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Interest in TSase as a drug target arose from the fact that this enzyme is not present in humans, while in bacteria, like <jats:italic>M. tuberculosis<\/jats:italic>, 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\u2005\u00c5 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. 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