Norepinephrine from tyrosine

In addition to collagen metabolism and scavenging ROS species to limit inflammation as noted above, ascorbate is required for the synthesis of norepinephrine from tyrosine, of carnitine from y-butyrobetaine whose immediate precursor is made by trimethylating lysine, for folinic acid production from folic acid. In the absence of ascorbate, the reduced activity of these processes slows nerve, energy and cardiac output, causingthe affected person to become exhausted and irritable. Scurvy is the old English word for ill-tempered. 

Both MAOis and TCAs have the capacity to inhibit tyrosine hydroxylase, one of the main enzymes modulating the synthesis of norepinephrine from tyrosine. Inhibition of tyrosine hydroxylase may result in a decreased concentration of norepinephrine in presynaptic storage vesicles, which will eventually lead to decreased secretion into the synaptic cleft. However, it is not yet clear if this effect is clinically significant. 

The pathway for the synthesis of serotonin from tryptophan is very similar to the pathway for the synthesis of norepinephrine from tyrosine (Fig. 48.7). The first enzyme of the pathway, tryptophan hydroxylase, uses an enzymic mechanism similar to that of tyrosine and phenylalanine hydroxylase and requires BH4 to hydroxylate the ring structure of tryptophan. The second step of the pathway is a decarboxylation reaction... 

Amino acid-derived hormones include the catecholamines, epinephrine and norepinephrine (qv), and the thyroid hormones, thyroxine and triiodothyronine (see Thyroid AND ANTITHYROID PREPARATIONS). Catecholamines are synthesized from the amino acid tyrosine by a series of enzymatic reactions that include hydroxylations, decarboxylations, and methylations. Thyroid hormones also are derived from tyrosine iodination of the tyrosine residues on a large protein backbone results in the production of active hormone. 

Catecholamines. The catecholamines, epinephrine (EPl adrenaline) (85), norepinephrine (NE noradrenaline) (86) (see Epinephrine and norepinephrine), and dopamine (DA) (2), are produced from tyrosine by the sequential formation of L-dopa, DA, NE, and finally EPl. EPl and NE produce their physiological effects via CC- and -adrenoceptors, a-Adrenoceptors can be further divided into CC - and a2-subtypes which in turn are divided... 

Catecholamines are biogenic amines with a catechol (o-dihydroxy-benzol) structure. They are synthesized in nerve endings from tyrosine and include dopamine, noradrenaline (norepinephrine) and adrenaline (epinephrine). 

Three amines—dopamine, norepinephrine, and epinephrine—are synthesized from tyrosine in the chromaffin cells of the adrenal medulla. The major product of the adrenal medulla is epinephrine. This compound constimtes about 80% of the catecholamines in the medulla, and it is not made in extramedullary tissue. In contrast, most of the norepinephrine present in organs innervated by sympathetic nerves is made in situ (about 80% of the total), and most of the rest is made in other nerve endings and reaches the target sites via the circu-... 

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... 

Anderson DJ, Puttfarcken PS, Jacobs 1, Faltynek C (2000) Assessment of nicotinic acetylcholine receptor-mediated release of [ H]-norepinephrine from rat brain slices using a new 96-well format assay. Neuropharmacology 39 2663-2672 Anney RJ, Olsson CA, Lotfi-Miri M, Patton GC, Williamson R (2004) Nicotine dependence in a prospective population-based study of adolescents the protective role of a functional tyrosine hydroxylase polymorphism. Pharmacogenetics 14 73-81 Auerbach A, Akk G (1998) Desensitization of mouse nicotinic acetylcholine receptor channels. 

Catecholamine Hormones The water-soluble compounds epinephrine (adrenaline) and norepinephrine (noradrenaline) are catecholamines, named for the structurally related compound catechol. They are synthesized from tyrosine. 

Other important nitrogen-containing compounds made from amino acids include the catecholamines (dopamine, norepinephrine, and epinephrine), which are synthesized from tyrosine creatine, which is synthesized from arginine and glycine histamine, which is synthesized from histidine and serotonin, which is synthesized from tryptophan. 

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. 

The most abundant alkaloid in Coryphantha macromeris, normacromerine, has been shown to originate from tyrosine (330). Tyramine and JV-methyltyramine are efficiently incorporated into normacromerine while octopamine and dopamine are poor precursors. Norepinephrine, epinephrine, normetanephrine, and meta-nephrine have all been shown to be biosynthetically incorporated into normacromerine, and they have also been shown to be naturally occurring trace intermediates in this cactus species (331, 334). Normacromerine is only slowly converted to macromerine in C. macromeris (332). The results indicate that alternative pathways to normacromerine exist precise conclusions regarding the biosynthesis of normacromerine must await further studies. 

Epinephrine [ep ee NEF rin] is one of five catecholamines—epinephrine, norepinephrine, dopamine, dobutamine, and isoproterenol—commonly used in therapy. The first three catecholamines occur naturally, the latter two are synthetic compounds (see Figure 6.7). Epinephrine is synthesized from tyrosine in the adrenal medulla and released, along with small quantities of norepinephrine, into the blood stream. Epinephrine interacts with both a and p receptors. At low doses, p effects (vasodilation) on the vascular system predominate, whereas at high doses, a effects (vasoconstrictor) are strongest. 

