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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Podust, L. M. Poulos, T. L. Waterman, M. R. |
| Description | Author Affiliation: Podust LM ( Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232-0146, USA. podustlm@ctrvax.vanderbilt.edu); |
| Abstract | Cytochrome P450 14alpha-sterol demethylases (CYP51) are essential enzymes in sterol biosynthesis in eukaryotes. CYP51 removes the 14alpha-methyl group from sterol precursors such as lanosterol, obtusifoliol, dihydrolanosterol, and 24(28)-methylene-24,25-dihydrolanosterol. Inhibitors of CYP51 include triazole antifungal agents fluconazole and itraconazole, drugs used in treatment of topical and systemic mycoses. 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. MTCYP51 exhibits the P450 fold with the exception of two striking differences-a bent I helix and an open conformation of BC loop-that define an active site-access channel running along the heme plane perpendicular to the direction observed for the substrate entry in P450BM3. Although a channel analogous to that in P450BM3 is evident also in MTCYP51, it is not open at the surface. The presence of two different channels, with one being open to the surface, suggests the possibility of conformationally regulated substrate-in/product-out openings in CYP51. 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. These new structures provide a basis for rational design of new, more efficacious antifungal agents as well as insight into the molecular mechanism of P450 catalysis. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 6 |
| Volume Number | 98 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2001-03-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Antifungal Agents Chemistry Cytochrome P-450 Enzyme System Enzyme Inhibitors Fluconazole Imidazoles Oxidoreductases Amino Acid Sequence Pharmacology Candida Albicans Drug Effects Enzymology Crystallography, X-Ray Cytochrome P-450 Enzyme Inhibitors Drug Resistance, Microbial Molecular Sequence Data Mycobacterium Tuberculosis Antagonists & Inhibitors Peptide Mapping Protein Structure, Tertiary Sterol 14-Demethylase Substrate Specificity Research Support, U.S. Gov't, P.H.S. Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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