Oxygen Activation by the Noncoupled Binuclear Copper Site in Peptidylglycine α-Hydroxylating Monooxygenase. Reaction Mechanism and Role of the Noncoupled Nature of the Active Site
- 20 March 2004
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of the American Chemical Society
- Vol. 126 (15), 4991-5000
- https://doi.org/10.1021/ja031564g
Abstract
Reaction thermodynamics and potential energy surfaces are calculated using density functional methods to investigate possible reactive Cu/O2 species for H-atom abstraction in peptidylglycine α-hydroxylating monooxygenase (PHM), which has a noncoupled binuclear Cu active site. Two possible mononuclear Cu/O2 species have been evaluated, the 2-electron reduced CuIIM−OOH intermediate and the 1-electron reduced side-on CuIIM−superoxo intermediate, which could form with comparable thermodynamics at the catalytic CuM site. The substrate H-atom abstraction reaction by the CuIIM−OOH intermediate is found to be thermodynamically accessible due to the contribution of the methionine ligand, but with a high activation barrier (∼37 kcal/mol, at a 3.0-Å active site/substrate distance), arguing against the CuIIM−OOH species as the reactive Cu/O2 intermediate in PHM. In contrast, H-atom abstraction from substrate by the side-on CuIIM−superoxo intermediate is a nearly isoenergetic process with a low reaction barrier at a comparable active site/substrate distance (∼14 kcal/mol), suggesting that side-on CuIIM−superoxo is the reactive species in PHM. The differential reactivities of the CuIIM−OOH and CuIIM−superoxo species correlate to their different frontier molecular orbitals involved in the H-atom abstraction reaction. After the H-atom abstraction, a reasonable pathway for substrate hydroxylation involves a “water-assisted” direct OH transfer to the substrate radical, which generates a high-energy CuIIM−oxyl species. This provides the necessary driving force for intramolecular electron transfer from the CuH site to complete the reaction in PHM. The differential reactivity pattern between the CuIIM−OOH and CuIIM−superoxo intermediates provides insight into the role of the noncoupled nature of PHM and dopamine β-monooxygenase active sites, as compared to the coupled binuclear Cu active sites in hemocyanin, tyrosinase, and catechol oxidase, in O2 activation.Keywords
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