Catecholamine biosynthesis tyrosine hydroxylase

Tyrosine is the immediate precursor of catecholamines, and tyrosine hydroxylase is the rate-limiting enzyme in catecholamine biosynthesis. Tyrosine hydroxylase is found in both soluble and particle-bound forms only in tissues that synthesize catecholamines it functions as an oxidoreductase, with tetrahydropteridine as a cofactor, to convert L-tyrosine to L-dihydroxyphenylalanine (L-dopa). 

L-Tyrosine metabohsm and catecholamine biosynthesis occur largely in the brain, central nervous tissue, and endocrine system, which have large pools of L-ascorbic acid (128). Catecholamine, a neurotransmitter, is the precursor in the formation of dopamine, which is converted to noradrenaline and adrenaline. The precise role of ascorbic acid has not been completely understood. Ascorbic acid has important biochemical functions with various hydroxylase enzymes in steroid, dmg, andhpid metabohsm. The cytochrome P-450 oxidase catalyzes the conversion of cholesterol to bUe acids and the detoxification process of aromatic dmgs and other xenobiotics, eg, carcinogens, poUutants, and pesticides, in the body (129). The effects of L-ascorbic acid on histamine metabohsm related to scurvy and anaphylactic shock have been investigated (130). Another ceUular reaction involving ascorbic acid is the conversion of folate to tetrahydrofolate. Ascorbic acid has many biochemical functions which affect the immune system of the body (131). 

Catecholamine biosynthesis begins with the uptake of the amino acid tyrosine into the sympathetic neuronal cytoplasm, and conversion to DOPA by tyrosine hydroxylase. This enzyme is highly localized to the adrenal medulla, sympathetic nerves, and central adrenergic and dopaminergic nerves. Tyrosine hydroxylase activity is subject to feedback inhibition by its products DOPA, NE, and DA, and is the rate-limiting step in catecholamine synthesis the enzyme can be blocked by the competitive inhibitor a-methyl-/)-tyrosine (31). 

A. Tyrosine Hydroxylase Is Rate-Limiting FOR Catecholamine Biosynthesis ... 

Tyrosine hydroxylase is the rate-limiting enzyme for the biosynthesis of catecholamines 212... 

Tyrosine hydroxylase is the rate-limiting enzyme for the biosynthesis of catecholamines. Tyrosine hydroxylase (TH) is found in all cells that synthesize catecholamines and is a mixed-function oxidase that uses molecular oxygen and tyrosine as its substrates and biopterin as its cofactor [1], TH is a homotetramer, each subunit of which has a molecular weight of approximately 60,000. It catalyzes the addition of a hydroxyl group to the meta position of tyrosine, thus forming 3,4-dihydroxy-L-phenylalanine (l-DOPA). 

The regulation of phosphorylation of tyrosine hydroxylase is affected by stimuli that increase Ca2+ or cAMP concentrations in neurons, including nerve impulse conduction and certain neurotransmitters in well-defined regions of the nervous system, in the adrenal medulla and in cultured pheochromocytoma cells. In addition, tyrosine hydroxylase phosphorylation is stimulated by nerve growth factor in certain cell types, possibly via the activation of ERKs. These changes in the phosphorylation of tyrosine hydroxylase have been shown to correlate with changes in the catalytic activity of the enzyme and in the rate of catecholamine biosynthesis. 

The enzymes involved in catecholamine biosynthesis have been studied intensively and are the targets of many drugs. The key enzyme is tyrosine hydroxylase, which requires a tetrahydrofolate coenzyme, O, and Fe +, and is quite specific. As usual for the first enzymes in a biosynthetic pathway, tyrosine hydroxylase is rate limiting, and... 

