The Catalytic Mechanism of the Pyridoxal-5 '-phosphate-Dependent Enzyme, Histidine Decarboxylase: A Computational Study

• Type: Article in International Scientific Journal
• Date: 2017

Authors

Fernandes, HS (Author) Other; Ramos, MJ (Author) FCUP; Nuno M F S A Cerqueira (Author) FCUP

Journal

Title: Chemistry - A European Journal

Vol. 23

Pages: 9162-9173

ISSN: 0947-6539

Publisher: Wiley-Blackwell

Indexing

ISI Web of Knowledge - 13 Citations

Other information

Authenticus ID: P-00M-V9H

DOI: 10.1002/chem.201701375

Abstract (EN): The catalytic mechanism of histidine decarboxylase (HDC), a pyridoxal-5'-phosphate (PLP)-dependent enzyme, was studied by using a computational QM/MM approach following the scheme M06-2X/6-311++ G(3df,2pd): Amber. The reaction involves two sequential steps: the decarboxylation of l-histidine and the protonation of the generated intermediate from which results histamine. The rate-limiting step is the first one (Delta G* = 17.6 kcal mol(-1); Delta G(r)= 13.7 kcal mol(-1)) and agrees closely with the available experimental kcat (1.73 s(-1)), which corresponds to an activa-tion barrier of 17.9 kcal mol(-1). In contrast, the second step is very fast (Delta G* = 1.9 kcalmol(-1)) and exergonic (Delta G(r)= -33.2 kcal mol(-1)). Our results agree with the available experimental data and allow us to explain the role played by several active site residues that are considered relevant according to site-directed mutagenesis studies, namely Tyr334B, Asp273A, Lys305A, and Ser354B. These results can provide insights regarding the catalytic mechanism of other enzymes belonging to family II of PLP-dependent decarboxylases.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 12