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Titolo:
Molecular basis of P450 inhibition and activation - Implications for drug development and drug therapy
Autore:
Szklarz, GD; Halpert, JR;
Indirizzi:
Univ Texas, Med Branch, Dept Pharmacol & Toxicol, Galveston, TX 77555 USA Univ Texas Galveston TX USA 77555 acol & Toxicol, Galveston, TX 77555 USA W Virginia Univ, Dept Basic Pharmaceut Sci, Morgantown, WV 26506 USA W Virginia Univ Morgantown WV USA 26506 eut Sci, Morgantown, WV 26506 USA
Titolo Testata:
DRUG METABOLISM AND DISPOSITION
fascicolo: 12, volume: 26, anno: 1998,
pagine: 1179 - 1184
SICI:
0090-9556(199812)26:12<1179:MBOPIA>2.0.ZU;2-B
Fonte:
ISI
Lingua:
ENG
Soggetto:
SITE-DIRECTED MUTAGENESIS; HUMAN CYTOCHROME-P450 3A4; CRYSTAL-STRUCTURE; DYNAMICS SIMULATION; 2B1; METABOLISM; SPECIFICITY; RESOLUTION; SEQUENCES; PRODUCT;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
25
Recensione:
Indirizzi per estratti:
Indirizzo: Halpert, JR Univ Texas, Med Branch, Dept Pharmacol & Toxicol, 301 Univ Blvd, Galveston, Univ Texas 301 Univ Blvd Galveston TX USA 77555 vd, Galveston,
Citazione:
G.D. Szklarz e J.R. Halpert, "Molecular basis of P450 inhibition and activation - Implications for drug development and drug therapy", DRUG META D, 26(12), 1998, pp. 1179-1184

Abstract

Three-dimensional homology models of cytochromes P450 (P450) 2B1 and P450 3A4 have been utilized along with site-directed mutagenesis to elucidate the molecular determinants of substrate specificity. Most of the key residuesidentified in 28 enzymes fall within five substrate recognition sites (SRSs) and have counterparts in bacterial P450 residues that regulate substratebinding or access. Docking of inhibitors into 28 models has provided a plausible explanation for changes in susceptibility to mechanism-based inactivation that accompany particular amino acid side-chain replacements. These studies provide a basis for predicting drug interactions due to P450 inhibition and for rational inhibitor design. In addition, the location of P450 3A4 residues capable of influencing homotropic stimulation by substrates and heterotropic stimulation by flavonoids has been identified. Steroid hydroxylation by the wild-type enzyme exhibits sigmoidal kinetics, indicative of positive cooperativity, Based on the 3A4 model and single-site mutants, a double mutant in SRS-P has been constructed that exhibits normal Michaelis-Menten kinetics. Results of modeling and mutagenesis studies suggest that thesubstrate and effector bind at adjacent sites within a single large cavityin P450 3A4. A thorough understanding of the location and structural requirements of the substrate-binding and effector sites in cytochrome P450 3A4 should prove valuable in rationalizing and predicting interactions among the multitude of drugs and other compounds that bind to the enzyme.

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Documento generato il 19/01/20 alle ore 12:20:09