The crystal structure of human dopamine β-hydroxylase at 2.9 Å resolution

Vendelboe, Trine V.; Harris, Pernille; Zhao, Yuguang; Walter, Thomas S.; Harlos, K.; Omari, Kamel El; Christensen, Hans Erik Mølager

doi:10.1126/sciadv.1500980

Cited by 97 publications

(126 citation statements)

References 68 publications

(100 reference statements)

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“…For many years, PHM was the only one of these three enzymes that had been crystallographically characterized. Recently, the first crystal structure of DβM was published [59]. Two different conformations of the enzyme were observed; one conformation, similar to PHM and called the open conformation, showed the two copper binding sites ~14 Å apart, while the other, called the closed conformation, showed the binding sites ~4 to 5 Å apart.…”

Section: Single Copper Active Sitesmentioning

confidence: 99%

Activation of dioxygen by copper metalloproteins and insights from model complexes

et al. 2016

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Nature uses dioxygen as a key oxidant in the transformation of biomolecules. Among the enzymes that are utilized for these reactions are copper-containing met-alloenzymes, which are responsible for important biological functions such as the regulation of neurotransmitters, dioxygen transport, and cellular respiration. Enzymatic and model system studies work in tandem in order to gain an understanding of the fundamental reductive activation of dioxygen by copper complexes. This review covers the most recent advancements in the structures, spectroscopy, and reaction mechanisms for dioxygen-activating copper proteins and relevant synthetic models thereof. An emphasis has also been placed on cofactor biogenesis, a fundamentally important process whereby biomolecules are post-translationally modified by the pro-enzyme active site to generate cofactors which are essential for the catalytic enzymatic reaction. Significant questions remaining in copper-ion-mediated O2-activation in copper proteins are addressed.

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Section: Single Copper Active Sitesmentioning

confidence: 99%

Activation of dioxygen by copper metalloproteins and insights from model complexes

et al. 2016

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“…The lack of magnetic coupling between these sites distinguishes this class as "noncoupled" binuclear copper monooxygenases, in contrast to coupled binuclear copper enzymes (tyrosinase, hemocyanin, etc.). Intriguingly, a recent structure of dimeric DβM (7) shows an "open" conformation reminiscent of PHM in one apo monomer (predicted Cu-Cu distance ∼14 Å) and a "closed" conformation in the second half-apo monomer with a significantly contracted core (predicted Cu-Cu distance ∼5 Å). This suggests that the domains containing Cu H and Cu M have some conformational flexibility; however, it is currently unknown whether this is relevant to turnover.…”

mentioning

confidence: 99%

Mechanism of O₂activation and substrate hydroxylation in noncoupled binuclear copper monooxygenases

Cowley

Solomon

2016

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

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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. C opper is an essential cofactor for many cellular processes requisite for life (1). In particular, one or multiple coppers are found in active sites of enzymes that bind, activate, and reduce O 2 using the biologically accessible Cu II /Cu I redox couple (2, 3). One important class of Cu-dependent O 2 -activating enzymes is responsible for the stereospecific C-H α-hydroxylation of hormones and glycine-extended neuropeptides for proper neurotransmitter regulation and hormone biosynthesis. These enzymes [peptidylglycine α-hydroxylating monooxygenase (PHM), dopamine β-monooxygenase (DβM), and tyramine β-monooxygenase (TβM)] feature two distinct Cu sites (designated Cu M and Cu H ) separated in the protein by an ∼11-Å distance ( Fig. 1) (4-6). The lack of magnetic coupling between these sites distinguishes this class as "noncoupled" binuclear copper monooxygenases, in contrast to coupled binuclear copper enzymes (tyrosinase, hemocyanin, etc.). Intriguingly, a recent structure of dimeric DβM (7) shows an "open" conformation reminiscent of PHM in one apo monomer (predicted Cu-Cu distance ∼14 Å) and a "closed" conformation in the second half-apo monomer with a significantly contracted core (predicted Cu-Cu distance ∼5 Å). This suggests that the domains containing Cu H and Cu M have some conformational flexibility; however, it is currently unknown whether this is relevant to turnover. The Cu M site, featuring a 2His/1Met ligand set, is the center involved in O 2 activation, and the Cu H site, supported by 3His coordination, is an unusual electron transfer (ET) site that provides the second electron required for turnover.Kinetic isotope studies on PHM, DβM, and TβM have established several important parameters of the mechanism of C-H hydroxylation. A large intrinsic substrate H/D isotope effect (10.6) on the C-H cleavage step in PHM...

