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 p...

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Bibliographic Details
Published in:Chemistry : a European journal 2017-07, Vol.23 (38), p.9162-9173
Main Authors: Fernandes, Henrique Silva, Ramos, Maria João, Cerqueira, Nuno M. F. S. A.
Format: Article
Language:English
Subjects:
Amber
Amino Acid Sequence
Catalysis
Catalytic Domain
Chemistry
Computation
computational chemistry
Computer applications
Decarboxylation
enzyme catalysis
Enzymes
Experimental data
Histamine
Histidine
Histidine decarboxylase
Histidine Decarboxylase - chemistry
Kinetics
Molecular Dynamics Simulation
Mutagenesis, Site-Directed
Phosphates
Protein Binding
Protein Conformation
Protonation
Pyridoxal Phosphate - chemistry
reaction mechanisms
Residues
Site-directed mutagenesis
Thermodynamics
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Summary: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.
ISSN:0947-6539
1521-3765
DOI:10.1002/chem.201701375