Tyrosine epinephrine synthesis

Pathway of epinephrine synthesis. Epinephrine and its precursor, norepinephrine, are synthesized from tyrosine. The synthesis occurs in the chromaffin cells of the adrenal medulla and in neurons of the central and peripheral nervous system. The first step, which is catalyzed by tyrosine hydroxylase, is the rate-limiting step in the pathway. 

Dopamine (5-hydroxylase is a copper-containing enzyme involved in the synthesis of the catecholamines norepinephrine and epinephrine from tyrosine in the adrenal medulla and central nervous system. During hy-droxylation, the Cu+ is oxidized to Cu " reduction back... 

Known most famously for their part in the fight or flight response to a threat, challenge or anger, adrenaline (epinephrine) and dopamine from the adrenal medulla and noradrenaline (norepinephrine), mainly from neurones in the sympathetic nervous system are known collectively as catecholamines. Synthesis follows a relatively simple pathway starting with tyrosine (Figure 4.7). 

In addition to their well known role in protein structure, amino acids also act as precursors to a number of other important biological molecules. For example, the synthesis of haem (see also Section 5.3.1), which occurs in, among other tissues, the liver begins with glycine and succinyl-CoA. The amino acid tyrosine which maybe produced in the liver from metabolism of phenylalanine is the precursor of thyroid hormones, melanin, adrenaline (epinephrine), noradrenaline (norepinephrine) and dopamine. The biosynthesis of some of these signalling molecules is described in Section 4.4. 

The adrenal medulla synthesizes two catecholamine hormones, adrenaline (epinephrine) and noradrenaline (norepinephrine) (Figure 1.8). The ultimate biosynthetic precursor of both is the amino acid tyrosine. Subsequent to their synthesis, these hormones are stored in intracellular vesicles, and are released via exocytosis upon stimulation of the producer cells by neurons of the sympathetic nervous system. The catecholamine hormones induce their characteristic biological effects by binding to one of two classes of receptors, the a- and )S-adrenergic receptors. These receptors respond differently (often oppositely) to the catecholamines. 

Corticosteroids also affect adrenomeduUary function by increasing epinephrine production the mechanism is exertion of a stimulatory action on two of the enzymes that regulate catecholamine synthesis, tyrosine hydroxylase, the rate-Umiting enzyme, and phenyl-ethanolamine Af-methyltransferase, which catalyzes the conversion of norepinephrine to epinephrine. Steroids also influence the metabolism of circulating catecholamines by inhibiting their uptake from the circulation by noimeuronal tissues (i.e., extraneuronal uptake see Chapter 9). This effect of corticoids may explain their permissive action in potentiating the hemodynamic effects of circulating catecholamines. 

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... 

Purines and pyrimidines are derived largely from amino acids. The biosynthesis of these precursors of DNA, RNA, and numerous coenzymes will be discussed in detail in Chapter 25. The reactive terminus of sphingosine, an intermediate in the synthesis of sphingolipids, comes from serine. Histamine, a potent vasodilator, is derived from histidine by decarboxylation. Tyrosine is a precursor of the hormones thyroxine (tetraiodothyronine) and epinephrine and of melanin, a complex polymeric pigment. The neurotransmitter serotonin (5-hydroxytryptamine) and the nicotinamide ring of NAD + are synthesized from tryptophan. Let us now consider in more detail three particularly important biochemicals derived from amino acids. 

Several other metabolic reactions require vitamin C as a cofactor. These include the catabolism of tyrosine and the s)mthesis of epinephrine from tyrosine and the synthesis of the bile acids. 

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). 

Norepinephrine and epinephrine are hormones in the class called catechoiami nes. The catecholamines are synthesized and stored in the adrenal gland. With exercise, nerve impulses stimulate the adrenal gland to release the hormones into the bloodstream. Elevated levels of the plasma catecholamines, in turn, induce the contraction or dilation of specific arteries, and the synthesis of cAMF in various cells. Norepinephrine and epinephrine are stored in and released by nerve endings and, for this reason, these hormones are also classed as neurotransmitters. The catecholamine biosynthetic pathway begins with tyrosine (Figure 9.85). 

