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FEBS Lett. 2014 Nov 3;588(21):3878-85. doi: 10.1016/j.febslet.2014.08.030. Epub 2014 Sep 12.

Sequence variation in CYP51A from the Y strain of Trypanosoma cruzi alters its sensitivity to inhibition.

Author information

1
Institute of Bioorganic Chemistry National Academy of Sciences of Belarus, Minsk 220141, Belarus.
2
Department of Biochemistry School of Medicine, Vanderbilt University, Nashville, TN 37232, USA.
3
Instituto de Histología y Embriología (IHEM-CONICET), Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Mendoza 5500, Argentina.
4
Department of Biomedical Engineering School of Engineering, Vanderbilt University, Nashville, TN 37232, USA.
5
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.

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.

KEYWORDS:

CYP51 sequence variation; Drug resistance; Sterol 14α-demethylase; Structure-based drug design; Trypanosoma cruzi

PMID:
25217832
PMCID:
PMC4252588
DOI:
10.1016/j.febslet.2014.08.030
[Indexed for MEDLINE]
Free PMC Article

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