Tyrosine hydroxylase dopamine/norepinephrine

Nadi NS, Head R, Grillo M, Hempstead J, Grannot-Reisfeld N, et al. 1981. Chemical deafferentation of the olfactory bulb Plasticity of the levels of tyrosine hydroxylase, dopamine and norepinephrine. Brain Res 213 365-377. 

Fig. 2. Biosynthetic pathway for epinephrine, norepinephrine, and dopamine. The enzymes cataly2ing the reaction are (1) tyrosine hydroxylase (TH), tetrahydrobiopterin and O2 are also involved (2) dopa decarboxylase (DDC) with pyridoxal phosphate (3) dopamine-P-oxidase (DBH) with ascorbate, O2 in the adrenal medulla, brain, and peripheral nerves and (4) phenethanolamine A/-methyltransferase (PNMT) with. Cadenosylmethionine in the adrenal...

The first step is catalysed by the tetrahydrobiopterin-dependent enzyme tyrosine hydroxylase (tyrosine 3-monooxygenase), which is regulated by end-product feedback is the rate controlling step in this pathway. A second hydroxylation reaction, that of dopamine to noradrenaline (norepinephrine) (dopamine [3 oxygenase) requires ascorbate (vitamin C). The final reaction is the conversion of noradrenaline (norepinephrine) to adrenaline (epinephrine). This is a methylation step catalysed by phenylethanolamine-jV-methyl transferase (PNMT) in which S-adenosylmethionine (SAM) acts as the methyl group donor. Contrast this with catechol-O-methyl transferase (COMT) which takes part in catecholamine degradation (Section 4.6). 

Synthesis of norepinephrine begins with the amino acid tyrosine, which enters the neuron by active transport, perhaps facilitated by a permease. In the neuronal cytosol, tyrosine is converted by the enzyme tyrosine hydroxylase to dihydroxyphenylalanine (dopa), which is converted to dopamine by the enzyme aromatic L-amino acid decarboxylase, sometimes termed dopa-decarboxylase. The dopamine is actively transported into storage vesicles, where it is converted to norepinephrine (the transmitter) by dopamine (3-hydroxylase, an enzyme within the storage vesicle. 

Pheochromocytoma is sometimes treated with metyrosine (cx-methyltyrosine), the -methyl analog of tyrosine. This agent is a competitive inhibitor of tyrosine hydroxylase, the rate-limiting step in the synthesis of dopamine, norepinephrine, and epinephrine (see Figure 6-5). Metyrosine is especially useful in symptomatic patients with inoperable or metastatic pheochromocytoma. Because it has access to the central nervous system, metyrosine can cause extrapyramidal effects due to reduced dopamine levels. 

Tyrosine hydroxylase FIGRRQSL Synthesis of l-DOPA, dopamine, norepinephrine, and epinephrine... 

FIGURE 5—31. Dopamine (DA) is produced in dopaminergic neurons from the precursor tyrosine (tyr), which is transported into the neuron by an active transport pump, called the tyrosine transporter, and then converted into DA by two of the same three enzymes that also synthesize norepinephrine (Fig. 5-17). The DA-synthesizing enzymes are tyrosine hydroxylase (TOH), which produces DOPA, and DOPA decarboxylase (DDC), which produces DA. 

The production of dopamine and norepinephrine in your brain begins with the amino acid tyrosine, which is obtained from your diet. Tyrosine is converted to the amino acid levodopa, or L-DOPA, by the en2yme tyrosine hydroxylase. One very important cofactor is iron. Without iron, tyrosine hydroxylase fails to function normally. People with anemia have reduced body levels of iron and, as consequently, may have reduced tyrosine hydroxylase activity and thus reduced production of norepinephrine and dopamine. The decreased brain levels of these important neurotransmitters may lead to a slight depression, although most likely only in people with severe anemia. Generally, in a normal healthy person, the production of these two neurotransmitters is not easily affected by the contents of the diet. 

Tyrosine is converted to dopa by the rate-limiting enzyme tyrosine hydroxylase, which requires tetrahydrobiopterin, and is inhibited by a-methyltyrosine. Dopa is decarboxylated to dopamine by L-aromatic amino acid decarboxylase, which requires pyridoxal phosphate (vitamin B6) as a coenzyme. Carbidopa, which is used with levodopa in the treatment of parkinsonism, inhibits this enzyme. Dopamine is converted to norepinephrine by dopamine P-hydroxylase, which requires ascorbic acid (vitamin C), and is inhibited by diethyldithiocarbamate. Norepinephrine is converted to epinephrine by phenylethanolamine A -methyltransferase (PNMT), requiring S-adeno-sylmethionine. The activity of PNMT is stimulated by corticosteroids. 

List of Abbreviations CKU, chronic ketamine users COMT, catechol-O-methyltransferase DA, dopamine DAT, DA transporters DLPFC, dorsolateral prefrontal cortex EC, entorhinal cortex MPFC, medial prefrontal cortex NET, norepinephrine transporters PFC, prefrontal cortex SN, substantia nigra VTA, ventral tegmental area TH, tyrosine hydroxylase WCST, Wisconsin Cart Sort Task WM, working memory... 