FIGURE 9.85 Biosynthesis of catecholstntnes. Tyrosine is used for the synthesis of various small molecules, which are used as hormones and neuiotransmitters. The nutritional biochemist mi t be especially interested in the pathway of epinephrine biosynthesis, as it requires the participation of four separate cofactors. These are fl) biopterin 2) pyridoxal phosphate 3) ascorbic acid and (4) S-adenosyl-mcthionine. 

Phenylalanine and tyrosine are also metabolized in higher organisms by two routes which are quantitatively less important but physiologically of the highest importance. The first leads to the adrenal hormones adrenaline (epinephrine) and noradrenaline (norepinephrine),which may be formed as in diagram 11 this pathway also leads to melanin (diagram 12). The second leads to the thyroid hormones thyroxine and triiodothyronine, the synthesis and breakdown of which are also discussed. 

Phenylalanine is an essential amino acid. Tyrosine is synthesized by hydroxylation of phenylalanine and therefore is not essential. However, if the hydroxylase system is deficient or absent, the tyrosine requirement must be met from the diet. These amino acids are involved in synthesis of a variety of important compounds, including thyroxine, melanin, norepinephrine, and epinephrine... 

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. 

THE AROMATIC FAMILY The aromatic family of amino acids includes phenylalanine, tyrosine, and tryptophan. Of these, only tyrosine is considered to be nonessential in mammals. Either phenylalanine or tyrosine is required for the synthesis of dopamine, epinephrine, and norepinephrine, an important class of biologically potent molecules referred to as the catecholamines (Special Interest Box 14.2). Tryptophan is a precursor in the synthesis of NAD+, NADP+, and the neurotransmitter serotonin. 

The first and rate-limiting step in the synthesis of these neuroffansmitters from tyrosine is the hydroxylation of the tyrosine ring by tyrosine hydroxylase, a teffahy-drobiopterin (BH4)-requiring enzyme. The product formed is dihydroxyphenylala-nine or DOPA. The phenyl ring with two adjacent OH groups is a catechol, and hence dopamine, norepinephrine, and epinephrine are called catecholamines. 

In adrenergic neurons, L-dopa is converted to NE by DA fl-hydroxylase or to epinephrine by phenyl-ethanolamine-N-methyl transferase. The rate of synthesis of DA is determined by the amount of available tyrosine hydroxylase, and is a key factor in determining the rate of neuronal firing or inhibition by DA. DA is metabolized by the enzyme catechol-0-methyl transferase and MAO. 

The epinephrine receptor causes the synthesis of cyclic AMP, which is an activator of an enzyme, a protein kinase C (see Figure 12-11). Protein kinases transfer phosphate from ATP to the hydroxyl group on the side chain of a serine, threonine, or tyrosine. Protein kinase C is a serine-specific kinase. Protein kinase C is a tettamer composed of two regulatory (R) subunits and two catalytic (C) subunits. When it has cAMP bound to it, the R subunit dissociates from the C subunits. The C subunits are now catalytically active. 

Tyrosine is either used for the biosynthesis of proteins, thyroxine, epinephrine, or melanin, or catabo-lized to yield fumaryl acetoacetate. The biosynthesis of proteins and thyroxine is discussed elsewhere this discussion is restricted to epinephrine and melanin synthesis and tyrosine catabolism. Dopa 3,4-dihydroxy-phenylalanine is an intermediate common to epinephrine and melanin. To yield epinephrine, dopa is first decarboxylated by an enzyme called dopa decarboxylase. This enzyme is present in several mammalian tissues, including the adrenal medulla, where the reaction yields hydroxytryptamine chloride. From this... 

The majority of catecholamine and serotonin biosynthesis occurs within the nerve terminals by synthetic enzymes transported from the neuronal cell bodies. In all catecholamine neurons, the rate-limiting step in synthesis is conversion of tyrosine to dihydroxyphenylalanine by tyrosine hydroxylase. Dihydroxyphenylalanine is then converted to DA, norepinephrine, and epinephrine through a sequential process involving L-aromatic amino acid decarboxylase (conversion of dihydroxyphenylalanine to DA), dopamine-P-hydroxylase (conversion of DA to norepinephrine), and phenylethanol-amine-N-methyltransferase (conversion of norepinephrine to epinephrine). Cell-specific expression of these enzymes determines the main neurotransmitter for an individual catecholamine neuron. The synthesis pathway for serotonin involves a two-step process in which tryptophan hydroxylase first converts tryptophan to 5-hydroxytryptophan, which is then converted to... 

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