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Solving the Catalytic Mechanism of Tryptophan Synthase: an Emergent Drug Target in the Treatment of Tuberculosis
Author(s) -
Teixeira Carla S. Silva,
Ramos Maria J.,
Sousa Sérgio F.,
Cerqueira Nuno M. F. S. A.
Publication year - 2020
Publication title -
chemcatchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.497
H-Index - 106
eISSN - 1867-3899
pISSN - 1867-3880
DOI - 10.1002/cctc.201901505
Subject(s) - enzyme , tryptophan synthase , tuberculosis , mechanism (biology) , catalysis , tryptophan , chemistry , combinatorial chemistry , atp synthase , drug target , drug , biochemistry , stereochemistry , computational biology , biology , pharmacology , medicine , physics , amino acid , pathology , quantum mechanics
Tryptophan Synthase (TSase) is an emergent therapeutic target in the treatment of tuberculosis. Interest in TSase as a drug target arose from the fact that this enzyme is not present in humans, while in bacteria, like M. tuberculosis , it catalyses the last two steps in the tryptophan biosynthetic pathway. Several inhibitors of TSase have recently been developed, with promising results. However, the exact catalytic mechanism of this enzyme has remained unexplained at the atomic level. The fact that TSase is a multifunctional enzyme, with two dimers, each one with two independent active sites, interconnected by a 25 Å tunnel, has made it a challenging enzyme, from the catalytic point of view. QM/MM calculations were used to analyze and explain the two steps catalyzed by this enzyme. The results provide an atomic‐level clarification of the full catalytic mechanism of this enzyme, offering also important clues for the development of new inhibitors against tuberculosis.