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

Area of Science:

• Biochemistry
• Enzymology
• Computational Chemistry

Background:

• Copper monooxygenase enzymes like peptidylglycine monooxygenase (PHM) and dopamine β-monooxygenase (DBM) play crucial roles in biological processes.
• Existing consensus mechanisms, often based on mononuclear copper sites, struggle to fully explain key experimental observations.

Purpose of the Study:

• To evaluate whether current consensus mechanisms for PHM and DBM adequately explain experimental findings.
• To investigate alternative mechanisms, particularly those involving conformational changes and dinuclear copper intermediates, that may better fit observed data.

Main Methods:

• Analysis of recent crystallographic and Quantum Mechanics/Molecular Mechanics (QMMM) reports.
• Comparison of experimental observations with predictions from canonical mononuclear mechanisms and proposed alternative mechanisms.

Main Results:

• Canonical mononuclear mechanisms fail to account for several experimental findings, including substrate-induced activation and distinct conformational states.
• An alternative mechanism involving a dinuclear copper intermediate, facilitated by an open-to-closed conformational transition, aligns better with experimental data.
• QMMM methodologies support the energetic feasibility of this alternative dinuclear mechanism.

Conclusions:

• The canonical mononuclear mechanisms for PHM and DBM are insufficient to explain all experimental observations.
• A mechanism involving a dinuclear copper intermediate and conformational cycling offers a more comprehensive explanation.
• Future research should focus on experimentally distinguishing between these competing mechanisms, especially regarding substrate-activated oxygen reactivity.