The tetrameric enzyme
tyrosine hydroxylase (TH), also designated as tyrosine 3-monooxygenase (TY3H), is the rate-limiting enzyme for catecholamine biosynthesis and has a theoretical molecular weight of 60 kDa. Encoded by the TH gene, TH catalyzes the conversion of the amino acid L-tyrosine to L-3,4- dihydroxyphenylalanine (
L-dopa) in the central nervous system and adrenal medulla. The precursor of catecholamines, L-dopa, is converted to
dopamine for use in the biosynthesis of neurotransmitters
norepinephrine (noradrenaline) and
epinephrine (adrenaline) (1) . Dysfunction in the TH gene, and thus the enzymatic activity by TH, dysregulates catecholamine synthesis.
Two transcription factor binding sites in the proximal region of the TH gene, the TPA-responsive element (TRE) and the c-AMP responsive element (CRE), have been implicated in the complex regulation of the TH gene. Dysregulation of breakdown for the amino acid, tyrosine, by TH is a result of a genetic disorder that results in Tyrosinemia (high levels of tyrosine in the blood, tissue and organs).
Tyrosine hydroxylase deficiency is a disorder that primarily affects movement, where individuals display symptoms that include lack of coordination when walking, postural tremors and unusual body positioning. TH deficient dopamine-responsive dystonia (DRD), also known as Segawa syndrome, is a rare genetic disorder that is associated with low levels of TH and is diagnosed during childhood with characteristic symptoms including increased muscle tone (dystonia) and signs of Parkinsonism like bradykinesia, tremors, rigidity and postural instability (2). Correspondingly, TH is also linked to
Parkinson's disease in older adults, where low dopamine levels are a consistent neurochemical abnormality. Functional polymorphisms of the TH gene may be involved in the pathogenesis of neuropsychiatric diseases such as schizophrenia and other affective disorders where dopamine is often dysregulated (3).
References
1. Hamanaka, Y., & Mizunami, M. (2019). Tyrosine hydroxylase-immunoreactive neurons in the mushroom body of the field cricket, Gryllus bimaculatus. Cell Tissue Res, 376(1), 97-111. doi:10.1007/s00441-018-2969-9
2. Li, L., & Zhou, F. M. (2013). Parallel dopamine D1 receptor activity dependence of l-Dopa-induced normal movement and dyskinesia in mice. Neuroscience, 236, 66-76. doi:10.1016/j.neuroscience.2012.12.065
3. Borkar, C. D., Bharne, A. P., Nagalakshmi, B., Sakharkar, A. J., Subhedar, N. K., & Kokare, D. M. (2018). Cocaine- and Amphetamine-Regulated Transcript Peptide (CART) Alleviates MK-801-Induced Schizophrenic Dementia-Like Symptoms. Neuroscience, 375, 94-107. doi:10.1016/j.neuroscience.2018.01.056