In norepinephrine synthesis

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

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. 

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. 

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... 

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. 

The coenzyme tetrahydrofolate (THF) is the main agent by which Ci fragments are transferred in the metabolism. THF can bind this type of group in various oxidation states and pass it on (see p. 108). In addition, there is activated methyl, in the form of S-adenosyl methionine (SAM). SAM is involved in many methylation reactions—e. g., in creatine synthesis (see p. 336), the conversion of norepinephrine into epinephrine (see p. 352), the inactivation of norepinephrine by methylation of a phenolic OH group (see p. 316), and in the formation of the active form of the cytostatic drug 6-mercaptopurine (see p. 402). 

Adrenergic neuron blockers cause a release of biogenic amines at neuron terminals. These dmgs can interfere in the synthesis, storage, and release of norepinephrine, dopamine, and serotonin. 

Nalepa I, Kreiner G, Kowalska M, Sanak M, Zelek-Molik A, Vetulani J (2002) Repeated imipramine electroconvulsive shock increase alpha(lA)-adrenoceptor mRNA level in rat prefrontal cortex. Eur J Clin Pharmacol 444 151-159 Nesse RM, Ciu-tis GC, Thyer BA, McCann DS, Huber-Smith MJ, Knopf RF (1985) Endocrine and cardiovascular responses during phobic anxiety. Psychosom Med 47 320-332 Nisenbaiun LK, Zigmund MJ, Sved AF, Abercrombie ED (1991) Prior exposure to chronic stress results in enhanced synthesis and release of hippocampal norepinephrine in response to a novel stressor. J Neurosci 11 1473-1484 Nutt DJ (1989) Altered alpha2-adrenoceptor sensitivity in panic disorder. Arch Gen Psychiatry 46 165-169... 

Since the enzyme that converts dopamine to norepinephrine (dopamine (3-hydroxylase) is located only within the vesicles, the transport of dopamine into the vesicle is an essential step in the synthesis of norepinephrine. This same transport system is essential for the storage of norepinephrine. There is a tendency for norepinephrine to leak from the vesicles into the cytosol. If norepinephrine remains in the cytosol, much of it will be destroyed by a mitochondrial enzyme, monoamine oxidase MAO). However, most of the norepinephrine that leaks out of the vesicle is rapidly returned to the storage vesicles by the same transport system that carries dopamine into the storage vesicles. It is important for a proper understanding of drug action to remember that this single transport system, called vesicular transport, is an essential element of both synthesis and storage of norepinephrine. 

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. 

Dopamine is the immediate precursor in the synthesis of norepinephrine (see Figure 6-5). Its cardiovascular effects were described above. Endogenous dopamine may have more important effects in regulating sodium excretion and renal function. It is an important neurotransmitter in the central nervous system and is involved in the reward stimulus relevant to addiction. Its deficiency in the basal ganglia leads to Parkinson s disease, which is treated with its precursor levodopa. Dopamine receptors are also targets for antipsychotic drugs. 

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. 

Regardless of the untested merits of the above work, methylation as a first step in the deactivation of noradrenaline in the body is just as plausible as is the evidence that methylation is the final step in the synthesis of adrenaline. The evidence for and against this route of synthesis has been discussed previously in this review. Tainter etal. (155) reported that in dogs under phenobarbital anesthesia Z-arterenol had a pressor activity 1.7 times that of Z-epinephrine. In this sense then, methylation might be considered a process of inactivation. However, they found in contrast that the acute toxicity of Z-epinephrine (LDso) was about four times that of Z-norepinephrine (114) 155). 

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. 

Nisenbaum LK, Zigmond MJ, Sved AF, Abercrombie ED (1991) Prior exposure to chronic stress results in enhanced synthesis and release of hippocampal norepinephrine in response to a novel stressor. J Neurosci 11 1478-1484. 

The adrenal gland, which produces epinephrine and norepinephrine, contains one of the highest concentrations of vitamin C of any body organ. It is believed that vitamin C may play a role in the synthesis of coitico-stetoids and epinephrine. 

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). 

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. 

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