3 years ago

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

The Catalytic Mechanism of the Pyridoxal-5′-phosphate-Dependent Enzyme, Histidine Decarboxylase: A Computational Study
Maria João Ramos, Henrique Silva Fernandes, Nuno M. F. S. A. Cerqueira
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 (ΔG≠=17.6 kcal mol−1; ΔGr=13.7 kcal mol−1) and agrees closely with the available experimental kcat (1.73 s−1), which corresponds to an activation barrier of 17.9 kcal mol−1. In contrast, the second step is very fast (ΔG≠=1.9 kcal mol−1) and exergonic (ΔGr=−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. Role model: The catalytic mechanism of histidine decarboxylase (HDC), a pyridoxal-5′-phosphate (PLP)-dependent enzyme, was studied by using a computational QM/MM approach. The results agree with the available experimental data and allow the role played by several active site residues that are considered relevant according to site-directed mutagenesis studies to be explained.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/chem.201701375

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