Computational Characterization of the Substrate-Binding Mode in Coproporphyrinogen III Oxidase

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

Autores

Pedro J Silva (Autor) Outra; Maria Joao Ramos (Autor) FCUP

Revista

Título: Journal of Physical Chemistry B

Vol. 115

Páginas: 1903-1910

ISSN: 1520-6106

Editora: American Chemical Society

Indexação

ISI Web of Knowledge - 7 Citações

Scopus - 5 Citações

Classificação Científica

FOS: Ciências exactas e naturais > Química

Outras Informações

ID Authenticus: P-002-TA8

DOI: 10.1021/jp110289d

Abstract (EN): Oxygen-dependent coproporphyrinogen III oxidase catalyzes the sequential decarboxylation of the propionate substituents present on the A and B rings of coproporphyrinogen III in the heme biosynthetic pathway. Although extensive experimental investigation of this enzyme has already afforded many insights into its reaction mechanism, several key features (such as the substrate binding mode, the characterization of the active site, and the initial substrate protonation state) remain poorly described. The molecular dynamics simulations described in this paper enabled the determination of a very promising substrate binding mode and the extensive characterization of the enzyme active site. The proposed binding mode is fully consistent with the known selectivity of the active site toward substituted tetrapyrroles and explains the lack of activity of the H131A, R135A, D274A, and R275A mutants and the reasons behind the nonoccurrence of catalysis on the C and D rings of the tetrapyrrole. An important role in this binding mode is fulfilled by G276, as its carbonyl oxygen intervenes in the substrate anchoring by hydrogen bonding its ring D pyrrole NH group. The presence of this interaction (which is only possible with the protonated NH pyrrole group) and the absence of positively charged side chains close to the pyrrole nitrogen (which might stabilize the N-deprotonated pyrrole postulated in some mechanistic proposals) show that the pyrrole ring is very unlikely to undergo deprotonation during the catalytic cycle and allow the discrimination between the previously postulated mechanistic proposals.

Idioma: Inglês

Tipo (Avaliação Docente): Científica

Nº de páginas: 8