Histamine, serotonin and the catecholamines (dopamine, epinephrine and norepinephrine) are synthesized from the aromatic amino acids histidine, tryptophan and phenylalanine, respectively. The biosynthesis of catecholamines in adrenal medulla cells and catecholamine-secreting neurons can be simply summarized as follows [the enzyme catalysing the reaction and the key additional reagents are in square brackets] phenylalanine — tyrosine [via liver phenylalanine hydroxylase + tetrahydrobiopterin] —> i.-dopa (l.-dihydroxyphenylalanine) [via tyrosine hydroxylase + tetrahydrobiopterin] —> dopamine (dihydroxyphenylethylamine) [via dopa decarboxylase + pyridoxal phosphate] — norepinephrine (2-hydroxydopamine) [via dopamine [J-hydroxylasc + ascorbate] —> epinephrine (jV-methyl norepinephrine) [via phenylethanolamine jV-methyltransferase + S-adenosylmethionine]. 

The catecholamines - dopamine, norepinephrine, and epinephrine are successively derived from tyrosine. S m-thesis occurs in the nerve terminals and in the adrenal gland. Tyrosine hydroxylase catalyzes the first step (Figure 10.2a) and is the major site of regulation (inhibition by dopamine and noradrenaline, activation by cAMP). This step gives rise to 3,4-dihydroxyphenylalanine (L-DOPA), which in turn is a substrate for L-aromatic acid decarboxylase. De-... 

Norepinephrine (NE), a catecholamine, was first identified as a neurotransmitter in 1946. In the peripheral nervous system, it is found as a neuro transmitter in the sympathetic postganglionic synapse. NE is synthesized by the enzyme dopamine-p-hydroxylase (DbH) from the precursor dopamine (which is derived from tyrosine via DOPA). The rate-limiting step is the production of DOPA by tyrosine hydroxylase, which can be activated through phosphorylation. NE is removed from the synapse by two mechanisms (1) catechol-O-methyl-transferase (COMT), which degrades intrasynaptic NE, and (2) the norepinephrine transporter (NET), the primary way of removing NE from the synapse. Once internalized, NE can be degraded by the intracellular enzyme monoamine oxidase (MAO). 

NE is synthesized by tyrosine hydroxylation (meta ring position) followed by decarboxylation and side chain p carbon hydroxylation. The synthesis of this catecholamine is regulated by tyrosine hydroxylase. Tyrosine hydroxylation is also a key step in the synthesis of two other important catecholamines, dopamine and epinephrine. NE is packaged via active transport into synaptic (or chromaffin) vesicles prior to release by neuronal depolarization. The effects of NE are mediated by adrenergic receptors (a or P) which are G protein coupled resulting in either increases or decreases in smooth muscle tone as well as increases in cardiac rate and contractility. These effects arise out of receptor mediated increases in intracellular Ca and activation or inhibition of various protein kinases. The effects of NE are terminated essentially as a result of its active transport into the presynaptic nerve ending via an energy and Na" dependent process which utilizes the norepinephrine transporter (NET). Ultimately, NE and other catecholamines are metabolized by monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT). 

Catecholamines are endogenous compounds and are synthesized in the brain, the adrenal medulla, and by some sympathetic nerve fibers. The biosynthesis of catecholamines begins with the hydroxylation of tyrosine by tyrosine hydroxylase to form L-dopa, which is decarboxylated by aromatic amino acid decarboxylase to form dopamine. Norepinephrine... 

Figure 29-3 Schematic diagram illustrating the dynamics of synthesis, exocytotic release (R), neuronal reuptake (NU), extraneurona uptake (EU), vesicular leakage (VL), vesicular sequestration (VS), and metabolism of norepinephrine (NE) in sympathetic nerve endings in relation to extraneuronal tissue and the bloodstream. Relative magnitudes of the various processes are reflected by the relative sizes of arrows. TH, Tyrosine hydroxylase MAO, monoamine oxidase COMT catechol-O-methyitransferase T R, tyrosine L-dopa, 3,4-dihydroxyphenyialanine DA, dopamine DHPG, 3,4-dihydroxyphenylglycol NMN, normetanephrine MHPG, 3-methoxy-4-hydroxypheny [glycol.

NADH exhibits a lower and higher V ,ax for the reductase than NADPH. Thus, the pterin coenzyme functions stoichiometrically (in the hydroxylase reaction) and catalytically (in the reductase reaction). Deficiency of dihydropteridine reductase causes a substantial decrease in the rate of phenylalanine hy-droxylation. Dihydropteridine reductase and tetrahydrobiopterin are involved in hydroxylation of tyrosine and of tryptophan to yield neurotransmitters and hormones (dopamine, norepinephrine, epinephrine, and serotonin). Unlike phenylalanine hydroxylase, dihydropteridine... 

