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Sequence variation in CYP51A from the Y strain of Trypanosoma cruzi alters its sensitivity to inhibition
Author(s) -
Cherkesova Tatiana S.,
Hargrove Tatiana Y.,
Vanrell M. Cristina,
Ges Igor,
Usanov Sergey A.,
Romano Patricia S.,
Lepesheva Galina I.
Publication year - 2014
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2014.08.030
Subject(s) - trypanosoma cruzi , strain (injury) , sensitivity (control systems) , chemistry , variation (astronomy) , microbiology and biotechnology , biology , biophysics , stereochemistry , anatomy , parasite hosting , physics , engineering , world wide web , computer science , electronic engineering , astrophysics
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.