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Titolo:
THE CATALYTIC SITE OF CYTOCHROME P4504A11 (CYP4A11) AND ITS L131F MUTANT
Autore:
DIERKS EA; ZHANG ZP; JOHNSON EF; DEMONTELLANO PRO;
Indirizzi:
UNIV CALIF SAN FRANCISCO,SCH PHARM,DEPT PHARMACEUT CHEM SAN FRANCISCOCA 94143 UNIV CALIF SAN FRANCISCO,SCH PHARM,DEPT PHARMACEUT CHEM SAN FRANCISCOCA 94143 SCRIPPS CLIN & RES INST,DEPT MOL & EXPT MED LA JOLLA CA 92037
Titolo Testata:
The Journal of biological chemistry
fascicolo: 36, volume: 273, anno: 1998,
pagine: 23055 - 23061
SICI:
0021-9258(1998)273:36<23055:TCSOCP>2.0.ZU;2-W
Fonte:
ISI
Lingua:
ENG
Soggetto:
ACID OMEGA-HYDROXYLASE; CDNA-DIRECTED EXPRESSION; LAURIC ACID; HUMAN LIVER; 20-HYDROXYEICOSATETRAENOIC ACID; BACILLUS-MEGATERIUM; SEQUENCE ALIGNMENT; CODING NUCLEOTIDE; CRYSTAL-STRUCTURE; ESCHERICHIA-COLI;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
40
Recensione:
Indirizzi per estratti:
Citazione:
E.A. Dierks et al., "THE CATALYTIC SITE OF CYTOCHROME P4504A11 (CYP4A11) AND ITS L131F MUTANT", The Journal of biological chemistry, 273(36), 1998, pp. 23055-23061

Abstract

CYP4A11, the principal known human fatty acid omega-hydroxylase, has been expressed as a polyhistidine-tagged protein and purified to homogeneity, Based on an alignment with P450(BM-3), the CYP4A11 L131F mutant has been constructed and similarly expressed. The two proteins are spectroscopically indistinguishable, but wildtype CYP4A11 primarily catalyzes omega-hydroxylation, and the L131F mutant only omega-1 hydroxylation, of lauric acid. The L131F mutant is highly uncoupled in that itslowly (omega-1)-hydroxylates lauric acid yet consumes NADPH at approximately the same rate as the wild-type enzyme. Wild-type CYP4A11 is inactivated by 1-aminobenzotriazole under turnover conditions but the L131F mutant is not. This observation, in conjunction with the binding affinities of substituted imidazoles for the two proteins, indicates that the L131F mutation decreases access of exogenous substrates to theheme site. Leu-131 thus plays a key role in controlling the regioselectivity of substrate hydroxylation and the extent of coupled versus uncoupled enzyme turnover. A further important finding is that the substituted imidazoles bind more weakly to CYP4A11 and its L131F mutant when these proteins are reduced by NADPH-cytochrome P450 reductase than by dithionite. This finding suggests that the ferric enzyme undergoes aconformational change that depends on both reduction of the iron and the presence of cytochrome P450 reductase and NADPH.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 04/04/20 alle ore 08:43:47