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“…A recent study reported the DBH crystal structure, revealing four domains (the DOMON (dopamine b-monooxygenase N-terminal) domain, which forms a possible metal-binding site and a ligandbinding pocket; the catalytic CuH and CuM domains; and the C-terminal dimerization domain), providing new molecular insights into the catalytic mechanism, as well as the destructive disorders of both physiological and neurological origin of the DBH enzyme and the DA system [60]. On the other hand, the enzymatic activity and plasma level of DBH show wide interindividual variation modulated by genetic inheritance [27].…”

Section: Discussionmentioning

confidence: 99%

Association of Dopamine Beta-Hydroxylase Polymorphisms with Alzheimer’s Disease, Parkinson’s Disease and Schizophrenia: Evidence Based on Currently Available Loci

Tang

Yao

et al. 2018

Cell Physiol Biochem

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Background/Aims: The neuropathies Alzheimer’s disease (AD), Parkinson’s disease (PD), and schizophrenia (SCZ) have different pathological mechanisms but share some common neurodegenerative features, such as gradual loss of neuronal structure and function. Dopamine beta-hydroxylase (DBH), a gene located in the chromosomal region 9q34, plays a crucial role in the process of converting dopamine into norepinephrine (NE). Several case–control studies have reported this pathway in the pathogenesis of AD, PD and SCZ. However, the results are controversial. Methods: We conducted a meta-analysis to estimate the associations between polymorphisms in this gene and AD, PD and SCZ. Seven databases (PubMed, Embase, Web of Science, China National Knowledge Infrastructure (CNKI), Wan Fang, SZ Gene and AD Gene) were searched to identify eligible studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to evaluate the associations of DBH variants with AD, PD and SCZ susceptibility. Results: A total of 41 studies involving 10506 cases and 15083 controls were included in our meta-analysis. The analysis results indicated that a lack of association (P > 0.05) was observed between most of the currently available DBH polymorphisms and the neurological diseases AD, PD and SCZ; however, the DBH rs1611131 (allelic model: OR = 0.889, 95% CI: 0.815 - 0.969; dominant model: OR = 0.868, 95% CI: 0.778 - 0.968), rs2283123 (allelic model: OR = 0.285, 95% CI: 0.095 - 0.862; dominant model: OR = 0.290, 95% CI: 0.094 -0.897) and rs2007153 (allelic model: OR = 2.196, 95% CI: 1.506 - 3.200; dominant model: OR = 2.985, 95% CI: 1.465 - 6.084; recessive model: OR = 2.729, 95% CI: 1.548 - 4.812) variants were shown to be significantly associated with the risk of AD (the former variant) and SCZ (the latter two variants). Conclusion: On the one hand, most DBH polymorphisms from the currently available loci showed no linkage to AD, PD or SCZ, indicating the lower possibility of these loci serving as genetic markers of the risks of diseases with neurodegenerative characteristics. On the other hand, the DBH rs2283123 and rs2007153 polymorphisms could have opposite effects on SCZ development in Caucasians and be more specific in Croatians, while the DBH rs1611131 minor variant might have a protective effect on AD risk in Caucasians; however, these results require further study.

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The crystal structure of human dopamine β-hydroxylase at 2.9 Å resolution

Abstract: This first structure of the enzyme converting dopamine to norepinephrine provides new perspectives on numerous disorders.

Cited by 97 publications

References 68 publications

Activation of dioxygen by copper metalloproteins and insights from model complexes

Activation of dioxygen by copper metalloproteins and insights from model complexes

Mechanism of O₂activation and substrate hydroxylation in noncoupled binuclear copper monooxygenases

Association of Dopamine Beta-Hydroxylase Polymorphisms with Alzheimer’s Disease, Parkinson’s Disease and Schizophrenia: Evidence Based on Currently Available Loci

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The crystal structure of human dopamine β-hydroxylase at 2.9 Å resolution

Abstract: This first structure of the enzyme converting dopamine to norepinephrine provides new perspectives on numerous disorders.

Cited by 97 publications

References 68 publications

Activation of dioxygen by copper metalloproteins and insights from model complexes

Activation of dioxygen by copper metalloproteins and insights from model complexes

Mechanism of O2activation and substrate hydroxylation in noncoupled binuclear copper monooxygenases

Association of Dopamine Beta-Hydroxylase Polymorphisms with Alzheimer’s Disease, Parkinson’s Disease and Schizophrenia: Evidence Based on Currently Available Loci

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Mechanism of O₂activation and substrate hydroxylation in noncoupled binuclear copper monooxygenases