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

作者：Fernandes Henrique Silva; Ramos Maria Joao; Cerqueira Nuno M F S A^*

来源：Chemistry - A European Journal, 2017, 23(38): 9162-9173.

DOI：10.1002/chem.201701375

• computational chemistry
• enzyme catalysis
• histamine
• histidine decarboxylase
• reaction mechanisms

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.

• 出版日期2017-7-6