Modelamiento computacional de la enzima acetohidroxiácido sintasa (AHAS) de Mycobacterium tuberculosis

Abstract

Tuberculosis is a disease caused by the pathogen Mycobacterium tuberculosis. It annually produces millions of deaths worldwide. The severity of this condition is caused by the progressive appearance of multidrug resistant strains (MDR-TB) and extensively drug resistant tuberculosis (XDR-TB). For this reason, it is common to use long treatments that produce unwanted effects in patients. Given the lack of effective and well tolerated drugs to treat tuberculosis, it is necessary to investigate new targets which will slow down the spread of the pathogen. The enzyme acetohydroxyacid synthase (AHAS) is amongst the most promising targets. AHAS is the first enzyme in the branched chain amino acid biosynthetic pathway (BCAAs). It has been already shown that AHAS is crucial for the survival of Arabidopsis thaliana, Candida albicans, Saccharomyces cerevisiae, and other organisms. Here, a model of Mycobacterium tuberculosis AHAS complex was obtained using the Swiss-Model. The model was derived from its closest structure, S. cerevisiae AHAS. The MtAHAS complex exhibited the same structural features described previously for AtAHAS and ScAHAS, including its resemblance to the Maltese cross. The interactions with cofactors and the most important motifs involved in the inhibition with methyl metsulfuron were elucidated using the software WinCoot and LigPlot. The hexadecameric complex of MtAHAS generated provides a platform for the rational design of enzyme inhibitors for the effective treatment of different strains of Mycobacterium tuberculosis.