Utilize este identificador para referenciar este registo: http://hdl.handle.net/10284/3295
Título: Computational Characterization of the Substrate-Binding Mode in Coproporphyrinogen III Oxidase
Autor: Silva, Pedro J.
Ramos, Maria João
Palavras-chave: Molecular dynamics
Coproporphyrinogen III oxidase
Active site characterization
Data: 2011
Editora: American Chemical Society
Citação: Journal of Physical Chemistry B. ISSN 1520-6106. 115, 8 (2011) 1903-1910.
Relatório da Série N.º: Journal of Physical Chemistry B;115, 8
Resumo: 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.
Peer review: yes
URI: http://hdl.handle.net/10284/3295
ISSN: 1520-6106
Versão do Editor: The definitive version is available at: http://pubs.acs.org/doi/abs/10.1021/jp110289d/ A versão definitiva está disponível em: http://pubs.acs.org/doi/abs/10.1021/jp110289d
Aparece nas colecções:FCS - Artigos em Revistas Científicas Internacionais com Arbitragem Científica

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