Reaction Mechanism of the Bicopper Enzyme Peptidylglycine α-Hydroxylating Monooxygenase

Abad, E.; Rommel, Judith B.; Kästner, Johannes

doi:10.1074/jbc.m114.558494

Cited by 34 publications

(39 citation statements)

References 61 publications

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“…The relationship between copper-ligation and E S or S S reactivity requires elucidation. An intriguing point for consideration of monocopper O 2 -chemistry is that a new computational study [71] suggests that the reactive species in PHM is a [Cu II -O 2 •− (H)] 2+ entity, i.e., with a protonated superoxide. HO 2 (aq) is a much stronger HAT reagent than is O 2 •− anion [64].…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

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Elaboration of copper–oxygen mediated C–H activation chemistry in consideration of future fuel and feedstock generation

Lee

Karlin

2015

Current Opinion in Chemical Biology

108

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To contribute solutions for current energy concerns, improvements in the efficiency of C-H bond cleavage chemistry, e.g., selective oxidation of methane to methanol, could minimize losses in natural gas usage or produce feedstocks for fuels. Oxidative C-H activation is also a component of polysaccharide degradation, affording alternative biofuels from abundant biomass. Thus, an understanding of active-site chemistry in copper monooxygenases, those activating strong C-H bonds is briefly reviewed. Then, recent advances in the synthesis-generation and study of various copper-oxygen intermediates are highlighted. Of special interest are cupric-superoxide, Cu-hydroperoxo and Cu-oxy complexes. Such investigations can contribute to an enhanced future application of C-H oxidation or oxygenation processes using air, as concerning societal energy goals.

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Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

“…HO 2 (aq) is a much stronger HAT reagent than is O 2 •− anion [64]. Even with the Lewis acidic Cu(II) ion present and ligated, perhaps [Cu II -O 2 •− (H)] 2+ , as suggested [71], is required to effect HAT chemistry producing R• + Cu II -OOH plus release of that “extra” proton.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Elaboration of copper–oxygen mediated C–H activation chemistry in consideration of future fuel and feedstock generation

Lee

Karlin

2015

Current Opinion in Chemical Biology

108

View full text Add to dashboard Cite

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“…the superoxide complex, [Cu–OO], and an axial isomer of a Cu(II)–oxyl species [22], [Cu–O], has been considered in computational studies, but no other quantitative studies exist. A comprehensive computational study was performed by Abad et al [27], but for another copper monooxygenase with a different active site. In studies of inorganic model systems, it has been suggested that a Cu(III)–hydroxy species could be responsible for the hydrogen-atom abstraction in the LPMOs [28–30].…”

Section: Introductionmentioning

confidence: 99%

Targeting the reactive intermediate in polysaccharide monooxygenases

Hedegård

Ryde

2017

J Biol Inorg Chem

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Lytic polysaccharide monooxygenases (LPMOs) are copper metalloenzymes that can enhance polysaccharide depolymerization through an oxidative mechanism, making them interesting for the production of biofuel from cellulose. However, the details of this activation are unknown; in particular, the nature of the intermediate that attacks the glycoside C–H bond in the polysaccharide is not known, and a number of different species have been suggested. The homolytic bond-dissociation energy (BDE) has often been used as a descriptor for the bond-activation power, especially for inorganic model complexes. We have employed quantum-chemical cluster calculations to estimate the BDE for a number of possible LPMO intermediates to bridge the gap between model complexes and the actual LPMO active site. The calculated BDEs suggest that the reactive intermediate is either a Cu(II)–oxyl, a Cu(III)–oxyl, or a Cu(III)–hydroxide, which indicate that O–O bond breaking occurs before the C–H activation step.Electronic supplementary materialThe online version of this article (doi:10.1007/s00775-017-1480-1) contains supplementary material, which is available to authorized users.

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“…This hypothesis is reasonable given that inactivation is turnover-dependent and that the PHM-catalyzed hydroxylation reaction likely proceeds through a substrate-based radical 39–42 . However, this proposed chemistry is inconsistent with our data and is thermodynamically challenging.…”

Section: Discussionmentioning

confidence: 86%

“…The formation of vinyl radical during the cinnamate-mediated inactivation of PHM is mechanistically relevant because this would require the formation of a PAM-based oxidant that is sufficiently strong to abstract a hydrogen atom from the α-carbon of cinnamate. If true, this may force a revision of the current models for PHM catalysis 39–42 .…”

Section: Introductionmentioning

confidence: 99%

Inactivation of peptidylglycineα-hydroxylating monooxygenase by cinnamic acid analogs

McIntyre

Lowe

Battistini

et al. 2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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Peptidylglycine α-amidating monooxygenase (PAM) is a bifunctional enzyme that catalyzes the final reaction in the maturation of α-amidated peptide hormones. Peptidylglycine α-hydroxylating monooxygenase (PHM) is the PAM domain responsible for the copper-, ascorbate- and O2-dependent hydroxylation of a glycine-extended peptide. Peptidylamidoglycolate lyase is the PAM domain responsible for the Zn(II)-dependent dealkylation of the α-hydroxyglycine-containing precursor to the final α-amidated peptide. We report herein that cinnamic acid and cinnamic acid analogs are inhibitors or inactivators of PHM. The inactivation chemistry exhibited by the cinnamates exhibits all the attributes of a suicide-substrate. However, we find no evidence for the formation of an irreversible linkage between cinnamate and PHM in the inactivated enzyme. Our data support the reversible formation of a Michael adduct between an active site nucleophile and cinnamate that leads to inactive enzyme. Our data are of significance given that cinnamates are found in foods, perfumes, cosmetics and pharmaceuticals.

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Reaction Mechanism of the Bicopper Enzyme Peptidylglycine α-Hydroxylating Monooxygenase

Cited by 34 publications

References 61 publications

Elaboration of copper–oxygen mediated C–H activation chemistry in consideration of future fuel and feedstock generation

Elaboration of copper–oxygen mediated C–H activation chemistry in consideration of future fuel and feedstock generation

Targeting the reactive intermediate in polysaccharide monooxygenases

Inactivation of peptidylglycineα-hydroxylating monooxygenase by cinnamic acid analogs

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