The hereditary absence of phenylalanine hydroxylase, which is found principally in the liver, is the cause of the biochemical defect phenylketonuria (Chapter 25, Section B).430 4308 Especially important in the metabolism of the brain are tyrosine hydroxylase, which converts tyrosine to 3,4-dihydroxyphenylalanine, the rate-limiting step in biosynthesis of the catecholamines (Chapter 25), and tryptophan hydroxylase, which catalyzes formation of 5-hydroxytryptophan, the first step in synthesis of the neurotransmitter 5-hydroxytryptamine (Chapter 25). All three of the pterin-dependent hydroxylases are under complex regulatory control.431 432 For example, tyrosine hydroxylase is acted on by at least four kinases with phosphorylation occurring at several sites.431 433 4338 The kinases are responsive to nerve growth factor and epidermal growth factor,434 cAMP,435 Ca2+ + calmodulin, and Ca2+ + phospholipid (protein kinase C).436 The hydroxylase is inhibited by its endproducts, the catecholamines,435 and its activity is also affected by the availability of tetrahydrobiopterin.436... 

The general scheme of the biosynthesis of catecholamines was first postulated in 1939 (29) and finally confirmed in 1964 (Fig. 2) (30). Although not shown in Figure 2, in some cases the amino acid phenylalanine [63-91-2] can serve as a precursor it is converted in the liver to (-)-tyrosine [60-18-4] by the enzyme phenylalanine hydroxylase. Four enzymes are involved in E formation in the adrenal medulla and certain neurons in the brain tyrosine hydroxylase, dopa decarboxylase (also referred to as L-aromatic amino acid decarboxylase), dopamine-P-hydroxylase, and phenylethanolamine iV-methyltransferase. Neurons that form DA as their transmitter lack the last two of these enzymes, and sympathetic neurons and other neurons in the central nervous system that form NE as a transmitter do not contain phenylethanolamine N-methyl-transferase. The component enzymes and their properties involved in the formation of catecholamines have been purified to homogeneity and their properties examined. The human genes for tyrosine hydroxylase, dopamine- 3-oxidase and dopa decarboxylase, have been cloned (31,32). It is anticipated that further studies on the molecular structure and expression of these enzymes should yield interesting information about their regulation and function. 

The effects of treatment with selegiline, an MAO-B inhibitor, on plasma levels of insulin-like growth factor I (IGF-I) (as indicator of GH secretion), levels of monoamines and their metabolites, and the activity and content of tyrosine hydroxylase — the rate-limiting enzyme in the biosynthesis of catecholamines — in the hypothalamus and hypophysis of old animals have been studied. It is believed that the antiaging effects of selegiline are due to restoration of hypothalamic hormones. 

Figure 16.11 Control of catecholamine biosynthesis in the adrenal medulla. TH, tyrosine hydroxylase DBH, dopamine hydroxylase PNMT, phenylethanolamine methyl-transferase ACTH, adrenocorticotropic hormone. The heavy arrows indicate major sites of regulation. (Reproduced by permission from Axelrod, J. Reisine TD. Stress hormones their interaction and regulation. Science 224 452-459, 1984.)...

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]. 

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... 

Metyrosine (23, a-methyl-L-tyrosine), a norepinephrine biosynthesis inhibitor, is in limited clinical use to help control hypertensive episodes and other symptoms of catecholamine overproduction in patients with the rare adrenal tumor pheochromocytoma (10). Metyrosine, a competitive inhibitor of tyrosine hydroxylase, inhibits the production of catecholamines by the tumor. Although metyrosine is useful in treating hypertension caused by excess catecholamine biosynthesis... 

L-Dopa is normally a trace intermediary metabolite in the biosynthesis of catecholamines, formed from L-tyrosine in a rate-limiting hydroxylation step by tyrosine hydroxylase, a phosphorylation-activated cytoplasmic mono-oxygenase. L-Dopa is readily decar-boxy ated by the cytoplasmic enzyme L-aro-matic amino acid decarboxylase ("dopa decarboxylase ) to form DA (2). The effects observed after systemic administration of l-... 

