Biosynthesis of norepinephrine

Dopamine- -hydroxylase is another copper enzyme that plays a major function in the biosynthesis of norepinephrine (40). A protective catalyst, superoxide dismutase, has been described to catalyze the dismu-tation of the superoxide anion free radical (41). Other enzymes known to contain copper are the laccases, the phenol oxidases, and the ascorbic acid oxidases (12). 

Biosynthesis of norepinephrine takes place within adrenergic neurons near the terminus... 

This interest in the nature of chemical transmission in the central nervous system continues to bear fruit. For example, studies on nerve terminals of postganglionic adrenergic fibers (6) and on the adrenal medulla had, over a period of many years, provided a fairly clear picture of the biosynthesis, release, reuptake, and destruction of the adrenergic transmitter norepinephrine. Other studies had shown that in patients with classical Parkinson s disease parts of the brain—the substantia nigra and corpus striatum—contained less dopamine than did normal brains (7). Dopamine is one of the intermediates in the biosynthesis of norepinephrine from phenylalanine. 

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... 

Rosenfeld, G., Leeper, L. C. and Udenfriend, S., Biosynthesis of norepinephrine and epinephrine by the isolated perfused calf adrenal. Arch. Biochem. Biophys. 74, 252 (1958). 

This enzyme has been shown to require PLP as a coenz mie and, contrary to many other similar enzymes, the coenzyme is easily dissociated H40). Preparations of this enzyme are also able to decarboxylate dihydroxy phenyl serine and 5-hydroxytryptophan (S40). Evidence has been obtained which appears to rule out dihydroxyphenyl serine as being a precursor in the biosynthesis of norepinephrine (see reference 40, p. 351). 

Is the site of reaction in the biosynthesis of norepinephrine from dopamine (see Problem 65 of Chapter 5) consistent with the principles outlined in this chapter Would it be easier or more difficult to duplicate this transformation nonenzymatically Explain. 

Figure 11.16 The biosynthesis of epinephrine from norepinephrine occurs by an Sjyj2 reaction with S-acfenosylmethionine.

Inhibition of norepinephrine biosynthesis can be achieved quite well by chronic oral administration of the tyrosine hydroxylase inhibitor CH-methyl-p-tyrosine (LXII) but reduction in blood pressure was not achieved in patients with essential hypertension (77). Another potent inhibitor, 3-iodotyrosine (LXIII) was also inactive in man (78). Apparently, substantial reduction of norepinephrine (50-70%) is not enough to achieve the desired effect. 

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. 

Adrenal Conical Hormones. The adrenal gland is made up of two parts, the medulla and the cortex, each of which secretes characteristic hormones. The hormones of the adrenal medulla art- the catecholamines, epinephrine adrenalin and norepinephrine (noradrenalint. which are closely related chemically, dil lning only in that epinephrine has an added methyl group. See Table I. In fact, animal experiments have established a metabolic pathway lor Ihe biosynthesis of both compounds Irom Ihe ammo acid pheny lal.inine. which involves enzy malic oxidation and decarboxylation reactions It is also to he noted ihui the isomeric form of norepinephrine is most important the natural D-lonn (which incidentally, is levorntatory) has many times die uciiviiy of die synthetic isomer. Epinephrine has a pronounced action upon the circulatory system, increasing both blood... 

Levodopa (L-dopa) is a natural intermediate in the biosynthesis of catecholamines in the brain and peripheral adrenergic nerve terminals. In the biologic sequence of events it is converted to dopamine, which in turn serves as a substrate of the neurotransmitter norepinephrine. Levodopa is used successfully in the treatment of Parkinson s syndrome, a disease characterized by dopamine deficiency. When levodopa is administered to an individual with this syndrome, the symptoms of Parkinson s disease are ameliorated, presumably because the drug is converted to dopamine and thereby counteracts the deficiency. Individuals treated with levodopa, especially older men, have been observed to experience a sexual rejuvenation. This effect has led to the belief that levodopa stimulates sexual powers. Consequently, studies with younger men complaining of decreased erectile ability have shown that levodopa increases libido and the incidence of penile erections. Overall, however, these effects are short lived and do not reflect continued satisfactory sexual function and potency. Thus, levodopa is not a true aphrodisiac. The increased sexual activity experienced by parkinsonian patients treated with levodopa may reflect improved well-being and partial recovery of normal sexual functions that were impaired by Parkinson s disease. 

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. 

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]. 

Methionine, USP. An adequate diet should provide the methionine ncccs.sary for normal metabolism in the human.. Viethionine is considered an essential amino acid in humans. It is the precursor in the biosynthesis of -adcnosylnie(hio-niiic, which is an important methylating coenzyme involved In a variety of methylations (e.g.. N-me(hyla(ion of norepinephrine to form epinephrine and O-methylation of catecholamines catalyzed by ca(cchul-CI-mcthyl(iansfcra.ses). Adenosylmcthionine also participates in the methylation of pho.sphatidylcthanolaininc to form phosphatidylcholine, but this pathway is not efficient enough to provide all of the choline required hy higher animals hence, adequate dietary availability of choline is ncces.sary. ... 

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... 

In a related vein, the subjective psychostimulant effects of amphetamine were attenuated following a 2-h pretreatment with a tyrosine- and phenylalanine-free amino acid mixture (118).These amino acids are biosynthetic precursors of the catecholamines, and deprivation would be expected to produce transient reductions in endogenous dopamine and norepinephrine. The authors concluded that tyrosine depletion attenuates the release of dopamine required for the psychostimulant effect. Interestingly, the pretreatment did not reduce the subjective appetite-suppressant (anorectic) effect of amphetamine. The study authors attributed this latter finding to a continued release of norepinephrine by amphetamine. Tyrosine depletion, however, would also attenuate norepinephrine biosynthesis and it may be more reasonable to conclude that the anorectic effect might be related to the often-overlooked ability of amphetamine to release neuronal serotonin. 

Other examples of PLP-requiring enzymes are the amino acid decarboxylases that lead to formation of amines, including several that are functional in nervous tissue (e.g., epinephrine, norepinephrine, serotonin, and y-aminobutyrate) cysteine desulfhydrase and serine hydroxymethyltransferase, which use PLP to effect the loss or transfer of amino acid side chains phosphorylase, which catalyzes phosphorolysis of the a-1,4-linkages of glycogen and cystathione beta-synthase in the transsulfiiration pathway of homocysteine. Additionally the biosynthesis of heme depends on the early... 

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