Evolutionary trace analysis of CYP51 family: implication for site-directed mutagenesis and novel antifungal drug design

• Published in: Journal of molecular modeling 2010-02, Vol.16 (2), p.279-284
• Main Authors: Sheng, Chunquan, Chen, Shuanghong, Ji, Haitao, Dong, Guoqiang, Che, Xiaoyin, Wang, Wenya, Miao, Zhenyuan, Yao, Jianzhong, Lü, Jiaguo, Guo, Wei, Zhang, Wannian
• Format: Article
• Language: English
• Subjects: Antifungal Agents; Candida albicans - enzymology; Candida albicans - genetics; Catalytic Domain - genetics; Characterization and Evaluation of Materials; Chemistry; Chemistry and Materials Science; Computer Appl. in Life Sciences; Computer Applications in Chemistry; Cytochrome P-450 Enzyme System - genetics; Drug Design; Evolution, Molecular; Fungal Proteins - genetics; Molecular Medicine; Mutagenesis, Site-Directed; Original Paper; Theoretical and Computational Chemistry
• ISSN: 1610-2940; 0948-5023
• DOI: 10.1007/s00894-009-0527-9

Lanosterol 14α-demethylase (CYP51) is an essential enzyme in the fungal life cycle and also an important target for the antifungal drug development. Based on the multiple sequence alignments of CYP51 family, an evolutionary tree of the CYP51 family was constructed by the evolutionary trace (ET) method. The identified trace residues could provide a reliable and rational guide to the design of CYP51 mutations and give more information about the detailed mechanism of substrate (drug) recognition and binding. The reliability of ET analysis to identify residues of functional importance was validated by the reported site-directed mutagenesis studies of CYP51s. Several residues in the active site were also validated by our mutagenesis studies. Mapping the identified trace residues onto the active site of the modeled structure of Candida albicans CYP51 (CACYP51) may provide useful information for the design of novel antifungal agents.