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Titolo:
Molecular modelling of lanosterol 14 alpha-demethylase (CYP51) from Saccharomyces cerevisiae via homology with CYP102, a unique bacterial cytochrome P450 isoform: Quantitative structure-activity relationships (QSARs) within two related series of antifungal azole derivatives
Autore:
Lewis, DFV; Wiseman, A; Tarbit, MH;
Indirizzi:
Univ Surrey, Sch Biol Sci, Guildford GU2 5XH, Surrey, England Univ SurreyGuildford Surrey England GU2 5XH ord GU2 5XH, Surrey, England Glaxo Wellcome Res & Dev Ltd, Ware SG12 0DP, Herts, England Glaxo WellcomeRes & Dev Ltd Ware Herts England SG12 0DP , Herts, England
Titolo Testata:
JOURNAL OF ENZYME INHIBITION
fascicolo: 3, volume: 14, anno: 1999,
pagine: 175 -
SICI:
8755-5093(1999)14:3<175:MMOL1A>2.0.ZU;2-Y
Fonte:
ISI
Lingua:
ENG
Soggetto:
MICROSOMAL CYTOCHROMES-P-450; CRYSTAL-STRUCTURE; AMINO-ACID; IMIDAZOLE; AGENTS; ITRACONAZOLE; BIOSYNTHESIS; DEMETHYLASE; INHIBITORS; SEQUENCES;
Keywords:
CYP51; lanosterol; 14 alpha-demethylase; inhibitors; QSAR; CYP102; antifungals; azole derivatives;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
45
Recensione:
Indirizzi per estratti:
Indirizzo: Lewis, DFV Univ Surrey, Sch Biol Sci, Guildford GU2 5XH, Surrey, England Univ Surrey Guildford Surrey England GU2 5XH , Surrey, England
Citazione:
D.F.V. Lewis et al., "Molecular modelling of lanosterol 14 alpha-demethylase (CYP51) from Saccharomyces cerevisiae via homology with CYP102, a unique bacterial cytochrome P450 isoform: Quantitative structure-activity relationships (QSARs) within two related series of antifungal azole derivatives", J ENZ INHIB, 14(3), 1999, pp. 175

Abstract

The construction of a three-dimensional molecular model of the fungal formof cytochrome P450 (CYP51) from Saccharomyces cerevisiae, based on homology with the haemoprotein domain of CYP102 from Bacillus megaterium (a uniquebacterial P450 of known crystal structure) is described. It is found that the endogenous substrate, lanosterol, can readily occupy the putative active site of the CYP51 model such that the known mono-oxygenation reaction, leading to C-14-demethylation of lanosterol, is the preferred route of metabolism for this particular substrate. Key amino acid contacts within the CYP51 active site appear to orientate lanosterol For oxidative attack at the C-14-methyl group, and the position of the substrate relative to the haem moiety is consistent with the pheny]-iron complexation studies reported by Tuck er ni. [J, Bioi. Chern., 267, 13175-13179 (1992)]. Typical azole inhibitors, such as ketoconazole, are able to fit the putative active site of CYP51by a combination of haem ligation, hydrogen bonding, pi-pi stacking and hydrophobic interactions within the enzyme's haem environment. The mode of action of azole antifungals, as described by the modelling studies, is supported by quantitative structure-activity relationship (QSAR) analyses on two groups of structurally related fungal inhibitors. Moreover, the results of molecular electrostatic isopotential (EIP) energy calculations are compatible with the proposed mode of binding between azole antifungal agents and the putative active site of CYP51, although membrane interactions may also have a rob in the antifungal activity of azole derivatives.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 31/03/20 alle ore 19:37:20