Disease relevance of CaO19.12645

• The 2.1- and 2.2-A crystal structures reported here for 4-phenylimidazole- and fluconazole-bound CYP51 from Mycobacterium tuberculosis (MTCYP51) are the first structures of an authentic P450 drug target [1].
• Inhibitors of CYP51 include triazole antifungal agents fluconazole and itraconazole, drugs used in treatment of topical and systemic mycoses [1].
• The Saccharomyces cerevisiae cytochrome P450 L1A1 (lanosterol 14 alpha-demethylase)-coding gene was used as a hybridization probe to isolate two HindIII fragments of 2.5 kb and 6.85 kb from a phage lambda library of Candida albicans nucleotide sequences [2].
• The tertiary structure of cytochrome P450 14 alpha demethylase--Candida albicans (P450 CA) is modeled on the basis of sequence alignment with two closely related proteins and the crystallographic structure of Pseudomonas putida P450cam [3].

High impact information on CaO19.12645

• Cytochrome P450 14alpha-sterol demethylases (CYP51) are essential enzymes in sterol biosynthesis in eukaryotes [1].
• CYP51 removes the 14alpha-methyl group from sterol precursors such as lanosterol, obtusifoliol, dihydrolanosterol, and 24(28)-methylene-24,25-dihydrolanosterol [1].
• Nucleotide sequence of cytochrome P450 L1A1 (lanosterol 14 alpha-demethylase) from Candida albicans [4].
• Three-dimensional models of wild-type and mutated forms of cytochrome P450 14alpha-sterol demethylases from Aspergillus fumigatus and Candida albicans provide insights into posaconazole binding [5].
• Mutations in and around the CYP51 active site have resulted in azole resistance [5].

Biological context of CaO19.12645

• We have undertaken site-directed mutation of C. albicans CYP51 to produce a recombinant mutant protein with the amino acid substitution R467K corresponding to a mutation observed clinically [6].
• Membrane fluidity alterations in a cytochrome P-450-deficient mutant of Candida albicans [7].
• These results suggest that a cytochrome P450 lesion in these yeasts have different phenotypes and may reflect different sterol requirements for the two organisms [8].
• CaALK8, an alkane assimilating cytochrome P450, confers multidrug resistance when expressed in a hypersensitive strain of Candida albicans [9].

Anatomical context of CaO19.12645

• Comparing the carbon monoxide difference spectra of microsomes from C. krusei with those of microsomes from C. albicans indicated that the total cytochrome P-450 content of C. krusei is similar to that of C. albicans [10].
• The C-14 alpha-desmethylase system in yeast cell membranes is cytochrome P-450 associated [11].
• Furthermore, terconazole reduced cytochrome P-450 levels in yeast microsomes at concentrations 10,000-fold below those at which it showed effects on rabbit liver microsomes [11].

Associations of CaO19.12645 with chemical compounds

• Mapping mutations identified in Candida albicans azole-resistant isolates indicates that azole resistance in fungi develops in protein regions involved in orchestrating passage of CYP51 through different conformational stages along the catalytic cycle rather than in residues directly contacting fluconazole [1].
• Since the widely accepted primary effect of imidazoles is the inhibition of cytochrome P-450-mediated demethylation of the ergosterol precursor lanosterol, strain D10 and its wild-type revertant, strain D10R, were grown in the presence of concentrations of clotrimazole, miconazole, and ketoconazole known to inhibit demethylation [12].
• Cytochrome P-450-dependent 14 alpha-demethylation of lanosterol in Candida albicans [13].
• Strong antifungal activity of SS750, a new triazole derivative, is based on its selective binding affinity to cytochrome P450 of fungi [14].
• A cytochrome P-450-deficient mutant of Candida albicans, strain D10, was employed to study the mode of action of imidazole antifungal agents [12].

Other interactions of CaO19.12645

• Unexpectedly, we also found that the two cytochrome genes, CYB5 encoding cytochrome b5 and NCP1 encoding the cytochrome P450 reductase, were not regulated markedly different from wild-type in the erg2, erg3, erg6, erg11 and erg24 strains of Candida albicans [15].

References