QM/MM study on the O 2 activation reaction of 4-hydroxylphenyl pyruvate dioxygenase reveals a common mechanism for ?-ketoglutarate dependent dioxygenase

The dioxygen activation catalyzed by 4-hydorxylphenyl pyruvate dioxygenase (HPPD) were reinvesti-gated by using hybrid quantum mechanics/molecular mechanics (QM/MM) approaches at the B3LYP/6-311 ++ G(d,p):AMBER level. These studies showed that this reaction consisted of two steps including the dioxygen addition/decarboxylation and hetero O -O bond cleavage, where the first step was found to be rate-determining. The former step initially runs on a septet potential energy surface (PES), then switches to a quintet PES after crossing a septet/quintet minimum energy crossing point (MECP) 5-7 M2, whereas the rest step runs on the quintet PES. The reliability of our theoretical predictions is supported by the excellent agreement of the calculated free-energy barrier value of 16.9 kcal/mol with available experi-mental value of 16-17 kcal/mol. The present study challenges the widely accepted view which holds that the O 2 activation catalyzed by alpha-keto glutamate (alpha-KG) dioxygenase mainly runs on the quintet PES and provides new insight into the catalytic mechanism of alpha-KG dioxygenase and/or other related Fe(II)-dependent oxygenase.(c) 2023 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.