Adrenaline precursors

The widespread co-occurrence of noradrenaline and adrenaline in itself suggests that noradrenaline is the immediate adrenaline precursor. This had been considered probable even before the natural occurrence of noradrenaline was known (70, 71), and the methylation of noradrenaline has since been shown both in vitro in adrenal preparations (110) and in vivo on perfusing the surviving adrenal (111). The methyl group can arise from methionine, probably formed from choline, in which the adrenal is extremely rich. A large proportion of the activity of administered (methyl-C ) methionine appears in the adrenal (460, 569). 

M.p. 103°C. Noradrenaline is released in the adrenal medulla with adrenaline, and also at the sympathetic nerve endings. Its release from a nerve fibre is followed by binding to a receptor molecule on the next nerve or muscle fibre, probably causing a change in the electrical charge of the receptor-cell membrane. Biosynthetically it normally serves as a precursor for adrenaline. 

FIGURE 27 5 Tyrosine is the biosynthetic precursor to a number of neurotransmit ters Each transformation IS enzyme catalyzed Hydroxy lation of the aromatic ring of tyrosine converts it to 3 4 dihyd roxyphenylalanine (l dopa) decarboxylation of which gives dopamine Hy droxylation of the benzylic carbon of dopamine con verts It to norepinephrine (noradrenaline) and methy lation of the ammo group of norepinephrine yields epi nephrine (adrenaline)... 

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). 

Certain amino acids and their derivatives, although not found in proteins, nonetheless are biochemically important. A few of the more notable examples are shown in Figure 4.5. y-Aminobutyric acid, or GABA, is produced by the decarboxylation of glutamic acid and is a potent neurotransmitter. Histamine, which is synthesized by decarboxylation of histidine, and serotonin, which is derived from tryptophan, similarly function as neurotransmitters and regulators. /3-Alanine is found in nature in the peptides carnosine and anserine and is a component of pantothenic acid (a vitamin), which is a part of coenzyme A. Epinephrine (also known as adrenaline), derived from tyrosine, is an important hormone. Penicillamine is a constituent of the penicillin antibiotics. Ornithine, betaine, homocysteine, and homoserine are important metabolic intermediates. Citrulline is the immediate precursor of arginine. 

It has been proposed that aziridines may be more widespread in biological systems than is generally realized [190]. Many drugs such as ephedrine (124 Scheme 11.18) and pronethalol (125) and endogenous metabolites such as adrenaline (126) contain a P-aminoalcohol moiety, which may act as a precursor to an aziridine metabolite that may explain the known carcinogenicity of some of these compounds such as pronethalol. 

Together with dopamine, adrenaline and noradrenaline belong to the endogenous catecholamines that are synthesized from the precursor amino acid tyrosine (Fig. 1). In the first biosynthetic step, tyrosine hydroxylase generates l-DOPA which is further converted to dopamine by the aromatic L-amino acid decarboxylase ( Dopa decarboxylase). Dopamine is transported from the cytosol into synaptic vesicles by a vesicular monoamine transporter. In sympathetic nerves, vesicular dopamine (3-hydroxylase generates the neurotransmitter noradrenaline. In chromaffin cells of the adrenal medulla, approximately 80% of the noradrenaline is further converted into adrenaline by the enzyme phenylethanolamine-A-methyltransferase. 

Adrenaline was the first hormone to be isolated. Noradrenaline was discovered in 1907 to be the precursor of adrenaline but it was not until 1946 that von Euler was able to convincingly prove that it acts as a neurotransmitter... 

Two amino acids, tyrosine and arginine are of particular importance as precursors of signalling molecules. As outlined in Figure 4.3, tyrosine is the amino acid precursor of thyroid hormones tri-iodothyronine (T3) and tetra-iodothyronine (T4) and also of catecholamines adrenaline (epinephrine) and noradrenaline (norepinephrine). 

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. 

Tyrosine (Tyr or Y) (4-hydroxyphenylalanine ((5)-2-amino-3-(4-hydroxyphenyl)-propanoic acid)) is a polar, neutral, aromatic amino acid with the formula H00CCH(NH2)CH2C6H50H and is the precursor of thyroxin, dopamine, norepinephrine (noradrenaline), epinephrine (adrenaline), and the pigment melanin. Being the precursor amino acid for the thyroid gland hormone thyroxin, a defect in this may result in hypothyroidism. Tyr is extremely soluble in water, a property that has proven useful in isolating this amino acid from protein hydrolysates. The occurrence of tyrosine- 0-sulfate as a constituent of human urine and fibrinogen has been reported. ... 

