The Copper-Enzyme Family of Dopamine β-Monooxygenase and Peptidylglycine α-Hydroxylating Monooxygenase: Resolving the Chemical Pathway for Substrate Hydroxylation

Klinman, Judith P.

doi:10.1074/jbc.r500011200

Cited by 363 publications

(422 citation statements)

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“…Because of favorable combinations of covalency and oxidation/reduction potentials, the activation of molecular oxygen by its coordination to one or two supported ͑i.e., ligated͒ Cu͑I͒ ions is common to a number of biological and inorganic catalytic processes. [26][27][28][29][30][31][32][33][34][35][36][37][38][39] In the case of monocopper species LCuO 2 , where L is a general ligand or ligands, one possible oxidation state that may be assigned to the complex is LCu͑II͒O 2 ͑−͒; thus, the copper atom has been oxidized by one electron and the O 2 fragment is formally a superoxide radical anion. Similarly, in the case of dicopper species ͑LCu͒ 2 O 2 , one possible oxidation state of the complex is formally ͓LCu͑II͔͒ 2 ͓͑O 2 ͒͑2−͔͒; in this instance, each copper atom has been oxidized by one electron and the O 2 fragment is formally a peroxide dianion.…”

Section: Application To Supported Cuo 2 and Cu 2 O 2 Systemsmentioning

confidence: 99%

The restricted active space followed by second-order perturbation theory method: Theory and application to the study of CuO2 and Cu2O2 systems

Malmqvist

Pierloot

Shahi

et al. 2008

The Journal of Chemical Physics

490

532

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A multireference second-order perturbation theory using a restricted active space self-consistent field wave function as reference ͑RASPT2/RASSCF͒ is described. This model is particularly effective for cases where a chemical system requires a balanced orbital active space that is too large to be addressed by the complete active space self-consistent field model with or without second-order perturbation theory ͑CASPT2 or CASSCF, respectively͒. Rather than permitting all possible electronic configurations of the electrons in the active space to appear in the reference wave function, certain orbitals are sequestered into two subspaces that permit a maximum number of occupations or holes, respectively, in any given configuration, thereby reducing the total number of possible configurations. Subsequent second-order perturbation theory captures additional dynamical correlation effects. Applications of the theory to the electronic structure of complexes involved in the activation of molecular oxygen by mono-and binuclear copper complexes are presented. In the mononuclear case, RASPT2 and CASPT2 provide very similar results. In the binuclear cases, however, only RASPT2 proves quantitatively useful, owing to the very large size of the necessary active space.

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Section: Application To Supported Cuo 2 and Cu 2 O 2 Systemsmentioning

confidence: 99%

The restricted active space followed by second-order perturbation theory method: Theory and application to the study of CuO2 and Cu2O2 systems

Malmqvist

Pierloot

Shahi

et al. 2008

The Journal of Chemical Physics

490

532

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“…Several classes with either binuclear or trinuclear copper active sites have been identified and their different strategies for O 2 activation have been elucidated (1). These include the multicopper oxidases that use three Cu ions to reduce O 2 to water with very little overpotential (2,3), the coupled binuclear Cu enzymes that are involved in dioxygen transport and monooxygenase reactivity (4), and the noncoupled binuclear Cu monooxygenases that activate O 2 for hydroxylation of peptides and hormones (5). Recently, a class of oxygen activating enzymes with a single copper center has been identified, the polysaccharride monooxygenases [PMOs; often termed lytic polysaccharide monooxygenases (LPMOs), reflecting their ability to break polysaccharides chains and loosen crystalline structure] (6-8), or AA9 to 11 enzymes (AA = auxiliary activity) in the Carbohydrate-Active enZYmes (CAZy) database (9).…”

mentioning

confidence: 99%

Spectroscopic and computational insight into the activation of O ₂ by the mononuclear Cu center in polysaccharide monooxygenases

Kjaergaard

Qayyum

Wong

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

203

252

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Strategies for O 2 activation by copper enzymes were recently expanded to include mononuclear Cu sites, with the discovery of the copper-dependent polysaccharide monooxygenases, also classified as auxiliary-activity enzymes 9-11 (AA9-11). These enzymes are finding considerable use in industrial biofuel production. Crystal structures of polysaccharide monooxygenases have emerged, but experimental studies are yet to determine the solution structure of the Cu site and how this relates to reactivity. From X-ray absorption near edge structure and extended X-ray absorption fine structure spectroscopies, we observed a change from four-coordinate Cu(II) to three-coordinate Cu(I) of the active site in solution, where three protein-derived nitrogen ligands coordinate the Cu in both redox states, and a labile hydroxide ligand is lost upon reduction. The spectroscopic data allowed for density functional theory calculations of an enzyme active site model, where the optimized Cu(I) and (II) structures were consistent with the experimental data. The O 2 reactivity of the Cu(I) site was probed by EPR and stopped-flow absorption spectroscopies, and a rapid one-electron reduction of O 2 and regeneration of the resting Cu(II) enzyme were observed. This reactivity was evaluated computationally, and by calibration to Cu-superoxide model complexes, formation of an end-on Cu-AA9-superoxide species was found to be thermodynamically favored. We discuss how this thermodynamically difficult one-electron reduction of O 2 is enabled by the unique protein structure where two nitrogen ligands from His1 dictate formation of a T-shaped Cu(I) site, which provides an open coordination position for strong O 2 binding with very little reorganization energy.X-ray absorption spectroscopy | DFT | dioxygen activation | biofuels

