Dopamine norepinephrine synthesis from

Known most famously for their part in the fight or flight response to a threat, challenge or anger, adrenaline (epinephrine) and dopamine from the adrenal medulla and noradrenaline (norepinephrine), mainly from neurones in the sympathetic nervous system are known collectively as catecholamines. Synthesis follows a relatively simple pathway starting with tyrosine (Figure 4.7). 

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. 

Autoreceptors appear to regulate transmitter synthesis and/or release. The mechanisms by which these receptors exert their activity in the nerve terminal is unknown, although processes involving protein phosphorylation, calmodulin, and protein carboxymethylation have been proposed. Released transmitter is believed to feed back to the terminal from which it was released and inhibit further release by binding to the autoreceptor. Although autoreceptors have been identified to dopamine, norepinephrine, serotonin, and GABA, the most detailed information to date concerns the norepinephrine autoreceptor, which shares properties with the a-receptor. 

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. 

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).

In 1817, die Swede Johann Arfvedson discovered the element lithium. Its biological effect is on intracellular influx of sodium during the process of axonal depolarization, which interferes with the synthesis and reuptake of neurotransmitters. In the 1950s, it began to be used in the treatment of bipolar disorder, because it dampens neurotransmission. It enhances the reuptake of dopamine, norepinephrine, and 5-HT into neuronal vesicles, reducing their action. It also reduces release of norepinephrine from synaptic vesicles and inhibits production of cAMP. It decreases the neuronal activity excited by 5-HT, dopamine, and epinephrine. 

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 ... 

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... 

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. 

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. 

The major clinical feature of patients with deficiency of dopamine p-hydroxylase is orthostatic hypotension caused by reduced synthesis and release of norepinephrine by sympathetic nerves. The deficiency is characterized neuro-chemically by decreased levels of norepinephruie and norepinephrine metabolites and increased levels of dopamine and dopamine metabolites. Diagnosis is best achieved from an increased ratio of plasma dopamine to norepinephrine. Copper deficiency in Menkes disease is due to defects in the gene coding for a copper-transporting adenosine triphosphatase. Because dopamine p-hydroxylase is a copper-dependent enzyme, the deficiency is associated with decreased activity of the enzyme and reduced production of norepinephrine from dopamine. Prompt diagnosis at childbirth is essential for copper-replacement therapy, and... 

Ascorbate increases the activity of hydroxylases needed for the conversion of p-hydroxyphenylpyruvate to homogentisate (Chapter 17), synthesis of norepinephrine from dopamine (Chapter 32), and two reactions in carnitine synthesis (Chapter 18). It is not known whether decreased activity of these enzymes contributes to the clinical characteristics of scurvy. Although ascorbic acid is needed for maximal activity of these enzymes in vivo and in vitro, most show some activity when other reducing agents are used. 

Copper is extremely important for the proper functioning of the body. It aids in the absorption of iron from the intestine and facilitates iron metabolism. It is critical for the formation of hemoglobin and red blood cells in the bone marrow. Copper is also necessary for the synthesis of collagen, a protein that is a major component of the cormective tissue. It is essential to the central nervous system in two important ways. First, copper is needed for the synthesis of norepinephrine and dopamine, two chemicals that are necessary for the transmission of nerve signals. Second, it is required for the deposition of the myelin sheath (a layer of insulation) around nerve cells. Release of cholesterol from the Uver depends on copper, as does bone development and proper function of the immune and blood clotting systems. 

Assay of phenylalanine hydroxylase in a liver biopsy from one patient showed 20% of normal adult control values, but dihydropteridine reductase activity (Fig. 20.2) was less than 1% of normal in the liver, brain, and other tissues. This latter deficiency presents regeneration of tetrahydrobiopterin, the cofactor for the hydroxylase reaction. Since the reductase enzyme reaction regenerates the cofactor for tyrosine and tryptophan hydroxylase, catecholamine and serotonin synthesis are compromised as well. Patient studies are scanty, but in one patient dopamine and serotonin were decreased in the cerebrospinal fluid, brain, and various other tissues, while norepinephrine metabolites were normal. While phenylalanine hydroxylase activity was lower than that of adult controls, it was not determined whether this value represented significantly decreased activity in children. 

The majority of catecholamine and serotonin biosynthesis occurs within the nerve terminals by synthetic enzymes transported from the neuronal cell bodies. In all catecholamine neurons, the rate-limiting step in synthesis is conversion of tyrosine to dihydroxyphenylalanine by tyrosine hydroxylase. Dihydroxyphenylalanine is then converted to DA, norepinephrine, and epinephrine through a sequential process involving L-aromatic amino acid decarboxylase (conversion of dihydroxyphenylalanine to DA), dopamine-P-hydroxylase (conversion of DA to norepinephrine), and phenylethanol-amine-N-methyltransferase (conversion of norepinephrine to epinephrine). Cell-specific expression of these enzymes determines the main neurotransmitter for an individual catecholamine neuron. The synthesis pathway for serotonin involves a two-step process in which tryptophan hydroxylase first converts tryptophan to 5-hydroxytryptophan, which is then converted to... 

The morphology of the carotid body resembles chromaffin tissues expressing catecholamines. Now it is fairly established that carotid bodies express dopamine and norepinephrine, whereas there is no convincing evidence for epinephrine. Type I cells from a variety of species express tyrosine hydroxylase (TH) and dopamine jS hydroxylase (DBH), the enzymes responsible for the synthesis of dopamine (DA) and norepinephrine (NE), respectively (10,20,91). In addition, nerve fibers (of sensory as well as autonomic origin) and ganghon cells also show TH immunoreactivity (91). The actions of DA and NE are terminated by a reuptake mechanism involving specific transporters. However, evidence for DA and/or NE transporters in the carotid body is lacking. 

The enzymatic introduction of a functional group into a biologically important molecule is not only specific with regard to the location at which the reaction occurs in the molecule (see Chapter 4, Problem 50), but also usually specific in the stereochemistry obtained. The biosynthesis of epinephrine first requires that a hydroxy group be introduced specifically to produce (—(-norepinephrine from the achiral substrate dopamine. (The completion of the synthesis of epinephrine wdl be presented in Problem 71 of Chapter 9.) Only the (—) enantiomer is functional in the appropriate physiological manner, so the synthesis must be highly stereoselective. 

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