Document Detail

The amino acid residues affecting the activity and azole susceptibility of rat CYP51 (sterol 14-demethylase P450).
MedLine Citation:
PMID:  11328599     Owner:  NLM     Status:  MEDLINE    
The amino acid residues affecting the function of rat sterol 14-demethylase P450 (CYP51) were examined by means of point mutation. Forty-five mutants with respect to 27 amino acid sites were constructed and expressed in Escherichia coli. Substitution of highly conserved Y131, E369, R372, or R382 decreased the expression of CYP51 protein, indicating some structural importance of these residues. Substitution of H314, T315, or S316 caused considerable effects on the catalytic activity, and T315 was identified as the "conserved threonine" of CYP51. H314 was important for maintenance of the activity of CYP51 and was a characteristic residue of this P450, because the position corresponding to this residue is occupied by an acidic amino acid in most other P450 species. A144 was identified as a residue affecting the interaction of CYP51 with ketoconazole. Substitution of A144 with I, which occupies the corresponding position in fungal CYP51, enhanced the ketoconazole susceptibility of rat CYP51 with little change in the catalytic activity, indicating an important role of this residue in determination of the ketoconazole susceptibility of CYP51. Alteration of the catalytic activity was caused by the substitution at some other sites, whereas substitution of a few highly conserved amino acids caused little alteration of the activity of CYP51.
Y Nitahara; K Kishimoto; Y Yabusaki; O Gotoh; Y Yoshida; T Horiuchi; Y Aoyama
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Journal of biochemistry     Volume:  129     ISSN:  0021-924X     ISO Abbreviation:  J. Biochem.     Publication Date:  2001 May 
Date Detail:
Created Date:  2001-04-30     Completed Date:  2001-10-04     Revised Date:  2010-04-06    
Medline Journal Info:
Nlm Unique ID:  0376600     Medline TA:  J Biochem     Country:  Japan    
Other Details:
Languages:  eng     Pagination:  761-8     Citation Subset:  IM    
Department of Bioengineering, Faculty of Engineering, Soka University, Hachioji, Tokyo 192-8577, Japan.
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MeSH Terms
Amino Acid Substitution / genetics,  physiology
Azoles / metabolism,  pharmacology*
Computer Simulation
Conserved Sequence / genetics,  physiology
Cytochrome P-450 Enzyme System / drug effects*,  genetics*,  metabolism
Enzyme Activation / genetics,  physiology
Isoleucine / genetics*,  metabolism
Models, Molecular
Oxidoreductases / drug effects*,  genetics*,  metabolism
Point Mutation / genetics*,  physiology
Protein Structure, Tertiary
Sequence Alignment
Reg. No./Substance:
0/Azoles; 73-32-5/Isoleucine; 9035-51-2/Cytochrome P-450 Enzyme System; EC 1.-/Oxidoreductases; EC 14-demethylase

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