Biosynthesis of dopamine

The synthesis of dopamine originates from the precursor the amino acid L-tyrosine, which must be transported across the blood-brain barrier into the dopaminergic neuron. The rate limiting step in the synthesis is the conversion of L-tyrosine to L-dihydroxyphenylalanine (L-DOPA) by the enzyme tyrosine hydroxylase (TH). L-DOPA is subsequently converted to dopamine by aromatic L-amino acid decarboxylase. The latter enzyme turns over so rapidly that L-DOPA levels in the brain are negligible under normal conditions.1 

Chart 1.1 Biosynthesis of dopamine. Dopamine (1) L-Tyrosine (2) L-3,4-dihydroxyphcnylalaninc (3, L-DOPA) TH, tyrosine hydroxylase AAAD, aromatic L-amino acid decarboxylase. 

FIGURE 23.7 Dopamine (DA) is synthesized within neuronal terminals from the precursor tyrosine by the sequential actions of the enzymes tyrosine hydroxylase, producing the intermediary L-dihydroxyphenylalanine (Dopa), and aromatic L-amino acid decarboxylase. In the terminal, dopamine is transported into storage vesicles by a transporter protein (T) associated with the vesicular membrane. Release, triggered by depolarization and entry of Ca2+, allows dopamine to act on postsynaptic dopamine receptors (DAR). Several distinct types of dopamine receptors are present in the brain, and the differential actions of dopamine on postsynaptic targets bearing different types of dopamine receptors have important implications for the function of neural circuits. The actions of dopamine are terminated by the sequential actions of the enzymes catechol-O-methyl-transferase (COMT) and monoamine oxidase (MAO), or by reuptake of dopamine into the terminal. 

Experienced users require more cocaine over time to obtain euphoria. Since cocaine typically is used intermittently, even heavy users go through frequent periods of withdrawal or crash. The symptoms of withdrawal are seen in users admitted to the hospital. 

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Tyrosine hydroxylase (TH) is an enzyme that catalyzes the hydroxylation of tyrosine to 3,4-dihydroxypheny-lalanine in the brain and adrenal glands. TH is the rate-limiting enzyme in the biosynthesis of dopamine. This non-heme iron-dependent monoxygenase requires the presence of the cofactor tetrahydrobiopterin to maintain the metal in its ferrous state. 

Intracellular Fe is usually tightly regulated, being bound by ferritin in an insoluble ferrihydrite core, and impaired Fe homeostasis has been linked to Parkinson s disease and Alzheimer s disease. A consistent neurochemical abnormality in Parkinson s disease is degeneration of dopaminergic neurons relating to a reduction of striatal dopamine levels. As tyrosine hydroxylase (Fig. 24) (494), an Fe enzyme, catalyzes the formation of l-DOPA, the rate-limiting step in the biosynthesis of dopamine, the disease can be considered as a tyrosine... 

FIGURE 6-4 The biosynthesis of dopamine, norepinephrine, and epinephrine. The enzymes involved are shown in blue essential cofactors in italics. The final step occurs only in the adrenal medulla and in a few epinephrine-containing neuronal pathways in the brainstem. 

Figure 13.4 Biosynthesis of dopamine from the essential amino add i-tyrosine and schematic...

Fig. 273. Biosynthesis of dopamine derivatives 1 Dopamine /5-monooxygenase 2 5-methyltetra-hydrofolate-dependent methyltransferase...

Little is known about factors which limit the production of amines. The metabolic reaction which limits the biosynthesis of dopamine and serotonin is believed not to be the decarboxylation of their biochemical precursors dopa and 5-hydroxytryptophane by the ubiquitous decarboxylase, but to be the hydroxylation of the parent compounds tyrosine, and tryptophane. 140-3,189) Under comparable experimental conditions the production of serotonin from 5-hydroxytryptophane took place 30-40 times faster than from tryptophane,and the production of dopamine and noradrenaline respectively from labelled dopa was 70-100 times faster than from labelled tyrosine. In the biosynthesis of noradrenaline, the hydroxylation of dopamine, catalysed by dopamine-j -oxidase, takes place fairly slowly and is considered to be a rate-limiting reaction. ... 

