|Topic:||Tyrosine-Derived Neurotransmitters .|
|Details:|| Much of the tyrosine that does not get incorporated into proteins is catabolized for energy production. Another significant fate of tyrosine is conversion to the catecholamines. The catecholamines are dopamine, norepinephrine, and epinephrine. All three catecholamines exert effects in numerous locations in the body as either a neurotransmitter or as a hormone. Within the central and peripheral nervous systems (CNS and PNS, respectively) the catecholamines exert their effects as neurotransmitters, in the periphery they do so as hormones. The details of catecholamine effects exerted via activation of specific receptors are only covered briefly in this section. For greater detail go to the Biochemistry of Nerve Transmission page.
Tyrosine is transported into catecholamine-secreting neurons and adrenal medullary chromaffin cells where catecholamine synthesis takes place. The first step in the process requires tyrosine hydroxylase which, like phenylalanine hydroxylase (of tyrosine synthesis), requires tetrahydrobiopterin (BH4, or also written H4B) as cofactor. The tyrosine hydroxylase reaction represents the rate-limiting reaction of catecholamine biosynthesis. The dependence of tyrosine hydroxylase on BH4 necessitates the coupling to the action of dihydropteridine reductase (encoded by the QDPR gene: quinoid dihydropteridine reductase) as is the situation for tryptophan hydroxylase (see below) and phenylalanine hydroxylase. The product of the tyrosine hydroxylase reaction is 3,4-dihydrophenylalanine (L-DOPA; more commonly just DOPA). The enzyme DOPA decarboxylase then converts DOPA to dopamine. The enzyme dopamine β-hydroxylase then converts dopamine to norepinephrine. Dopamine β-hydroxylase is a major vitamin C and copper (Cu2+)-dependent enzyme whose activity is negatively affected in Menkes disease. The last step of catecholamine biosynthesis is the conversion of norepinephrine to epinephrine which involves a methylation reaction. The enzyme phenylethanolamine N-methyltransferase catalyzes this methylation reaction utilizing S-adenosylmethionine (SAM or AdoMet) as a methyl donor. In addition to epinephrine synthesis, the last reaction generates S-adenosylhomocysteine. Within the substantia nigra (largest of four nuclei in the basal ganglia of the midbrain), and some other regions of the brain, synthesis proceeds only to dopamine. Within the locus coeruleus (a brainstem nucleus in the dorsal pontine tegmentum) the end product of the pathway is norepinephrine. Within adrenal medulla chromaffin cells, tyrosine is converted to norepinephrine and epinephrine.
The tyrosine hydroxylase gene (symbol: TH) is located on chromosome 11p15.5 and is composed of 14 exons that generate three alternatively spliced mRNAs that encode tyrosine hydroxylase isoforms a, b, and c, Mutations in the TH gene are associated with the development of Segawa syndrome. Segawa syndrome is an autosomal recessive disorder that manifests in early infancy as a DOPA-responsive dystonia. Two distinct phenotypes are associated with Segawa syndrome, one that manifests very early and presents with symptoms of greater severity, and a later onset less severe type that responds better to L-DOPA therapy.
DOPA decarboxylase (also known as aromatic L-amino acid decarboxylase, AADC) is encoded by the DDC gene which is located on chromosome 7p12.2 and is composed of 18 exons that generate multiple alternatively spliced mRNAs. The DDC encoded enzyme is also responsible for the conversion of 5-hydroxytryptophan to serotonin (see next section) and tryptophan to tryptamine.
The dopamine β-hydroxylase gene (symbol: DBH) is located on chromosome 9q34 and is composed of 12 exons that encode a protein of 617 amino acids. Dopamine β-hydroxylase is found as both a soluble and a membrane-bound enzyme dependent upon whether or not the signal peptide from the precursor protein is present.
The phenylethanolamine N-methyltransferase gene (symbol: PNMT) is located on chromosome 17q12 and is composed of 5 exons that generate two alternatively spliced mRNAs, one of which is non-coding, the other encodes a protein of 282 amino acids.
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