Mechanism of O2 activation and substrate hydroxylation in noncoupled binuclear copper monooxygenases.

Autor: Cowley RE; Department of Chemistry, Stanford University, Stanford, CA 94305., Tian L; Department of Chemistry, Stanford University, Stanford, CA 94305., Solomon EI; Department of Chemistry, Stanford University, Stanford, CA 94305; Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, Stanford University, Menlo Park, CA 94025 edward.solomon@stanford.edu.
Jazyk: angličtina
Zdroj: Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2016 Oct 25; Vol. 113 (43), pp. 12035-12040. Date of Electronic Publication: 2016 Oct 10.
DOI: 10.1073/pnas.1614807113
Abstrakt: Peptidylglycine α-hydroxylating monooxygenase (PHM) and dopamine β-monooxygenase (DβM) are copper-dependent enzymes that are vital for neurotransmitter regulation and hormone biosynthesis. These enzymes feature a unique active site consisting of two spatially separated (by 11 Å in PHM) and magnetically noncoupled copper centers that enables 1e - activation of O 2 for hydrogen atom abstraction (HAA) of substrate C-H bonds and subsequent hydroxylation. Although the structures of the resting enzymes are known, details of the hydroxylation mechanism and timing of long-range electron transfer (ET) are not clear. This study presents density-functional calculations of the full reaction coordinate, which demonstrate: (i) the importance of the end-on coordination of superoxide to Cu for HAA along the triplet spin surface; (ii) substrate radical rebound to a Cu II hydroperoxide favors the proximal, nonprotonated oxygen; and (iii) long-range ET can only occur at a late step with a large driving force, which serves to inhibit deleterious Fenton chemistry. The large inner-sphere reorganization energy at the ET site is used as a control mechanism to arrest premature ET and dictate the correct timing of ET.
Competing Interests: The authors declare no conflict of interest.
Databáze: MEDLINE
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