Tyrosine is also the metabolic precursor to the neurotransmitter dopamine and the catecholamine hormones norepinephrine (noradrenaline) and epinephrine (adrenaline), as well as to the alkaloids in opium, including morphine. 

Hormones can modify the concentration of precursors, particularly the lipolytic hormones (growth hormone, glucagon, adrenaline) and cortisol. The lipolytic hormones stimulate lipolysis in adipose tissue so that they increase glycerol release and the glycerol is then available for gluconeogenesis. Cortisol increases protein degradation in muscle, which increases the release of amino acids (especially glutamine and alanine) from muscle (Chapter 18). 

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. 

Noradrenaline is not only present in the sympathetic nerve endings but in the glandular cells of the adrenal medulla as well. The contents of noradrenaline in the medulla is dependent on the functional state of the gland and the species. Noradrenaline is always the precursor of adrenaline. In the central nervous system there are regions with a high noradrenaline content the hypothalamus and vegetative centers. 

Dopamine is an endogenous catecholamine and an immediate precursor of adrenaline and noradrenaline. At low doses it stimulates vascular DAI dopaminergic receptors, especially those in renal, mesenteric and coronary vessels. As the dose increases it progressively stimulates 31 and al adrenoceptors. Thus, depending on the dose it may act as a renal vasodilator, a myocardial inotrope, or a peripheral vasoconstrictor. Dopamine also causes release of noradrenaline from autonomic nerve endings (DA2 receptors). 

ADRENAL MEDULLA HORMONES. Adrenaline (epinephrine) and its immediate biological precursor noradrenaline (norepinephrine, levartei-nol) are the principal hormones of the adult adrenal medulla. See Fig.l. Some of the physiological effects produced by adrenaline arc contraction of the dilator muscle of the pupil of the eye (mydriasis), relaxation of the smooth muscle of the bronchi constriction of most small blood vessels dilation of some blood vessels, notably those in skeletal muscle increase in heart rate and force of ventricular conlraction relaxation of the smooth muscle of the intestinal tract and either contraction or relaxation, or both, of uterine smooth muscle. Electrical stimulation of appropriate sympathetic (adrenergic) nerves can produce all the aforementioned effects with exception of vasodilation in skeletal muscle. 

Dopa and dopamine are important compounds because they are the precursors oxidase (Chapter 50) hydroxyiates stereospecifically at the benzyiic position to to adrenaline in humans. Decarboxylation of dopa gives dopamine, which an give noradrenaline (norepinephrine). 

Dopamine Is also the precursor for noradrenaline and adrenaline biosynthesis. 

Dopamine is also the precursor for noradrenaline and adrenaline biosynthesis. Phosphatidylethanolamine is the precursor for choline synthesis, Section 14.2.1. ... 

It was named Dopamine because it was a monoamine, and its synthetic precursor was 3,4-dihydroxyphenylalanine (L-DOPA). He was awarded Nobel Prize in 2000 along with Eric Kandel and Paul Greengard in Medicine for showing that dopamine is not just a precursor of noradrenaline and adrenaline, but also neurotransmitter as well. DO is a type of neurotransmitter naturally produced in by the human body. It is also a neurohormone released by the hypothalamus. It is a chemical messenger that is similar to adrenaline and affects the brain processes that control movement, emotional response, and the capacity to feel pleasure and pain. It is vital for performing balanced and controlled movements [172,173], In the extra-cellular fluid of the central nervous system, the basal DO concentration is very low (0.01-1 pM). Abnormal levels of DO have been linked with Parkinson s disease, Tourette s syndrome, Schizophrenia, attention deficit hyperactive disorder and generation of pituitary tumours [174-176],... 

DOPAMINE RECEPTOR AGONISTS act to stimulate dopamine receptors, and these have a major neurotransmitter role in the CNS. Dopamine is also a precursor in the formation of the catecholamine monoamine neurotransmitter noradrenaline and the hormone adrenaline. 

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