Dynamics of tyrosine hydroxylase mediated regulation of dopamine synthesis

Poorvi Kaushik, Fredric A Gorin, Shireen Vali

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

Abstract

Tyrosine hydroxylase's catalysis of tyrosine to dihydroxyphenylalanine (DOPA) is the highly regulated, rate-limiting step catalyzing the synthesis of the catecholamine neurotransmitter dopamine. Phosphorylation, cofactor-mediated regulation, and the cell's redox status, have been shown to regulate the enzyme's activity. This paper incorporates these regulatory mechanisms into an integrated dynamic model that is capable of demonstrating relative rates of dopamine synthesis under various physiological conditions. Most of the kinetic equations and substrate parameters used in the model correspond with published experimental data, while a few which were not available in literature have been optimized based on explicit assumptions. This kinetic pathway model permits a comparison of the relative regulatory contributions made by variations in substrate, phosphorylation, and redox status on enzymatic activity and permits predictions of potential disease states. For example, the model correctly predicts the recent observation that individuals with haemochromatosis and having excessive iron accumulation are at increased risk for acquiring Parkinsonism, a defect in neuronal dopamine synthesis (Bartzokis et al., 2004; Costello et al., 2004). Alpha synuclein mediated regulation of tyrosine hydroxylase has also been incorporated in the model, allowing an insight into the over-expression and aggregation of alpha synuclein in Parkinson's disease.

Original languageEnglish (US)
Pages (from-to)147-160
Number of pages14
JournalJournal of Computational Neuroscience
Volume22
Issue number2
DOIs
StatePublished - Apr 2007

Keywords

  • Alpha synuclein
  • Dopamine
  • Iron
  • Kinetic model
  • Parkinson's disease
  • Phosphorylation
  • Tyrosine hydroxylase

ASJC Scopus subject areas

  • Neuroscience(all)

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