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- Title
Reaction Mechanism of Mycobacterium Tuberculosis Glutamine Synthetase Using Quantum Mechanics/Molecular Mechanics Calculations.
- Authors
Moreira, Cátia; Ramos, Maria J.; Fernandes, Pedro Alexandrino
- Abstract
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.
- Subjects
MYCOBACTERIUM tuberculosis; MYCOBACTERIOSIS; GLUTAMINE synthetase; LIGASES; CHEMICAL reactions
- Publication
Chemistry - A European Journal, 2016, Vol 22, Issue 27, p9218
- ISSN
0947-6539
- Publication type
Article
- DOI
10.1002/chem.201600305