Catecholamines are synthesized from the amino acid tyrosine, and serotonin from tryptophan as shown in Figure 29-2. The rate-limiting step in catecholamine biosynthesis involves conversion of tyrosine to 3,4-dihydroxyphenylalanine (L-dopa) by the enzyme, tyrosine hydroxylase. A related enzyme, tryptophan hydroxylase, catalyzes conversion of tryptophan to 5-hydroxytryptophan in the first step of serotonin synthesis. 

Adrenal medullary cells have plasma membrane receptors for acetylcholine (ACh) of the neuronal nicotinic subtype (Nn). These receptors are cation channels that span the plasma membrane and are activated by ACh to rapidly increase Na" " and K+ permeabilities (Na" " influx rate 5 x 10 ions/s), causing the cells to depolarize and release their catecholamines by exocytosis. The cholinergic stimulation of exocytosis is accompanied by an activation of tyrosine hydroxylase activity within the adrenal medullary cell, and this promotes biosynthesis of... 

Enzymes that are active in the biosynthesis and processing of hormones are important markers of endocrine cells. Immunoreactivity for aromatic L-amino acid decarboxylase, for example, is widely distributed in neuroendocrine (NE) cells. Tyrosine hydroxylase, dopamine 3-hydroxylase, and phenylethanolamine JV-methyl transferase, in contrast, have a more limited tissue distribution and are confined to known sites of catecholamine biosynthesis. Immunolocalization of these enzymes permits catecholamine-synthesizing abilities to be deduced from paraffin sections. The presence of immunoreactive enzyme, however, does not necessarily imply that the enzyme is present in a functional form. 

Figure 9-1. Biosynthesis of catecholamines. Denotes enzyme in transformation AADC = aromatic L-amino acid decarboxylase COMT = catechol-o-methyl transferase DBH = dopamine-B-hydroxylase MAO = monoamine oxidase PNMT = phenylethanolamine-N-methyl transferase TH = tyrosine hydroxylase.

Serotonin, or 5-hydroxytryptamine (5-HT), is another monoamine whose important central effects have only been recognized recently. It had previously been known as a vasoconstrictor in the plasma. Once identified chemically, it was found to be widely distributed in the body. After determination of significant brain levels in the hypothalamus, medulla, midbrain, and other areas (Table 12-3), and after establishing its biosynthetic paths, serotonin became recognized as a neurotransmitter. 5-HT is presently less well understood than are the catecholamines. Figure 12-3 outlines its biosynthesis from the essential amino acid tryptophan. Try enters the brain by active transport (as is L-dopa) and is hydroxylated there by tryptophan hydroxylase, which is an enzyme similar to if not identical to, tyrosine hydroxylase. 

Metyrosine is oc-methyl tyrosine, which competes with tyrosine for sites on tyrosine hydroxylase—the enzyme responsible for the rate-limiting step in catecholamine biosynthesis. Thus, it decreases catecholamine biosynthesis, resulting in a decrease in circulating levels of catecholamines. Metyrosine is a tyrosine hydroxylase inhibitor. 

These three neurotransmitters are synthesized in a common pathway from the amino acid L-tyrosine. Tyrosine is supplied in the diet or is synthesized in the liver from the essential amino acid phenylalanine by phenylalanine hydroxylase (see Chapter 39). The pathway of catecholamine biosynthesis is shown in Figure 48.4. 

Biosynthesis of norepinephrine takes piace within adrenergic neurons near the terminus of the axon and junction with the effector cell. The biosynthetic pathway (Fig. 13,1) begins with the active transport of the amino acid L-tyrosine into the adrenergic neuron cell (1). In the first step within the cytoplasm, the enzyme tyrosine hydroxylase (tyrosine-3-monooxygenase) oxidizes the 3 position of tyrosine to form the catechol amino acid L-dopa. This is the rate-limiting step in norepinephrine biosynthesis, and the activity of tyrosine hydroxylase is carefully controlled (3). The enzyme is under feedback inhibition control by product catecholamines and is... 

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