The Catalytic Mechanism of the Marine-Derived Macrocyclase PatGmac

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

Autores

Natercia F Bras (Autor) FCUP; Ferreira, P (Autor) Outra; Calixto, AR (Autor) Outra; Jaspars, M (Autor) Outra; Houssen, W (Autor) Outra; Naismith, JH (Autor) Outra; Pedro A Fernandes (Autor) FCUP; Ramos, MJ (Autor) FCUP

Revista

Título: Chemistry - A European Journal

Vol. 22

ISSN: 0947-6539

Editora: Wiley-Blackwell

Indexação

ISI Web of Knowledge - 14 Citações

Scopus - 15 Citações

Outras Informações

ID Authenticus: P-00M-3BH

DOI: 10.1002/chem.201601670

Abstract (EN): Cyclic peptides are a class of compounds with high therapeutic potential, possessing bioactivities including antitumor and antiviral (including anti-HIV). Despite their desirability, efficient design and production of these compounds has not been achieved to date. The catalytic mechanism of patellamide macrocyclization by the PatG macrocyclase domain has been computationally investigated by using quantum mechanics/molecular mechanics methodology, specifically ONIOM(M06/6-311++G(2d,2p):ff94//B3LYP/6-31G(d):ff94). The mechanism proposed herein begins with a proton transfer from Ser783 to His 618 and from the latter to Asp548. Nucleophilic attack of Ser783 on the substrate leads to the formation of an acyl-enzyme covalent complex. The leaving group Ala-Tyr-Asp-Gly (AYDG) of the substrate is protonated by the substrate's N terminus, leading to the breakage of the P1-P1' bond. Finally, the substrate's N terminus attacks the P1 residue, decomposing the acyl-enzyme complex forming the macrocycle. The formation and decomposition of the acyl-enzyme complex have the highest activation free energies (21.1 kcal mol(-1) and 19.8 kcal mol(-1) respectively), typical of serine proteases. Understanding the mechanism behind the macrocyclization of patellamides will be important to the application of the enzymes in the pharmaceutical and biotechnological industries.

Idioma: Inglês

Tipo (Avaliação Docente): Científica

Nº de páginas: 9