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“…The most studied enzymes in this family are peptidylglycine ␣-hydroxylating monooxygenase (PHM) 3 and dopamine ␤-monooxygenase (D␤M) (1). PHM catalyzes the conversion of C-terminal glycine-extended peptides to their ␣-hydroxylated products, the first step in the amidation of peptide hormones, required for a range of biological activities (2).…”

mentioning

confidence: 99%

“…Each copper site assumes a unique coordination environment and a distinct mechanistic function. Cu M serves as the site of dioxygen binding and activation, whereas the Cu H site functions as an electron transfer site in the reaction mechanism (1,14). The Cu M site is coordinated by two histidine residues, a weakly bound methionine, and one or two water molecules, depending on the oxidation state.…”

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confidence: 99%

Mechanism of the Insect Enzyme, Tyramine β-Monooxygenase, Reveals Differences from the Mammalian Enzyme, Dopamine β-Monooxygenase

Hess

McGuirl

Klinman

2008

Journal of Biological Chemistry

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Tyramine ␤-monooxygenase (T␤M) catalyzes the synthesis of the neurotransmitter, octopamine, in insects. Kinetic and isotope effect studies have been carried out to determine the kinetic mechanism of T␤M for comparison with the homologous mammalian enzymes, dopamine ␤-monooxygenase and peptidylglycine ␣-hydroxylating monooxygenase. A new and distinctive feature of T␤M is very strong substrate inhibition that is dependent on the level of the co-substrate, O 2 , and reductant as well as substrate deuteration. This has led to a model in which tyramine can bind to either the Cu(I) or Cu(II) forms of T␤M, with substrate inhibition ameliorated at very high ascorbate levels. The rate of ascorbate reduction of the E-Cu(II) form of T␤M is also reduced at high tyramine, leading us to propose the existence of a binding site for ascorbate to this class of enzymes. These findings may be relevant to the control of octopamine production in insect cells.The copper hydroxylases are a unique class of enzymes that are found in eukaryotes and play a critical role in the biosynthesis of neurotransmitters and hormones. The most studied enzymes in this family are peptidylglycine ␣-hydroxylating monooxygenase (PHM) 3 and dopamine ␤-monooxygenase (D␤M) (1). PHM catalyzes the conversion of C-terminal glycine-extended peptides to their ␣-hydroxylated products, the first step in the amidation of peptide hormones, required for a range of biological activities (2). D␤M catalyzes the hydroxylation of dopamine to yield norepinephrine and, thus, is vital for the regulation of these neurotransmitters (3-5). More recently, a third member of this enzyme family was identified, tyramine ␤-monooxygenase (6). T␤M is the insect homolog of D␤M, sharing 39% identity and 55% similarity with the mammalian enzyme. T␤M similarly catalyzes the hydroxylation of tyramine at the ␤-carbon position (Scheme 1). Although tyramine plays no role in mammalian physiology, the product of T␤M, octopamine, has been shown to act as a neurotransmitter in invertebrates, regulating physiological functions such as neuromuscular transmission, behavioral development, and ovulation (7-9). One advantage to studies with T␤M is the much more facile expression system for this enzyme in relation to D␤M (10), which makes it possible to pursue structure/function relationships. In this paper, we report a detailed analysis of the kinetic behavior of the wild type T␤M, an essential first step in understanding this complex enzyme system.All three of the copper hydroxylases employ two noncoupled, mononuclear Cu centers for oxygenase activity, termed Cu M and Cu H . Structural information pertaining to the active site of the enzymes is derived primarily from the crystal structure for PHM and extended X-ray absorption fine structure studies with both D␤M and PHM (11-13). Each copper site assumes a unique coordination environment and a distinct mechanistic function. Cu M serves as the site of dioxygen binding and activation, whereas the Cu H site functions as an electron transfer site in the reac...

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The Copper-Enzyme Family of Dopamine β-Monooxygenase and Peptidylglycine α-Hydroxylating Monooxygenase: Resolving the Chemical Pathway for Substrate Hydroxylation

Cited by 363 publications

References 29 publications

The restricted active space followed by second-order perturbation theory method: Theory and application to the study of CuO2 and Cu2O2 systems

The restricted active space followed by second-order perturbation theory method: Theory and application to the study of CuO2 and Cu2O2 systems

Spectroscopic and computational insight into the activation of O ₂ by the mononuclear Cu center in polysaccharide monooxygenases

Mechanism of the Insect Enzyme, Tyramine β-Monooxygenase, Reveals Differences from the Mammalian Enzyme, Dopamine β-Monooxygenase

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The Copper-Enzyme Family of Dopamine β-Monooxygenase and Peptidylglycine α-Hydroxylating Monooxygenase: Resolving the Chemical Pathway for Substrate Hydroxylation

Cited by 363 publications

References 29 publications

The restricted active space followed by second-order perturbation theory method: Theory and application to the study of CuO2 and Cu2O2 systems

The restricted active space followed by second-order perturbation theory method: Theory and application to the study of CuO2 and Cu2O2 systems

Spectroscopic and computational insight into the activation of O 2 by the mononuclear Cu center in polysaccharide monooxygenases

Mechanism of the Insect Enzyme, Tyramine β-Monooxygenase, Reveals Differences from the Mammalian Enzyme, Dopamine β-Monooxygenase

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Spectroscopic and computational insight into the activation of O ₂ by the mononuclear Cu center in polysaccharide monooxygenases