Tyrosine hydroxylase phosphorylation in vivo

@article{Dunkley2019TyrosineHP,
  title={Tyrosine hydroxylase phosphorylation in vivo},
  author={Peter R Dunkley and Phillip W Dickson},
  journal={Journal of Neurochemistry},
  year={2019},
  volume={149}
}
Tyrosine hydroxylase (TH) is the rate‐limiting enzyme in the synthesis of the catecholamines dopamine, noradrenaline and adrenaline. One of the major mechanisms for controlling the activity of TH is protein phosphorylation. TH is phosphorylated at serine residues 8, 19, 31 and 40. There have been a number of previous reviews focused on TH phosphorylation in vitro and in situ. This review on TH phosphorylation in vivo has three main sections focusing on: (1) the methods used to investigate TH… 
Structural mechanism for tyrosine hydroxylase inhibition by dopamine and reactivation by Ser40 phosphorylation
TLDR
The authors present the cryo-EM structures of full-length human TH in the apo form and bound with DA, as well as the structure of Ser40 phosphorylated TH, and discuss the inhibitory and stabilizing effects of DA on TH and its counteraction by Ser40-phosphorylation.
Subcellular distribution of human tyrosine hydroxylase isoforms 1 and 4 in SH‐SY5Y cells
TLDR
This is the first study to show a difference in subcellular distribution between two human TH isoforms under basal and stimulated conditions.
NT5DC2 affects the phosphorylation of tyrosine hydroxylase regulating its catalytic activity
TLDR
It is proposed that NT5DC2 could work to inhibit the DOPA synthesis by decreasing the phosphorylation of TH at its Ser40 by promoting dephosphorylation or by inhibiting kinase activity.
Enhanced tyrosine hydroxylase activity induces oxidative stress, causes accumulation of autotoxic catecholamine metabolites, and augments amphetamine effects in vivo
TLDR
It is demonstrated that increased TH alone is sufficient to produce oxidative stress in vivo, build up autotoxic dopamine metabolites, and augment methamphetamine toxicity.
Changes in Tyrosine Hydroxylase Activity and Dopamine Synthesis in the Nigrostriatal System of Mice in an Acute Model of Parkinson’s Disease as a Manifestation of Neurodegeneration and Neuroplasticity
TLDR
The data obtained indicate a difference in the regulation of dopamine synthesis between DA-neuron bodies and their axons, which must be considered for the further development of symptomatic pharmacotherapy aimed at increasing TH activity.
Degradation of Tyrosine Hydroxylase by the Ubiquitin-Proteasome System in the Pathogenesis of Parkinson’s Disease and Dopa-Responsive Dystonia
TLDR
The molecular mechanism underlying the neurodegeneration process in dopamine-containing neurons is reviewed and the novel degradation pathway of TH through the ubiquitin-proteasome system is focused on to advance understanding of the etiology of Parkinson’s disease and dopa-responsive dystonia.
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TLDR
H hierarchical phosphorylation provides a mechanism whereby the two major human TH isoforms can be differentially regulated with only isoform 1 responding to the ERK pathway, whereas isoform 2 is more sensitive to calcium-mediated events.
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TLDR
Evidence is provided for the first time that TH phosphorylation at Ser31 and Ser40 occurs for up to 24 h in vivo and leads to TH activation independent of TH protein synthesis, suggesting that the sustained phase of TH activation occurs in vivo.
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TLDR
Sustained phosphorylation of TH at Ser40 provides a novel mechanism for increasing TH activity and this leads to increased catecholamine synthesis, a selective target for drugs or pathology in neurons that contain TH and synthesize dopamine, noradrenaline or adrenaline.
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TLDR
It is shown that cdk5 phosphorylates TH at serine 31 and that this phosphorylation is associated with an increase in total TH activity, and co-expression ofcdk5 and its regulatory activator p35 with TH increases the stability of TH.
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TLDR
It is reported that THSer(P)-31 co-distributes with the Golgi complex and synaptic-like vesicles in rat and human dopaminergic cells and indicates that Ser-31 phosphorylation may regulate TH subcellular localization by enabling its transport along microtubules, notably toward the projection terminals.
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TLDR
The common roles of E332 and Y371 indicate that the low- and high-affinity catecholamine binding sites are colocalized in the active site, but due to simultaneous binding, may exist in separate monomers of the TH tetramer.
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TLDR
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Tyrosine hydroxylase activity is regulated by two distinct dopamine‐binding sites
Tyrosine hydroxylase (TH), the rate‐limiting enzyme in the biosynthesis of the catecholamines dopamine, noradrenaline and adrenaline, is regulated acutely by feedback inhibition by the catecholamines
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