Biology: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 may cause tyrosine hydroxylase deficiency (THD), a rare neurometabolic disorder inherited in an autosomal recessive manner.[2] Patients with severe THD may have defective catecholamine synthesis resulting in major neurological and motor deficits.[3] 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.[4] This activation is altered by upstream cis-acting motifs – AP1, AP2, and cAMP response element.[4] The cAMP response element, 38-45 base pairs upstream, plays a bigger role in gene regulation than the others.[5]
References
- ↑ 1.0 1.1 Nurse, Colin A.; Salman, Shaima; Scott, Angela L. (2018-05-01). "Hypoxia-regulated catecholamine secretion in chromaffin cells" (in en). Cell and Tissue Research 372 (2): 433–441. doi:10.1007/s00441-017-2703-z. ISSN 1432-0878. PMID 29052004.
- ↑ "Personalized Medicine to Improve Treatment of Dopa-Responsive Dystonia—A Focus on Tyrosine Hydroxylase Deficiency". J. Pers. Med. 11 (1186): 1186. November 2021. doi:10.3390/jpm11111186. PMID 34834538.
- ↑ 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" (in en). Neurology 56 (2): 260–263. doi:10.1212/WNL.56.2.260. ISSN 0028-3878. PMID 11160968. https://n.neurology.org/content/56/2/260.
- ↑ 4.0 4.1 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." (in en). Proceedings of the National Academy of Sciences 90 (8): 3471–3475. doi:10.1073/pnas.90.8.3471. ISSN 0027-8424. PMID 7682705. Bibcode: 1993PNAS...90.3471K.
- ↑ 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. doi:10.1016/S0021-9258(18)82311-0. ISSN 0021-9258. PMID 8101843.
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