Catecholamine biosynthesis

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 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). 

Lee MK, Kim HS. Inhibitory effects of protoberberine alkaloids from the roots of Coptis japonica on catecholamine biosynthesis in PC12 cells. Planta Med 1996 62 31-34. 

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. 

Pharmacology Vitamin C, a water-soluble vitamin, is an essential vitamin in man however, its exact biological functions are not fully understood. It is essential for the formation and the maintenance of intercellular ground substance and collagen, for catecholamine biosynthesis, for synthesis of carnitine and steroids, for conversion of folic acid to folinic acid and for tyrosine metabolism. 

Segal DS, Callaghan M, MandeU AJ Alterations in behaviour and catecholamine biosynthesis induced by lithium. Nature 254 58-59, 1975 Seguela P, Wadiche J, Dineley-Miller K, et al Molecular cloning, functional properties, and distribution of rat brain dJ a nicotinic cation channel highly permeable to calcium. J Neurosci 13 596-604, 1993... 

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... 

Keywords Biopterin Catecholamine biosynthesis Dystonia Hyperphenylalaninemia NO biosynthesis Pterin Tetrahydrobiopterin... 

Figure 16.10 Catecholamine biosynthesis and metabolism. MAO, monoamine oxidase COMT, catecholamine-O-methyltransferase SAM, 5-adenosylmethionine.

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.)...

The metabolic pathways of phenylalanine and tyrosine are identical, because the essential phenylalanine must be converted to tyrosine to become metabolized. Figure 20.22 illustrates this pathway, which is termed the liver pathway to distinguish it from those leading to catecholamine biosynthesis. It is localized in the cytosol, with the exception of tyrosine transaminase, which is also present in the mitochondria. 

Potter BM, Bruno JP (1989) Food intake of rats depleted of dopamine as neonates is impaired by inhibition of catecholamine biosynthesis. Neurosci Lett 707 295-300. 

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... 

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. 

Schallreuter KU et al. (1994) Defective tetrahydrobiopterin and catecholamine biosynthesis in the depigmentation disorder vitiligo. Biochim Biophys Acta 1226(2) 181-192... 

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. 

Orally administered amines do not cross the blood-brainbarrier, but neutral amino acids such as a-methyldopa are transported into the brain by a specific carrier system. a-Meth-yldopa is subsequently concentrated in neuronal cells, where it becomes a substrate in the catecholamine biosynthesis and is transformed into a-methylnoradrenaline (180). 

The next step in the catecholamine biosynthesis is side-chain hydroxylation of DA to NE. The enzyme dopamine (3-hydroxylase (DBH) catalyzes this reaction. This enzyme, like TH, is a mixed-function oxidase utilizing molecular 02, in this case to add the OH onto the (3-carbon of the phenelthylamine side chain. DBH is a Cu2+-containing enzyme that, with ascorbic acid (Vitamin C) as a cofactor, carries out the necessary electron transfers. 

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. 

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