Copper monooxygenase reactivity: Do consensus mechanisms accurately reflect experimental observations?

Evan F. Welch, Katherine W. Rush, Renee J. Arias, Ninian J. Blackburn

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


An important question is whether consensus mechanisms for copper monooxygenase enzymes such as peptidylglycine monooxygenase (PHM) and dopamine β-monooxygenase (DBM) generated via computational and spectroscopic approaches account for important experimental observations. We examine this question in the light of recent crystallographic and QMMM reports which suggest that alternative mechanisms involving an open to closed conformational cycle may be more representative of a number of experimental findings that remain unaccounted for in the canonical mononuclear mechanisms. These include (i) the almost negligible reactivity of the catalytic copper site (CuM) with oxygen in the absence of substrate, (ii) the carbonyl chemistry and in particular the substrate-induced activation exemplified by the lowered CO stretching frequency, (iii) the peroxide shunt chemistry which demands an intermediate that facilitates equilibrium between a Cu(II)-peroxo state and a Cu(I)-dioxygen state, and (iv) clear evidence for both closed and open conformational states in both PHM and DBM. An alternative mechanism involving a dinuclear copper intermediate formed via an open to closed conformational transition appears better able to accommodate these experimental observations, as well as being shown by QMMM methodologies to be energetically feasible. This suggests that future experiments should be designed to distinguish between these competing mechanisms and the factors that govern the oxygen reactivity of the copper centers. In particular, determining how oxygen reactivity is activated by binding of substrate, should be considered an important new challenge.

Original languageEnglish (US)
Article number111780
JournalJournal of Inorganic Biochemistry
StatePublished - Jun 2022


  • Copper
  • DBM
  • Dinuclear copper
  • Dopamine
  • Mononuclear copper
  • Monooxygenase
  • Oxygen
  • PHM
  • Peptidylglycine
  • Superoxide

ASJC Scopus subject areas

  • Biochemistry
  • Inorganic Chemistry


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