Dopamine (DA) and norepinephrine (NE) are allosteric inhibitors of tyrosine hydroxylase and regulate catecholamine synthesis when the adrenal medulla is quiescent (unstimulated). Continuous stimulation of the adrenal medulla (as during prolonged stress) promotes tyrosine hydroxylase activity primarily because the turnover of DA and NE is rapid. Tyrosine hydroxylase activity is also regulated by cAMP and by cholinergic nerve activity. The enzyme is active when phos-phorylated (Chapter 30). Tonic cholinergic impulses maintain the activity of tyrosine hydroxylase, whereas... 

The answer is e. (Murray, pp 307-346. Scriver, pp 1667—1724. Sack, pp 121-138. Wilson, pp 287—3177) In humans, tyrosine can be formed by the hydroxylation of phenylalanine. This reaction is catalyzed by the enzyme phenylalanine hydroxylase. A deficiency of phenylalanine hydroxylase results in the disease called phenylketonuria [PKU(261600)]. In this disease it is usually the accumulation of phenylalanine and its metabolites rather than the lack of tyrosine that is the cause of the severe mental retardation ultimately seen. Once formed, tyrosine is the precursor of many important signal molecules. Catalyzed by tyrosine hydroxylase, tyrosine is hydroxylated to form L-dihydroxyphenylalanine (dopa), which in turn is decarboxylated to form dopamine in the presence of dopa decarboxylase. Then, norepinephrine and finally epinephrine are formed from dopamine. All of these are signal molecules to some degree. Dopa and inhibitors of dopa decarboxylase are used in the treatment of Parkinson s disease, a neurologic disorder. Norepinephrine is a transmitter at smooth-muscle junctions innervated by sympathetic nerve libers. Epinephrine and dopamine are catecholamine transmitters synthesized in sympathetic nerve terminals and in the adrenal gland. Tyrosine is also the precursor of thyroxine, the major thyroid hormone, and melanin, a skin pigment. 

Fates of tyrosine. Tyrosine can be degraded by oxidative processes to ace-toacetate and fumarate which enter the energy generating pathways of the citric acid cycle to produce ATP as indicated in Figure 38-2. Tyrosine can be further metabolized to produce various neurotransmitters such as dopamine, epinephrine, and norepinephrine. Hydroxylation of tyrosine by tyrosine hydroxylase produces dihydroxyphenylalanine (DORA). This enzyme, like phenylalanine hydroxylase, requires molecular oxygen and telrahydrobiopterin. As is the case for phenylalanine hydroxylase, the tyrosine hydroxylase reaction is sensitive to perturbations in dihydropteridine reductase or the biopterin synthesis pathway, anyone of which could lead to interruption of tyrosine hydroxylation, an increase in tyrosine levels, and an increase in transamination of tyrosine to form its cognate a-keto acid, para-hydroxyphenylpyruvate, which also would appear in urine as a contributor to phenylketonuria. 

Tetrahydrobiopterin (BH4) is required in the synthesis of neurotransmitters such as norepinephrine and serotonin, which are produced in brain. BH4 is required in the reaction catalyzed by tyrosine hydroxylase in which tyrosine is hydrox-ylated to form L-dopa (a precursor of several neurotransmitters including dopamine and norepinephrine), and the reaction catalyzed by tryptophan hydroxylase in which tryptophan is hydroxylated to form 5-hydroxytryptophan. L-Dopa and 5-hydroxytryptophan must be supplied to individuals lacking the capacity to synthesize BH4 because the latter molecule does not cross the blood-brain barrier. 

Noradrenergic and adrenergic neurons also contain the enzyme dopamine (i-hydroxylase. Like tyrosine hydroxylase, this enzyme is a mixed function oxygenase. The electron donor in this case is ascorbic acid rather than tetrahydrobiopterin, and dopamine is the primary substrate. The enzyme has been well characterized and is a tetramer of 75,000-Da subunits, which are copper-containing glycoproteins. No major regulatory systems are known for this enzyme. It appears that there are sufficient enzyme molecules present in cells in which this enzyme is expressed to completely convert all the dopamine that is formed into norepinephrine. 

The subcellular localization of the enzyme is interesting. In contrast to tyrosine hydroxylase, which is localized to the cytoplasmic compartment, dopamine hydroxylase is largely contained within the aminergic storage vesicles. Thus, it appears that dopamine, which is synthesized in the cytosol, must be taken up into these vesicles in order to be converted to norepinephrine. Approximately 50% of the enzyme is associated with the membranous portion of the vesicles, whereas the other 50% is in a soluble form within the vesicle. During synaptic transmission noradrenergic neurons release both norepinephrine and its biosynthetic enzyme by an exocytotic mechanism. While most of the released norepinephrine is taken back up by the terminal, the enzyme is believed to diffuse of the synaptic cleft into the extracellular fluid and eventually into the serum. There are relatively large amounts of dopamine p-hydroxylase in human serum that are believed to arise from release from sympathetic neurons. 

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