TH (gene)

The TH gene codes for the enzyme tyrosine hydroxylase.

Gene product

Tyrosine hydroxylase is the rate limiting enzyme responsible for the transformation of L-Tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA), a catecholamine precursor. Catecholamines, dopamine, epinephrine, and norepinephrine, signal different stressors so the body can activate pathways to return towards homeostasis. In response to fetal hypoxia, catecholamines can maintain glucose levels, but also naturally increases during gestation.[1] Catecholamine secretions typically follows sympathetic nervous stimulation in adults, but in a fetus, this system for secretion is not yet developed or understood. However, there is some plasticity observed as when adults lose nerve function, they revert to this non-neurogenic catecholamine release system.[1]

Gene regulation

Mutations in the TH gene, especially in the tetramerization and catalytic domain, cause catecholamine synthesis problems and result in major neurological and motor deficits.[2] Activation of the TH gene requires cyclic adenosine monophosphate (cAMP) to cause a conformation change upon binding to protein kinase A (PKA). PKA can phosphorylate both the TH gene for transcription and the tyrosine hydroxylase protein to increase its efficiency.[3] This activation is altered by upstream cis-acting motifs – AP1, AP2, and cAMP response element.[3] The cAMP response element, 38-45 base pairs upstream, plays a bigger role in gene regulation than the others.[4]

References
  1. Nurse, Colin A.; Salman, Shaima; Scott, Angela L. (2018-05-01). "Hypoxia-regulated catecholamine secretion in chromaffin cells". Cell and Tissue Research. 372 (2): 433–441. doi:10.1007/s00441-017-2703-z. ISSN 1432-0878. PMID 29052004.
  2. Furukawa, Y.; Graf, W. D.; Wong, H.; Shimadzu, M.; Kish, S. J. (2001-01-23). "Dopa-responsive dystonia simulating spastic paraplegia due to tyrosine hydroxylase (TH) gene mutations". Neurology. 56 (2): 260–263. doi:10.1212/WNL.56.2.260. ISSN 0028-3878. PMID 11160968.
  3. Kim, K. S.; Park, D. H.; Wessel, T. C.; Song, B.; Wagner, J. A.; Joh, T. H. (1993-04-15). "A dual role for the cAMP-dependent protein kinase in tyrosine hydroxylase gene expression". Proceedings of the National Academy of Sciences. 90 (8): 3471–3475. Bibcode:1993PNAS...90.3471K. doi:10.1073/pnas.90.8.3471. ISSN 0027-8424. PMC 46322. PMID 7682705.
  4. Kim, K. S.; Lee, M. K.; Carroll, J.; Joh, T. H. (1993-07-25). "Both the basal and inducible transcription of the tyrosine hydroxylase gene are dependent upon a cAMP response element". The Journal of Biological Chemistry. 268 (21): 15689–15695. ISSN 0021-9258. PMID 8101843.
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