PT  - JOURNAL ARTICLE
AU  - P. J. Loll
AU  - C. T. Sharkey
AU  - S. J. O'Connor
AU  - C. M. Dooley
AU  - E. O'Brien
AU  - M. Devocelle
AU  - K. B. Nolan
AU  - B. S. Selinsky
AU  - D. J. Fitzgerald
TI  - <em>O</em>-Acetylsalicylhydroxamic Acid, a Novel Acetylating Inhibitor of Prostaglandin H<sub>2</sub> Synthase: Structural and Functional Characterization of Enzyme-Inhibitor Interactions
AID  - 10.1124/mol.60.6.1407
DP  - 2001 Dec 01
TA  - Molecular Pharmacology
PG  - 1407--1413
VI  - 60
IP  - 6
4099  - http://molpharm.aspetjournals.org/content/60/6/1407.short
4100  - http://molpharm.aspetjournals.org/content/60/6/1407.full
SO  - Mol Pharmacol2001 Dec 01; 60
AB  - 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.