Mechanisms of tryptophan and tyrosine hydroxylase

Roberts, Kenneth M.; Fitzpatrick, Paul F.

doi:10.1002/iub.1144

Cited by 73 publications

(58 citation statements)

References 53 publications

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“…There are few examples in nature of mechanisms for site-specific hydroxylation of specific aromatic amino acid residues in proteins. One class of enzymes which accomplishes this task is the iron and tetrahydropterin-dependent amino acid hydroxylases 34, 35 . These enzymes utilize a protein-bound Fe IV =O oxidant to perform the oxidative chemistry on unmodified phenylalanine and tryptophan residues.…”

Section: Discussionmentioning

confidence: 99%

Roles of Copper and a Conserved Aspartic Acid in the Autocatalytic Hydroxylation of a Specific Tryptophan Residue during Cysteine Tryptophylquinone Biogenesis

et al. 2017

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The first posttranslational modification step in the biosynthesis of the tryptophan-derived quinone cofactors is the auto-catalytic hydroxylation of a specific Trp residue at the C-7 position on the indole side-chain. Subsequent modifications are catalyzed by modifying enzymes, but the mechanism by which this first step occurs is unknown. LodA possesses a cysteine tryptophylquinone (CTQ) cofactor. Metal analysis, as well as spectroscopic and kinetic studies of the mature and precursor forms of a D512A LodA variant provide evidence that copper is required for the initial hydroxylation of the precursor protein; and that if alternative metals are bound, the modification does not occur and the precursor is unstable. It is shown that the mature native LodA also contains loosely bound copper which affects the visible absorbance spectrum and quenches the fluorescence spectrum that is attributed to the mature CTQ cofactor. When copper is removed the fluorescence appears and when it is added back to the protein the fluorescence is quenched, indicating that copper reversibly binds in the proximity of CTQ. Removal of copper does not diminish the enzymatic activity of LodA. This distinguishes LodA from enzymes with protein-derived tyrosylquinone cofactors in which copper is present near the cofactor and is absolutely required for activity. Mechanisms are proposed for the role of copper in the hydroxylation of the un-activated Trp side-chain. These results demonstrate that the reason that the highly conserved Asp512 is critical for LodA, and possibly all tryptophylquinone enzymes, is not because it is required for catalysis but because it is necessary for CTQ biosynthesis, more specifically to facilitate the initial copper-dependent hydroxylation of a specific Trp residue.

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Section: Discussionmentioning

confidence: 99%

Roles of Copper and a Conserved Aspartic Acid in the Autocatalytic Hydroxylation of a Specific Tryptophan Residue during Cysteine Tryptophylquinone Biogenesis

et al. 2017

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“…TH, TPH1, and TPH2 belong to the AAAH family of enzymes that catalyze the hydroxylation of their respective aromatic amino acids in the presence of molecular oxygen, tetrahydrobiopterin (BH4), and iron [5,6]. In addition to TH, TPH1, and TPH2, phenylalanine hydroxylase (PAH) is also a member of this family and is responsible for the catalytic conversion of phenylalanine into tyrosine [5,7]. All the AAAHs occupy key regulatory positions in their metabolic pathways ( Figure 1) [7][8][9][10].…”

Section: Aaahs and Human Diseasementioning

confidence: 99%

“…In addition to TH, TPH1, and TPH2, phenylalanine hydroxylase (PAH) is also a member of this family and is responsible for the catalytic conversion of phenylalanine into tyrosine [5,7]. All the AAAHs occupy key regulatory positions in their metabolic pathways ( Figure 1) [7][8][9][10].…”

