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Titolo:
THE INTERACTION OF ARGININE-106 OF HUMAN PROSTAGLANDIN G H SYNTHASE-2WITH INHIBITORS IS NOT A UNIVERSAL COMPONENT OF INHIBITION MEDIATED BY NONSTEROIDAL ANTIINFLAMMATORY DRUGS/
Autore:
GREIG GM; FRANCIS DA; FALGUEYRET JP; OUELLET M; PERCIVAL MD; ROY P; BAYLY C; MANCINI JA; ONEILL GP;
Indirizzi:
MERCK FROSST CTR THERAPEUT RES,DEPT BIOCHEM & MOL BIOL,POB 1005 POINTE CLAIRE PQ H9R 4P8 CANADA MERCK FROSST CTR THERAPEUT RES,DEPT BIOCHEM & MOL BIOL POINTE CLAIRE PQ H9R 4P8 CANADA MERCK FROSST CTR THERAPEUT RES,DEPT MED CHEM POINTE CLAIRE PQ H9R 4P8CANADA
Titolo Testata:
Molecular pharmacology
fascicolo: 5, volume: 52, anno: 1997,
pagine: 829 - 838
SICI:
0026-895X(1997)52:5<829:TIOAOH>2.0.ZU;2-J
Fonte:
ISI
Lingua:
ENG
Soggetto:
SELECTIVE-INHIBITION; ANTIINFLAMMATORY DRUGS; CRYSTAL-STRUCTURE; CYCLOOXYGENASE; ASPIRIN; ACID; PURIFICATION; BIOSYNTHESIS; EXPRESSION; MECHANISM;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
39
Recensione:
Indirizzi per estratti:
Citazione:
G.M. Greig et al., "THE INTERACTION OF ARGININE-106 OF HUMAN PROSTAGLANDIN G H SYNTHASE-2WITH INHIBITORS IS NOT A UNIVERSAL COMPONENT OF INHIBITION MEDIATED BY NONSTEROIDAL ANTIINFLAMMATORY DRUGS/", Molecular pharmacology, 52(5), 1997, pp. 829-838

Abstract

The three-dimensional cocrystal structures of ovine prostaglandin G/Hsynthase-1 (PGHS-1) with S-flurbiprofen and murine PGHS-2 with S-flurbiprofen and indomethacin reveal that the carboxylate acid groups of these nonsteroidal anti-inflammatory drugs (NSAIDs) form a salt bridge with the guanidinium group of Arg120 in PGHS-1 and Arg106 in PGHS-2. Mutagenesis studies confirmed that the Arg120 residue of PGHS-1 is critical for binding of substrate and inhibitors through ionic interactions of its guanidinium group with the carboxylate moieties of arachidonic acid and certain NSAIDs. We report here that the analogous R106E substitution in human PGHS-2 results in a catalytically active enzyme with a 30-fold higher K-m value for arachidonic acid. Comparison of the inhibition of hPGHS-2(R106E) with wild-type hPGHS-2 by 11 structurally diverse selective and nonselective PGHS inhibitors revealed a 0-1000-fold decrease in inhibitory potency on the mutant enzyme. The loss of inhibitory potency of NSAIDs on hPGHS-2(R106E) could not be correlated with the presence or absence of a carboxylate functional group in the inhibitor, as was demonstrated previously for the PGHS-1(R120E) mutant, or with the selective or nonselective nature of the PGHS inhibitor. The decreases in the inhibitory potencies on hPGHS-2(R106E) by the carboxylate-containing NSAIDs flurbiprofen, indomethacin, meclofenamic acid, and diclofenac on hPGHS-2(R106E) were 965-, 48-, 5.5-, and 4.5-fold, respectively. The nonuniversal requirement for interaction of the carboxylate group of certain NSAIDs with the Arg106 residue in hPGHS-2 is supported by the observation that the methyl ester derivative of indomethacin was a more potent inhibitor than indomethacin on both hPGHS-2 and hPGHS-2(R106E). The greatest loss of potency for inhibition of hPGHS-2(R106E) was observed with the hPGHS-2-selective sulfonamide-containing inhibitors NS-398 and flosulide. The PGHS-2-selective inhibitor DuP697 and a desbromo-sulfonamide analogue of DuP697 displayed equivalent potency on hPGHS-2(R106E) and hPGHS-2. The change in inhibitory potency of NS-398 on hPGHS-2(R106E) was due to a difference in the kinetics of inhibition, with NS-398 displaying time-dependent inhibition of hPGHS-2 but time-independent inhibition of PGHS-2(R106E). The time-dependent inhibition of hPGHS-2 by DuP697 was not affected by the presence of the R106E mutation. We conclude that the Arg106 residue of hPGHS-2 is involved in binding arachidonic acid and certain NSAIDs, but interactions with Arg106 are not a universal requirement for inhibitionby either carboxylate-containing NSAIDs or PGHS-2-selective inhibitors.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 22/10/20 alle ore 03:24:46