an active-site serine residue. We report the synthesis and characterization of a novel acetylating agent, O-acetylsalicylhydroxamic acid (AcSHA), which inhibits PGE2 synthesis in vivo and blocks the cyclooxygenase activity of PGHS in vitro. AcSHA requires the presence of the active-site residue Ser-529 to be active against human PGHS-1; the S529A mutant is resistant to inactivation by the inhibitor. Analysis of PGHS inactivation by AcSHA, coupled with the X-ray crystal structure of the complex of ovine PGHS-1 with AcSHA, confirms that the inhibitor elicits its effects via acetylation of Ser-529 in the cyclooxygenase active site. The crystal structure reveals an intact inhibitor molecule bound in the enzyme's cyclooxygenase active-site channel, hydrogen bonding with Arg-119 of the enzyme. The structure-activity profile of AcSHA can be rationalized in terms of the crystal structure of the enzyme-ligand complex. AcSHA may prove useful as a lead compound to facilitate the development of new acetylating inhibitors.
O-acetylsalicylhydroxamic acid, a novel acetylating inhibitor of prostaglandin H2 synthase: structural and functional characterization of enzyme-inhibitor interactions.,Loll PJ, Sharkey CT, O'Connor SJ, Dooley CM, O'Brien E, Devocelle M, Nolan KB, Selinsky BS, Fitzgerald DJ Mol Pharmacol. 2001 Dec;60(6):1407-13. PMID:11723249
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.