Norepinephrine synthesis

Nagatsu T., Levitt M., Udenfriend S. (1964). Tyrosine hydroxylase, the initial step in norepinephrine synthesis. J. Biol. Chem. 239, 2910 17. 

Alousi, A. and Weiner, N. The regulation of norepinephrine synthesis in sympathetic nerves effect of nerve stimulation, cocaine, and catecholamine-releasing agents. Proc. Natl Acad. Sci. U.S.A. 56 1491-1496,1966. 

In addition to impairing norepinephrine storage and thereby enhancing its catabolism, reserpine impairs the vesicular uptake of dopamine, the immediate precursor of norepinephrine. Since dopamine must be taken up into the adrenergic vesicles to undergo hydroxylation and form norepinephrine, reserpine administration impairs norepinephrine synthesis. The combined effects of the blockade of dopamine and norepinephrine vesicular uptake lead to transmitter depletion. 

DRUGS THAT INTERFERE WITH NOREPINEPHRINE SYNTHESIS... 

Dopamine s role in the coordination of movement can be partially understood by examining Parkinson s disease. This illness is associated with low levels of dopamine in the brain and is characterized by spastic motion of the eyelids as well as rhythmic tremors of the hands and other parts of the body. One method of treating Parkinson s disease is to increase the concentration of dopamine in the brain. This is most effectively accomplished by administering the precursor of dopamine, L-dopa. In order to prevent concentrations of norepinephrine from increasing as well, L-dopa is given in conjunction with a drug that inhibits norepinephrine synthesis. 

WLmalasena, K., Herman, H. H., and May, S. W. (1989). Effects of dopamine p-monooxy-genase substrate analogues on ascorbate levels and norepinephrine synthesis in adrenal chromaffin granule ghosts. /. Biol. Chem. 264,124-130. 

Wooten, F.G., Weise, V.K. and Kopin, IJ. (1977) Norepinephrine synthesis contributes to the accumulation of catecholamines after ligation of rat sciatic nerves. Brain Res. 136 174-177. 

Spector, S., Gordon, R., Sjoerdsma, A. and Udenfriend, S. (1967) End-product inhibition of tyrosine hydroxylase as a possible mechanism for regulation of norepinephrine synthesis. Mol. Pharmacol. 23 549-555. 

Weiner, N., Cloutier, G., Bjur, R. and Pfeffer, R.l. (1972) Modification of norepinephrine synthesis in intact tissue by drugs and during short-term adrenergic nerve stimulation. 

No. Therapy should not be initiated for at least 2 weeks post removal of MAO inhibitor therapy, because otherwise a hypertensive crisis may result. This effect is largely due to the increase in norepinephrine synthesis produced with L-dopa therapy, due to the uptake of L-dopa by peripheral noradrenergic nerve terminals and subsequent conversion to norepinephrine. 

Methyldopa is taken up into the adrenergic nerve terminus and enters the norepinephrine synthesis pathway. It is converted, by dopa decarboxylase, into a-methylnorepinephrine, a potent a2 agonist. a-Methyldopa is generally considered to be a pro-drug. 

Although the adrenal medulla is the major site of epinephrine synthesis, it is also synthesized in a few neurons that use epinephrine as a neurotransmitter. These neurons contain the above pathway for norepinephrine synthesis and in addition contain the enzyme that ffansfers a methyl group from SAM to norepinephrine to form epinephrine. Thus, epinephrine synthesis is dependent on the presence of adequate levels of B12 and folate (see Chapter 40). 

Name examples of inhibitors of acetylcholine and norepinephrine synthesis, storage, and release. Predict the effects of these inhibitors on the function of the major organ systems. 

Figure 2.4A Norepinephrine synthesis, release and degradation. 1). Norephinephrine is synthesized from the amino acid tyrosine. Tyrosine is hydroxylated to dopa which is then carboxylated to dopamine. 2). Dopamine (empty squares) diffuses into synaptic vesicles where the enzyme dopamine P-hydroxylase hydroxylates dopamine, forming norepinephrine (solid squares).

A. Disulfiram inhibits aldehyde dehydrogenase, leading to accumulation of acetaldehyde after ethanol ingestion. In addition, it inhibits dopamine betahy-droxylase (necessary for norepinephrine synthesis), resulting in norepinephrine depletion at presynaptic sympathetic nerve endings and leading to vasodilation and orthostatic hypotension. 

The hydroxylation of the amino acid tyrosine to dopa (3,4-dihydroxyphenyl-alanine) is the rate-limiting step in catecholamine biosynthesis [231,257] (Table 1, p. 103). It is catalysed by the enzyme tyrosine hydroxylase. Norepinephrine synthesis is regulated at the tyrosine hydroxylase step by feed-back inhibition, i.e. tyrosine hydroxylase activity decreases as the concentration of endogenous norepinephrine increases [230]. 

Ascorbic acid s chemical structure makes it an electron donor and therefore a reducing agent. AA has thus been involved in two different biochemical functions redox/ antioxidant properties and enzymatic cofactor. AA has been demonstrated to be an electron donor for different enzymes. Among these enzymes, three are involved in collagen hydroxylation (Bates et al., 1972 Levene et al., 1972). Two are involved in carnitine synthesis (Nelson et al., 1981 Dunn et al., 1984). The remaining are respectively involved in norepinephrine synthesis (Kuo, 1979) and tyrosine synthesis (La Duand Zannoni, 1964). Deficiency in AA has thus been associated with extracellular matrix defects that are probably involved in vascular problems observed in scurvy. 

Other recent reports which indirectly tend to weaken the concept that norepinephrine is the sole alerting neurohumor indicate that (1) imipramine hyperactivity may result from blocking uptake and reducing nervous impulse flow in central serotonin neurons (2) drugs which Inhibit uptake of catecholamines also block serotonin accumulation in rabbit brain stem preparations (3) the increase in overt stimulation caused by 5-hydroxy-tryptophan may be associated with Impaired norepinephrine synthesis rather than increased norepinephrine release and (4) norepinephrine and dopamine inhibit electrical activity of central neurons as determined microelectro-phoretically although another study indicated that norepinephrine does cause neuronal excitation ... 

Norepinephrine is also derived from an amino acid— tyrosine. The administration of tyrosine to rats with high blood pressure dramatically reduces blood pressure. This effect seems to be caused by the stimulation of norepinephrine synthesis in the brain. Some have conjectured that, in the future, tyrosine may be used in the treatment of behavioral disorders such tis depression. 

Little is known about how fumarate takes part in the hydroxylation reaction. Experiments with C -labeled fumarate indicate that it is not stoichiometrically converted to another compound during the reaction. Recently it has been observed that the fumarate stimulation is a function of the reducing agent concentration in the absence of ascorbate fumarate no longer stimulates norepinephrine synthesis (Levin and Kaufman, 1961). 

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