title: Sequence variation in CYP51A from the Y strain of Trypanosoma cruzi alters its sensitivity to inhibition.
abstract: CYP51 (sterol 14α-demethylase) is an efficient target for clinical and agricultural antifungals and an emerging target for treatment of Chagas disease, the infection that is caused by multiple strains of a protozoan pathogen Trypanosoma cruzi. Here, we analyze CYP51A from the Y strain T. cruzi. In this protein, proline 355, a residue highly conserved across the CYP51 family, is replaced with serine. The purified enzyme retains its catalytic activity, yet has been found less susceptible to inhibition. These biochemical data are consistent with cellular experiments, both in insect and human stages of the pathogen. Comparative structural analysis of CYP51 complexes with VNI and two derivatives suggests that broad-spectrum CYP51 inhibitors are likely to be preferable as antichagasic drug candidates.
authors.affiliation: Institute of Bioorganic Chemistry National Academy of Sciences of Belarus, Minsk 220141, Belarus.
authors.forename: Tatiana S
authors.initials: TS
authors.lastname: Cherkesova
authors.affiliation: Department of Biochemistry School of Medicine, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Tatiana Y
authors.initials: TY
authors.lastname: Hargrove
authors.affiliation: Instituto de Histología y Embriología (IHEM-CONICET), Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Mendoza 5500, Argentina.
authors.forename: M Cristina
authors.initials: MC
authors.lastname: Vanrell
authors.affiliation: Department of Biomedical Engineering School of Engineering, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Igor
authors.initials: I
authors.lastname: Ges
authors.affiliation: Institute of Bioorganic Chemistry National Academy of Sciences of Belarus, Minsk 220141, Belarus.
authors.forename: Sergey A
authors.initials: SA
authors.lastname: Usanov
authors.affiliation: Instituto de Histología y Embriología (IHEM-CONICET), Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Mendoza 5500, Argentina.
authors.forename: Patricia S
authors.initials: PS
authors.lastname: Romano
authors.affiliation: Department of Biochemistry School of Medicine, Vanderbilt University, Nashville, TN 37232, USA; Center for Structural Biology, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: galina.i.lepesheva@vanderbilt.edu.
authors.forename: Galina I
authors.initials: GI
authors.lastname: Lepesheva
mesh_terms: D058888:14-alpha Demethylase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D055162:Biocatalysis; D014355:Chagas Disease / Q000188:drug therapy / Q000201:enzymology; D017124:Conserved Sequence; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000201:enzymology*
chemical_list: D058888:14-alpha Demethylase Inhibitors; D003577:Cytochrome P-450 Enzyme System
keywords: CYP51 sequence variation; Drug resistance; Sterol 14α-demethylase; Structure-based drug design; Trypanosoma cruzi