RT Journal Article
SR Electronic
T1 <em>O</em>-Acetylsalicylhydroxamic Acid, a Novel Acetylating Inhibitor of Prostaglandin H<sub>2</sub> Synthase: Structural and Functional Characterization of Enzyme-Inhibitor Interactions
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1407
OP 1413
DO 10.1124/mol.60.6.1407
VO 60
IS 6
A1 P. J. Loll
A1 C. T. Sharkey
A1 S. J. O'Connor
A1 C. M. Dooley
A1 E. O'Brien
A1 M. Devocelle
A1 K. B. Nolan
A1 B. S. Selinsky
A1 D. J. Fitzgerald
YR 2001
UL http://molpharm.aspetjournals.org/content/60/6/1407.abstract
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.