While both dopamine and norepinephrine are derived from tyrosine, serotonin (5-hydroxytryptamine, 5-HT) is derived from tryptophan. All three transmitters are very important... 

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). 

Thyroid hormone, 3,4-dihydroxy phenylalanine (dopa), melanin, dopamine, norepinephrine, and epinephrine are produced from tyrosine. 

Tyrosine can be decarboxylated to tyramine by aromatic L-amino acid decarboxylase of intestinal bacteria. Tyramine, which is present in large amounts in certain foods (e.g., aged cheeses, red wines), is converted by monoamine oxidase (MAO) to the aldehyde derivatives. However, individuals who are receiving MAO inhibitors for the treatment of depression can accumulate high levels of tyramine, causing release of norepinephrine from sympathetic nerve endings and of epinephrine from the adrenal medulla. This results in peripheral vasoconstriction and increased cardiac output, which lead to hypertensive crises that can cause headaches, palpitations, subdural hemorrhage, stroke, or myocardial infarction. 

Norepinephrine is synthesized from tyrosine in the chromaffin cells of the adrenal medulla in response to fright, cold, and exercise... 

Among the most important neurotransmitters are acetylcholine (ACh), amino acids and their derivatives, and certain polypeptides known as neuropeptides. In fact, the mammalian nervous system is said to employ over 30 different substances as neurotransmitters. For the record, among the amino acids and their derivatives (called biogenic amines) are many that are also hormonally active in the bloodstream, and include the catecholamines dopamine, norepinephrine, and epinephrine, as derived sequentially from tyrosine, whereas y-aminobutyric acid (GABA), histamine, and serotonin are derived from glutamate, histidine, and tryptophan, respectively. The subject interfaces with the biochemical aspects of psychology, which may also be referred to as the mind-body connection, or psychosomatics. 

Methylation by S-adenosylmethionine converts norepinephrine into epinephrine. The biosynthetic pathway from tyrosine to dopamine, and the other catecholamines is shown in Figure 21.32. 

Glycine and glutamate are amino acids that serve directly as neurotransmitters are. y-Aminobutyric acid (GABA), the decarboxylation product of glutamate, is also a neurotransmitter. Amino acid metabolites that function in neurotransmission include histamine (from histidine), serotonin (from tryptophan), and catecholamines (epinephrine, dopamine, and norepinephrine), which are derived from tyrosine. 

The adrenal medulla forms part of the sympathetic nervous system and is the primary site for the production of the catecholamines—epinephrine (adrenaline) and norepinephrine (noradrenaline), which are primary hormones (also called biogenic amines). The cells of the medulla are arranged in lobules and the medulla contains chromaffin cells, which are modified postganglionic cells of the sympathetic nervous system. The medulla produces catecholamines from tyrosine and their structures contain catechol and amine groups (Figure 10.3.3). 

Fig 26.13. Structure of epinephrine and norepinephrine. Epinephrine and norepinephrine are synthesized from tyrosine and act as both hormones and neurotransmitters. They are catecholamines, the term catechol referring to a ring structure containing two hydroxyl groups. 

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. 

Norepinephrine is synthesized from tyrosine, stored in presynaptic vesicles, and released from vesicles upon the arrival of axonal action potentials. After its release into synapses, unbound norepinephrine is taken back into presynaptic neurons by norepinephrine transporters, which terminate its effect. The reuptake process clears 70-90%... 

Tyramine is formed in foods such as cheese by the bacterial degradation of milk and other proteins, firstly to tyrosine and other amino acids, and the subsequent deearboxylation of the tyrosine to tyramine. This interaction is therefore not associated with fresh foods, but with those which have been allowed to over-ripen or mature in some way, or if spoilage occurs. Tyramine is an indirectly-acting sympathomimetic amine, one of its actions being to release noradrenaline (norepinephrine) from the adrenergic neurones associated with blood vessels, which causes a rise in blood pressure by stimulating their constriction. ... 

The accumulation of phenylalanine and its metabolites may interfere with the metabolism of other amino acids. Stein and Moore, and later Knox, showed that in phenylketonuric patients the amount of other amino acids in the plasma is decreased while phenylalanine accumulates. This interaction between the amino acids metabolism acquires particular significance in view of the mode of amino acid uptake in the brain. The investigators demonstrated that phenylalanine inhibits tyrosine uptake in the brain. Thus, in the presence of large amounts of phenylalanine, protein synthesis in the brain might be inhibited. Furthermore, because of the absence of tyrosine, the biosynthesis of well-known neuroregulators derived from tyrosine, such as norepinephrine and 3,4-dihydroxyphenylethyl-amine, could also be reduced in the brain. 

One of the most potent inhibitors of tyrosine hydroxylase is a-methyltyro-sine. This substance blocks catecholamine biosynthesis and thereby depletes tissue catecholamines in animals [42,231, 256,257]. In man, daily doses of 1-4 g inhibit catecholamine biosynthesis to the extent of 50-70% [71]. Studies with radioactively labelled dopa have shown that the biosynthesis of dopa and norepinephrine from t5n osine is blocked while the conversion from dopa to norepinephrine is not affected [67]. 

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