The Catalytic Mechanism of Carboxylesterases: A Computational Study

• Type: Article in International Scientific Journal
• Date: 2014

Authors

Aranda, J (Author) Other; Cerqueira, NMFSA (Author) Other; Fernandes, PA (Author) FCUP; Roca, M (Author) Other; Tunon, I (Author) Other; Ramos, MJ (Author) FCUP

Journal

Title: Biochemistry

Vol. 53

Pages: 5820-5829

ISSN: 0006-2960

Publisher: American Chemical Society

Indexing

ISI Web of Knowledge - 26 Citations

Scopus - 26 Citations

Scientific classification

FOS: Natural sciences > Biological sciences

Other information

Authenticus ID: P-009-V33

DOI: 10.1021/bi500934j

Abstract (EN): The catalytic mechanism of carboxylesterases (CEs, EC 3.1.1.1) is explored by computational means. CEs hydrolyze ester, amide, and carbamate bonds found in xenobiotics and endobiotics. They can also perform transesterification, a reaction important, for instance, in cholesterol homeostasis. The catalytic mechanisms with three different substrates (ester, thioester, and amide) have been established at the M06-2X/6-311++G**//B3LYP/6-31G* level of theory. It was found that the reactions proceed through a mechanism involving four steps instead of two as is generally proposed: (i) nucleophilic attack of serine to the substrate, forming the first tetrahedral intermediate, (ii) formation of the acylenzyme complex concomitant with the release of the alcohol product, (iii) nucleophilic attack of a water or alcohol molecule forming the second tetrahedral intermediate, and (iv) the release of the second product of the reaction. The results agree very well with the available experimental data and show that the hydrolytic and the transesterification reactions are competitive processes when the substrate is an ester. In all the other studied substrates (thioester or amide), the hydrolytic and transesterification process are less favorable and some of them might not even take place under in vivo conditions.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 10