TH (gene)

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The TH gene codes for the enzyme tyrosine hydroxylase.

Contents

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]

Related Research Articles

<span class="mw-page-title-main">Catecholamine</span> Class of chemical compounds

A catecholamine is a monoamine neurotransmitter, an organic compound that has a catechol and a side-chain amine.

Protein kinase A Family of enzymes

In cell biology, protein kinase A (PKA) is a family of enzymes whose activity is dependent on cellular levels of cyclic AMP (cAMP). PKA is also known as cAMP-dependent protein kinase. PKA has several functions in the cell, including regulation of glycogen, sugar, and lipid metabolism. It should not be confused with 5'-AMP-activated protein kinase.

CREB Class of proteins

CREB-TF is a cellular transcription factor. It binds to certain DNA sequences called cAMP response elements (CRE), thereby increasing or decreasing the transcription of the genes. CREB was first described in 1987 as a cAMP-responsive transcription factor regulating the somatostatin gene.

<small>L</small>-DOPA Chemical compound

l-DOPA, also known as levodopa and l-3,4-dihydroxyphenylalanine, is an amino acid that is made and used as part of the normal biology of some plants and animals, including humans. Humans, as well as a portion of the other animals that utilize l-DOPA, make it via biosynthesis from the amino acid l-tyrosine. l-DOPA is the precursor to the neurotransmitters dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline), which are collectively known as catecholamines. Furthermore, l-DOPA itself mediates neurotrophic factor release by the brain and CNS. l-DOPA can be manufactured and in its pure form is sold as a psychoactive drug with the INN levodopa; trade names include Sinemet, Pharmacopa, Atamet, and Stalevo. As a drug, it is used in the clinical treatment of Parkinson's disease and dopamine-responsive dystonia.

Biological crosstalk refers to instances in which one or more components of one signal transduction pathway affects another. This can be achieved through a number of ways with the most common form being crosstalk between proteins of signaling cascades. In these signal transduction pathways, there are often shared components that can interact with either pathway. A more complex instance of crosstalk can be observed with transmembrane crosstalk between the extracellular matrix (ECM) and the cytoskeleton.

Tyrosine hydroxylase Enzime found in Homo sapiens that converts l-tyrosine to l-dopa, the precursor of cathecolamines

Tyrosine hydroxylase or tyrosine 3-monooxygenase is the enzyme responsible for catalyzing the conversion of the amino acid L-tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA). It does so using molecular oxygen (O2), as well as iron (Fe2+) and tetrahydrobiopterin as cofactors. L-DOPA is a precursor for dopamine, which, in turn, is a precursor for the important neurotransmitters norepinephrine (noradrenaline) and epinephrine (adrenaline). Tyrosine hydroxylase catalyzes the rate limiting step in this synthesis of catecholamines. In humans, tyrosine hydroxylase is encoded by the TH gene, and the enzyme is present in the central nervous system (CNS), peripheral sympathetic neurons and the adrenal medulla. Tyrosine hydroxylase, phenylalanine hydroxylase and tryptophan hydroxylase together make up the family of aromatic amino acid hydroxylases (AAAHs).

Neuromedin B (NMB) is a bombesin-related peptide in mammals. It was originally purified from pig spinal cord, and later shown to be present in human central nervous system and gastrointestinal tract.

PRKACA Protein-coding gene in the species Homo sapiens

The catalytic subunit α of protein kinase A is a key regulatory enzyme that in humans is encoded by the PRKACA gene. This enzyme is responsible for phosphorylating other proteins and substrates, changing their activity. Protein kinase A catalytic subunit is a member of the AGC kinase family, and contributes to the control of cellular processes that include glucose metabolism, cell division, and contextual memory. PKA Cα is part of a larger protein complex that is responsible for controlling when and where proteins are phosphorylated. Defective regulation of PKA holoenzyme activity has been linked to the progression of cardiovascular disease, certain endocrine disorders and cancers.

CREB1 Mammalian protein found in Homo sapiens

CAMP responsive element binding protein 1, also known as CREB-1, is a protein that in humans is encoded by the CREB1 gene. This protein binds the cAMP response element, a DNA nucleotide sequence present in many viral and cellular promoters. The binding of CREB1 stimulates transcription.

ATF1 Protein-coding gene in the species Homo sapiens

Cyclic AMP-dependent transcription factor ATF-1 is a protein that in humans is encoded by the ATF1 gene.

CAMK2G

Calcium/calmodulin-dependent protein kinase type II gamma chain is an enzyme that in humans is encoded by the CAMK2G gene.

Activating transcription factor 2 Protein-coding gene in the species Homo sapiens

Activating transcription factor 2, also known as ATF2, is a protein that, in humans, is encoded by the ATF2 gene.

cAMP responsive element modulator Protein-coding gene in the species Homo sapiens

cAMP responsive element modulator is a protein that in humans is encoded by the CREM gene, and it belongs to the cAMP-responsive element binding protein family. It has multiple isoforms, which act either as repressors or activators. CREB family is important for in regulating transcription in response to various stresses, metabolic and developmental signals. CREM transcription factors also play an important role in many physiological systems, such as cardiac function, circadian rhythms, locomotion and spermatogenesis.

PRKAR2B

cAMP-dependent protein kinase type II-beta regulatory subunit is an enzyme that in humans is encoded by the PRKAR2B gene.

AKAP5 Protein-coding gene in the species Homo sapiens

A-kinase anchor protein 5 is a protein that in humans is encoded by the AKAP5 gene.

PRKACB Protein-coding gene in the species Homo sapiens

cAMP-dependent protein kinase catalytic subunit beta is an enzyme that in humans is encoded by the PRKACB gene.

CREBL1 Protein-coding gene in the species Homo sapiens

CAMP responsive element binding protein-like 1, also known as CREBL1, is a protein which in humans is encoded by the CREBL1 gene.

In the field of molecular biology, the cAMP-dependent pathway, also known as the adenylyl cyclase pathway, is a G protein-coupled receptor-triggered signaling cascade used in cell communication.

Dopamine-responsive dystonia (DRD) also known as Segawa syndrome (SS), is a genetic movement disorder which usually manifests itself during early childhood at around ages 5–8 years.

Tyrosine hydroxylase deficiency (THD) is a disorder caused by disfunction of tyrosine hydroxylase, an enzyme involved in the biosynthesis of dopamine. This condition is one of the causes of dopa-responsive dystonia.

References

  1. 1 2 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. S2CID   13798149.
  2. ↑ Nygaard G, Szigetvar PD, Grindheim AK, Ruoff P, Martinez A, Jaavik J, Kleppe R, Flydal MI (November 2021). "Personalized Medicine to Improve Treatment of Dopa-Responsive Dystonia—A Focus on Tyrosine Hydroxylase Deficiency". J. Pers. Med. 11 (1186): 1186. doi: 10.3390/jpm11111186 . PMC   8625014 . PMID   34834538.
  3. ↑ 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. S2CID   489075.
  4. 1 2 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.
  5. ↑ 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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