Evidence for an N-halohistidyl Intermediate in the Catalytic Cycle of Vanadium Chloroperoxidase (VCPO) and an Artificial Enzyme derived from VCPO: A Computational Investigation

Vanadium haloperoxidases play an important catalytic role in the natural production of antibiotics which are difficult to make in the laboratory. Understanding the catalytic mechanism of these enzymes will aide in the production of artificial enzymes useful in bioengineering the synthesis of drugs and useful chemicals. However, the catalytic mechanism remains not fully understood yet. In this paper, we investigate one of the key steps of the catalytic mechanism using QM/MM. Our investigation reveals a new N-haloxy histidyl intermediate in the catalytic cycle of vanadium chloroperoxidase (VCPO). This new intermediate, in turn, yields an explanation for the known inhibition of the enzyme by substrate under acidic conditions (pH<4). Additionally, we examine the possibility of replacing V in VCPO by Nb or Ta using QM modeling. We report the new result that the Gibbs free energy barrier of several steps of the catalytic cycle are lower in the case of artificial enzymes, incorporating NbO43- or TaO43- instead of VO43-. Our results suggest that these new artificial enzymes may catalyze the oxidation of halide faster than the natural enzyme.