Reaction Mechanism of Mycobacterium Tuberculosis Glutamine Synthetase Using Quantum Mechanics/Molecular Mechanics Calculations

• Type: Article in International Scientific Journal
• Date: 2016

Authors

Moreira, C (Author) Other; Ramos, MJ (Author) FCUP; Pedro A Fernandes (Author) FCUP

Journal

Title: Chemistry - A European Journal

Vol. 22

Pages: 9218-9225

ISSN: 0947-6539

Publisher: Wiley-Blackwell

Indexing

ISI Web of Knowledge - 20 Citations

Scopus - 21 Citations

Other information

Authenticus ID: P-00K-QX2

DOI: 10.1002/chem.201600305

Abstract (EN): This paper is devoted to the understanding of the reaction mechanism of mycobacterium tuberculosis glutamine synthetase (mtGS) with atomic detail, using computational quantum mechanics/molecular mechanics (QM/MM) methods at the ONIOM M06-D3/6-311++G(2d,2p):ff99SB//B3LYP/6-31G(d):ff99SB level of theory. The complete reaction undergoes a three-step mechanism: the spontaneous transfer of phosphate from ATP to glutamate upon ammonium binding (ammonium quickly loses a proton to Asp54), the attack of ammonia on phosphorylated glutamate (yielding protonated glutamine), and the deprotonation of glutamine by the leaving phosphate. This exothermic reaction has an activation free energy of 21.5 kcal mol(-1), which is consistent with that described for Escherichia coli glutamine synthetase (15-17 kcal mol(-1)). The participating active site residues have been identified and their role and energy contributions clarified. This study provides an insightful atomic description of the biosynthetic reaction that takes place in this enzyme, opening doors for more accurate studies for developing new anti-tuberculosis therapies.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 8