Section: Aaahs and Human Diseasementioning

confidence: 99%

Tyrosine and tryptophan hydroxylases as therapeutic targets in human disease

Waløen

Kleppe

Martı́nez

et al. 2016

Expert Opinion on Therapeutic Targets

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The ancient and ubiquitous monoamine signalling molecules serotonin, dopamine, norepinephrine, and epinephrine are involved in multiple physiological functions. The aromatic amino acid hydroxylases tyrosine hydroxylase (TH), tryptophan hydroxylase 1 (TPH1), and tryptophan hydroxylase 2 (TPH2) catalyse the rate-limiting steps in the biosynthesis of these monoamines. Genetic variants of TH, TPH1, and TPH2 genes are associated with neuropsychiatric disorders. The interest in these enzymes as therapeutic targets is increasing as new roles of these monoamines have been discovered, not only in brain function and disease, but also in development, cardiovascular function, energy and bone homeostasis, gastrointestinal motility, hemostasis, and liver function. Areas covered: Physiological roles of TH, TPH1, and TPH2. Enzyme structures, catalytic and regulatory mechanisms, animal models, and associated diseases. Interactions with inhibitors, pharmacological chaperones, and regulatory proteins relevant for drug development. Expert opinion: Established inhibitors of these enzymes mainly target their amino acid substrate binding site, while tetrahydrobiopterin analogues, iron chelators, and allosteric ligands are less studied. New insights into monoamine biology and 3D-structural information and new computational/experimental tools have triggered the development of a new generation of more selective inhibitors and pharmacological chaperones. The enzyme complexes with their regulatory 14-3-3 proteins are also emerging as therapeutic targets.

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“…) through the insertion of a single atom from molecular oxygen onto the amino acid substrate aromatic ring. The remaining oxygen atom is reduced to water in a reaction, in which BH 4 acts as an electron donor (Roberts and Fitzpatrick ).…”

mentioning

confidence: 99%

“…Tyrosine hydroxylase (TH; EC 1.14.16.2; tyrosine 3-monooxygenase) is a non-haeme iron- and tetrahydrobiopterin (BH 4 )-dependent enzyme that catalyses the rate-limiting step in catecholamine biosynthesis (Nagatsu et al 1964) through the insertion of a single atom from molecular oxygen onto the amino acid substrate aromatic ring. The remaining oxygen atom is reduced to water in a reaction, in which BH 4 acts as an electron donor (Roberts and Fitzpatrick 2013).…”

mentioning

confidence: 99%

The quaternary structure of human tyrosine hydroxylase: effects of dystonia‐associated missense variants on oligomeric state and enzyme activity

Szigetvari

Muruganandam

Kallio

et al. 2018

Journal of Neurochemistry

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Tyrosine hydroxylase ( TH ) is a multi‐domain, homo‐oligomeric enzyme that catalyses the rate‐limiting step of catecholamine neurotransmitter biosynthesis. Missense variants of human TH are associated with a recessive neurometabolic disease with low levels of brain dopamine and noradrenaline, resulting in a variable clinical picture, from progressive brain encephalopathy to adolescent onset DOPA ‐responsive dystonia ( DRD ). We expressed isoform 1 of human TH ( hTH 1) and its dystonia‐associated missense variants in E. coli, analysed their quaternary structure and thermal stability using size‐exclusion chromatography, circular dichroism, multi‐angle light scattering, transmission electron microscopy, small‐angle X‐ray scattering and assayed hydroxylase activity. Wild‐type ( WT ) hTH 1 was a mixture of enzymatically stable tetramers (85.6%) and octamers (14.4%), with little interconversion between these species. We also observed small amounts of higher order assemblies of long chains of enzyme by transmission electron microscopy. To investigate the role of molecular assemblies in the pathogenesis of DRD , we compared the structure of WT hTH 1 with the DRD ‐associated variants R410P and D467G that are found in vicinity of the predicted subunit interfaces. In contrast to WT hTH 1, R410P and D467G were mixtures of tetrameric and dimeric species. Inspection of the available structures revealed that Arg‐410 and Asp‐467 are important for maintaining the stability and oligomeric structure of TH . Disruption of the normal quaternary enzyme structure by missense variants is a new molecular mechanism that may explain the loss of TH enzymatic activity in DRD . Unstable missense variants could be targets for pharmacological intervention in DRD , aimed to re‐establish the normal oligomeric state of TH.

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Mechanisms of tryptophan and tyrosine hydroxylase

Cited by 73 publications

References 53 publications

Roles of Copper and a Conserved Aspartic Acid in the Autocatalytic Hydroxylation of a Specific Tryptophan Residue during Cysteine Tryptophylquinone Biogenesis

Roles of Copper and a Conserved Aspartic Acid in the Autocatalytic Hydroxylation of a Specific Tryptophan Residue during Cysteine Tryptophylquinone Biogenesis

Tyrosine and tryptophan hydroxylases as therapeutic targets in human disease

The quaternary structure of human tyrosine hydroxylase: effects of dystonia‐associated missense variants on oligomeric state and enzyme activity

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