Tyrosine Hydroxylase

links: reference: 4-24-2021

Tyrosine Hydroxylase (TH) #

• Hydroxylates L-Tyrosine into L-DOPA.

• Cofactors: P5P, BH4, and Vitamin D

• Tyrosine Hydroxylase and Regulation of Dopamine Synthesis

  • It is the rate-limiting step of Catecholamine synthesis since Dopamine binds to it competititvely against tetrahydrobiopterin, which TH uses along with oxygen.
    • Something like that at least Tyrosine hydroxylase activity is regulated by two distinct dopamine-binding sites

• Enhanced tyrosine hydroxylase activity induces oxidative stress, causes accumulation of autotoxic catecholamine metabolites, and augments amphetamine effects in vivo

  • This may not be a big deal considering this happens with dopamine regardless.

• Regulation of Tyrosine Hydroxylase Activity and Phosphorylation at Ser19 and Ser40 via Activation of Glutamate NMDA Receptors in Rat Striatum

  • Forskolin, an activator of Adenylyl Cyclase, stimulated Tyrosine Hydroxylase phosphorylation at Ser40 and caused a significant increase in DOPA accumulation.
  • NMDA reduced forskolin-mediated increases in both Ser40 phosphorylation and DOPA accumulation. NMDA reduced the increase in phospho-Ser40-tyrosine hydroxylase produced by okadaic acid, an inhibitor of protein phosphatase 1 and 2A.
    • This paper thus concludes that In the Striatum, Glutamate decreases Tyrosine Hydroxylase phosphorylation at Ser40 via activation of NMDARs by reducing cAMP production.
      • Yeah that reduction in cAMP is basically something I never thought of. It must be by proxy of Ca2+->CAM->PDE, or something else interesting with CAMK maybe? The CaMKII/NMDAR complex as a molecular memory

Residues #

• 
  • Ser19: Increases rate of Ser40 phosphorylation.
    • Two-fold increase of activity through the 14-3-3 proteins.
  • Ser31: Slight increase in activity. Two-fold lower KM for THB.
  • Ser40:
    • Dephosphorylated by PP2A.
  • Protein Kinase A: Ser40 - alleviation of feedback inhibition. Two-fold lower KM for THB. and 300-fold decrease in catecholamine binding affinity.
  • MAPKAPK2: 40, somewhat 19. Alleivation of feedback inhibition.
  • ERK: 31, somewhat 8. Increases activation 2-fold.
  • CDK5: 31.
  • CAMK II: 19, 40 to a lesser extent. Binding of 14-3-3.
    • Looks like PP1 inhibits CAMK II.
  • PRAK: 19. Binding of 14-3-3.