title: Evolutionary trace analysis of CYP51 family: implication for site-directed mutagenesis and novel antifungal drug design.
abstract: Lanosterol 14alpha-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.
authors: School of Pharmacy, Military Key Laboratory of Medicinal Chemistry, Second Military Medical University, Shanghai, People's Republic of China.
authors: Chunquan
authors: C
authors: Sheng
authors: Shuanghong
authors: S
authors: Chen
authors: Haitao
authors: H
authors: Ji
authors: Guoqiang
authors: G
authors: Dong
authors: Xiaoyin
authors: X
authors: Che
authors: Wenya
authors: W
authors: Wang
authors: Zhenyuan
authors: Z
authors: Miao
authors: Jianzhong
authors: J
authors: Yao
authors: Jiaguo
authors: J
authors: Lü
authors: Wei
authors: W
authors: Guo
authors: Wannian
authors: W
authors: Zhang
mesh_terms: D000935:Antifungal Agents; D002176:Candida albicans / Q000201:enzymology* / Q000235:genetics; D020134:Catalytic Domain / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D015195:Drug Design; D019143:Evolution, Molecular; D005656:Fungal Proteins / Q000235:genetics*; D016297:Mutagenesis, Site-Directed
chemical_list: D000935:Antifungal Agents; D005656:Fungal Proteins; C465525:cytochrome P-450 CYP51, Candida albicans; D003577:Cytochrome P-450 Enzyme System