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

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.