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

• Tipo: Artigo em Revista Científica Internacional
• Data: 2016

Autores

Moreira, C (Autor) Outra; Ramos, MJ (Autor) FCUP; Pedro A Fernandes (Autor) FCUP

Revista

Título: Chemistry - A European Journal

Vol. 22

Páginas: 9218-9225

ISSN: 0947-6539

Editora: Wiley-Blackwell

Indexação

ISI Web of Knowledge - 20 Citações

Scopus - 21 Citações

Outras Informações

ID Authenticus: 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.

Idioma: Inglês

Tipo (Avaliação Docente): Científica

Nº de páginas: 8