Computational Mechanistic Studies Addressed to the Transimination Reaction Present in All Pyridoxal 5 '-Phosphate-Requiring Enzymes

• Tipo: Artigo em Revista Científica Internacional
• Data: 2011

Autores

Cerqueira, NMFSA (Autor) FCUP; Fernandes, PA (Autor) FCUP; Ramos, MJ (Autor) FCUP

Revista

Título: Journal of Chemical Theory and Computation

Vol. 7 Nº 4

Páginas: 1356-1368

ISSN: 1549-9618

Editora: American Chemical Society

Indexação

ISI Web of Knowledge - 47 Citações

Scopus - 45 Citações

Classificação Científica

FOS: Ciências exactas e naturais > Química

Outras Informações

ID Authenticus: P-002-RX0

DOI: 10.1021/ct1002219

Abstract (EN): The pyridoxal-5'-phosphate-dependent enzymes (PLP enzymes) catalyze a myriad of biochemical reactions, being actively involved in the biosynthesis of amino acids and amino acid-derived metabolites as well as in the biosynthetic pathways of amino sugars and in the synthesis or catabolism of neurotransmitters. Although the scope of PLP-catalyzed reactions initially appears to be bewilderingly diverse, there is a simple unifying principle: In the resting state, the cofactor (PLP) is covalently bonded to the amino group of an active site lysine, forming an internal aldimine. Once the amino substrate interacts with the active site, a new Schiff base is generated, commonly referred to as the external aldimine. Only after this step, the mechanistic pathway for each PLP-catalyzed reaction diverges. In this paper, density functional methods have been applied to investigate this common step present in all PLP-dependent enzymes-the transimination reaction. The results indicate that the reaction involves three sequential steps: (i) formation of a tetrahedral intermediate with the active site lysine and the amino substrate bonded to the PLP cofactor; (ii) nondirect proton transfer between the amino substrate and the lysine residue; and (iii) formation of the external aldimine after the dissociation of the lysine residue. The overall reaction is exothermic (-12.0 kcal/mol), and the rate-limiting step is the second one with 12.6 kcal/mol for the activation energy.

Idioma: Inglês

Tipo (Avaliação Docente): Científica

Nº de páginas: 13