Solving the Catalytic Mechanism of Tryptophan Synthase: an Emergent Drug Target in the Treatment of Tuberculosis

• Type: Article in International Scientific Journal
• Date: 2020

Authors

Teixeira, CSS (Author) Other; Ramos, MJ (Author) FCUP; Sergio Filipe Sousa (Author) FCUP; Nuno M F S A Cerqueira (Author) FCUP

Journal

Title: ChemCatChem

Vol. 12 No. 4

Pages: 227-237

ISSN: 1867-3880

Publisher: Wiley-Blackwell

Indexing

ISI Web of Knowledge - 10 Citations

Scopus - 9 Citations

Other information

Authenticus ID: P-00R-935

DOI: 10.1002/cctc.201901505

Abstract (EN): 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 angstrom 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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 11