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). 

One step in the biosynthesis of morphine is the reaction of dopamine with p-hydroxyphenylacetaldehyde to give (S)-norcoclaurine. Assuming that the reaction is acid-catalyzed, propose a mechanism. 

As the result of a screening program examining microbial fermentation products for pharmacological activity (other than antibiotic activity), fusaric acid (10) was isolated from Fusarium oxysporum following the discovery that extracts were potent inhibitors of dopamine p-hydroxylase, and thus interfered with the biosynthesis in vivo of the pressor neurohormone, norepinephrine. To refine this lead, amidation of 10 via the acid chloride was carried out... 

L-dopa is effective in the treatment of Parkinson s disease, a disorder characterised by low levels of dopamine, since L-dopa is metabolised into dopamine. However, this biosynthesis normally occurs in both the peripheral nervous system (PNS) and the central nervous system CNS. The related drug carbidopa inhibits aromatic L-amino acid decarboxylase only in the periphery, since it does not cross the blood-brain barrier. So, when carbidopa is given with L-dopa, it reduces the biosynthesis of L-dopa to dopamine in the periphery and, thus, increases the bioavailability of L-dopa for the dopaminergic neurons in the brain. Hence, carbidopa increases the clinical efficacy of L-dopa for Parkinsonian patients. 

The first two antidepressants, iproniazid and imipramine, were developed in the same decade. They were shown to reverse the behavioural and neurochemical effects of reserpine in laboratory rodents, by inhibiting the inactivation of these monoamine transmitters (Leonard, 1985). Iproniazid inhibits MAO (monoamine oxidase), an enzyme located in the presynaptic neuronal terminal which breaks down NA, 5-HT and dopamine into physiologically inactive metabolites. Imipramine inhibits the reuptake of NA and 5-HT from the synaptic cleft by their transporters. Therefore, both of these drugs increase the availability of NA and 5-HT for binding to postsynaptic receptors and, therefore, result in enhanced synaptic transmission. Conversely, lithium, the oldest but still most frequently used mood stabiliser (see below), decreases synaptic NA (and possibly 5-HT) activity, by stimulating their reuptake and reducing the availability of precursor chemicals required in the biosynthesis of second messengers. 

These patients suffer from a genetic defect of dopamine synthesis, caused by reduced GTP cyclohydrolase activity. This enzyme is rate-limiting in the biosynthesis of tetra-hydrobiopterin, a cofactor of the dopamine-synthesizing enzyme tyrosine hydroxylase (see Fig. 40-2). 

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. 

Dopamine is an intermediate product in the biosynthesis of noradrenaline. Furthermore it is an active transmitter by itself in basal ganglia (caudate nucleus), the nucleus accumbens, the olfactory tubercle, the central nucleus of the amygdala, the median eminence and some areas in the frontal cortex. It is functionally important, for example in the extra-pyramidal system and the central regulation of emesis. In the periphery specific dopamine receptors (Di-receptors) can be found in the upper gastrointestinal tract, in which a reduction of motility is mediated, and on vascular smooth muscle cells of splanchnic and renal arteries. Beside its effect on specific D-receptors, dopamine activates, at higher concentrations, a- and -adrenoceptors as well. Since its clinical profile is different from adrenaline and noradrenaline there are particular indications for dopamine, like situations of circulatory shock with a reduced kidney perfusion. Dopamine can dose-dependently induce nausea, vomiting, tachyarrhythmia and peripheral vasoconstriction. Dopamine can worsen cardiac ischaemia. 

Dopamine (3,4-dihydroxyphenyl-P-ethylamine, DA) (4.34) is a catecholamine intermediate in the biosynthesis of NE and epinephrine. There are several very important... 

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