Theoretical studies on farnesyltransferase: Evidence for thioether product coordination to the active-site zinc sphere

• Type: Article in International Scientific Journal
• Date: 2007

Authors

Sergio Filipe Sousa (Author) Other; Pedro Alexandrino Fernandes (Author) FCUP; Maria Joao Ramos (Author) FCUP

Journal

Title: Journal of Computational Chemistry

Vol. 28

Pages: 1160-1168

ISSN: 0192-8651

Publisher: Wiley-Blackwell

Indexing

ISI Web of Knowledge - 32 Citations

Scopus - 34 Citations

Scientific classification

FOS: Natural sciences > Chemical sciences

Other information

Authenticus ID: P-004-ABP

DOI: 10.1002/jcc.20577

Abstract (EN): Farnesyltransferase (FTase), an interesting zinc metaloenzyme, has been the subject of great attention in anticancer research over the last decade. However, despite the major accomplishments in the field, some very pungent questions on the farnesylation mechanism still persist. In this study, the authors have analyzed a mechanistic paradox that arises from the existence of several contradicting and inconclusive experimental evidence regarding the existence of direct coordination between the active-site zinc cation and the thioether from the farnesylated peptide product, which include UV-vis spectroscopy data on a Co2+-substituted FTase, two X-ray crystallographic structures of the FTase-product complex, and extended X-ray absorption fine structure results. Using high-level theoretical calculations on two models of different sizes, and QM/MM calculations on the full enzyme, the authors have shown that the farnesylated product is Zn coordinated, and that a subsequent step where this Zn bond is broken is coherent with the available kinetic results. Furthermore, an explanation for the contradicting experimental evidence is suggested. (C) 2007 Wiley Periodicals, Inc.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 9