Synthesis of neurotransmitters

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]. 

Histamine is synthesized from the amino acid histidine by simple decarboxylation catalysed by histidine decarboxylase. Serotonin is synthesized primarily in platelets, the gastro-intestinal (GI) tract and the brain from the indolyl amino acid tryptophan tryptophan — 5-hydroxytryptophan [via tryptophan hydroxylase + tetrahydrobiopterin] — 5-hydroxy-tryptamine (serotonin) [via 5-hydroxytryptophan decarboxylase]. 

The release of NTs into the synaptic cleft from exocytosing synaptic vesicles has been outlined above. Dopamine release is promoted by the stimulants amphetamine and tobacco-derived nicotine. The amphetamine-derived stimulants methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) promote dopamine and serotonin release (Table 6.2). 

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The initial neurological symptoms of hypoxia and hypoglycemia result from reduced synthesis of neurotransmitters rather than a global cerebral energy deficit 594... 

Phenylalanine (Phe or F) (2-amino-3-phenyl-propanoic acid) is a neutral, aromatic amino acid with the formula HOOCCH(NH2)CH2C6H5. It is classified as nonpolar because of the hydrophobic nature of the benzyl side chain. Tyr and Phe play a significant role not only in protein structure but also as important precursors for thyroid and adrenocortical hormones as well as in the synthesis of neurotransmitters such as dopamine and noradrenaline. The genetic disorder phenylketonuria (PKU) is the inability to metabolize Phe. This is caused by a deficiency of phenylalanine hydroxylase with the result that there is an accumulation of Phe in body fluids. Individuals with this disorder are known as phenylketonurics and must abstain from consumption of Phe. A nonfood source of Phe is the artificial sweetener aspartame (L-aspartyl-L-phenylalanine methyl ester), which is metabolized by the body into several by-products including Phe. The side chain of Phe is immune from side reactions, but during catalytic hydrogenations the aromatic ring can be saturated and converted into a hexahydrophenylalanine residue. ... 

Mental activity requires ion transport, the synthesis of neurotransmitters and their release into the synapse. 

Figure 13.27 A possible mechanism by which a low blood glucose level could give rise to central fatigue. A low blood glucose level reduces the rate of glucose utilisation in the brain which decreases the ATP/ADP concentration ratio in the presunaptic neurone. This reduces the energy available for synthesis of neurotransmitters, packaging of neurotransmitter molecules into vesicles and exocytosis of neurotransmitter into synaptic cleft. This decreases electrical activity in postsynaptic neurones and hence in the motor pathway.

Synthesis of neurotransmitters and brain function via decarboxylase reactions (58,102)... 

Synthesis of neurotransmitter. Drugs that block the synthesis of neurotransmitter will eventually deplete the presynaptic terminal and impair transmission. For example, metyrosine (Demser)... 

Anyone taking diuretics for longer than six months may experience a folate, or folic acid, deficiency. Folic acid plays a part in the health and reproduction of virtually every cell in the body. It is responsible for protein metabolism, the prevention of neural tube defects in pregnancy, blood cell production, and the synthesis of neurotransmitters. Individuals with folate deficiencies may suffer from anemia, depression and other mood disorders, and may give birth to babies with neural tube defects. Supplementation with folic acid may be useful in reversing these effects. 

In some mammalian cells, enzymes comprising partial spans of biosynthetic pathways are inside and some outside the mitochondrial matrix space. Therefore, in the liver, six mitochondrial membrane transport proteins are required for urea synthesis, three for gluconeogenesis [7,8], and three others participate in ammonia-genesis [9] in the kidney. The synthesis of neurotransmitter substances such as acetylcholine, glutamate and y-amino butyric acid requires the participation of metabolite transporters in mitochondrial membranes of nervous tissue [9,10]. 

Pyridoxl phosphate is required for synthesis of neurotransmitters serotonin and norepinephrine. 

Neurotransmitter synthesis. A drug may increase or decrease the synthesis of neurotransmitters. 

Vitamin B6 is required for the formation of pyridoxal phosphate, an important cofactor in nitrogen metabolism. Deficiencies of vitamin B6 are caused by a lack of the vitamin in the diet or by the administration of drugs such as isoniazid, which interfere with its metabolism. Synthesis of neurotransmitters, NAD, and heme are decreased, resulting in neurologic and pellegra-like symptoms and anemia. 

Nervous system abnormalities may be attributed in part to diminished synthesis of neurotransmitters rather than to inadequate synthesis of ATP. In pyruvate dehydrogenase complex deficiency, diminished levels of acetyl-CoA cause decreased production of acetylcholine in pyruvate carboxylase deficiency, decreased production of... 

Tetrahydrobiopterin (BH4) is required in the synthesis of neurotransmitters such as norepinephrine and serotonin, which are produced in brain. BH4 is required in the reaction catalyzed by tyrosine hydroxylase in which tyrosine is hydrox-ylated to form L-dopa (a precursor of several neurotransmitters including dopamine and norepinephrine), and the reaction catalyzed by tryptophan hydroxylase in which tryptophan is hydroxylated to form 5-hydroxytryptophan. L-Dopa and 5-hydroxytryptophan must be supplied to individuals lacking the capacity to synthesize BH4 because the latter molecule does not cross the blood-brain barrier. 

The alterations produced by THC and other cannabinoids in biogenic amine levels as well as on uptake, release and synthesis of neurotransmitters and effects on enzymes have been the subject of numerous investigations (for reviews see [8,52,55,114,115]). It is beyond the scope of the present summary to try to analyse and put into a proper perspective the wealth of data published so far. It is our subjective view that the mode of action of cannabi-mimetic compounds is somehow directly associated with prostaglandin metabolism (see, in particular, the series of papers by Burstein [115,116]), and/or reduction of hippocampal acetylcholine turnover observed in rats [117,118]. The latter effect is enantiospecific and follows the known SAR of the cannabinoids. This in vivo selectivity of action suggests that the THC may activate specific transmitter receptors which indirectly modulate the activity of the cholinergic neurons in the septalhippocampal pathway. 

The events that take place at a synapse, that is synthesis of neurotransmitter, storage in vesicles, release, interaction with receptors and eventual inactivation provide targets for drug action (Chapter 3). Inactivation of a neurotransmitter can be by re-uptake into the neuron it was released from (as with noradrenaline and dopamine), or by the action of enzymes in the synaptic cleft (as with acetylcholine). 

A small subset of patients with hyperphenylalaninemia show an appropriate reduction in plasma phenylalanine levels with dietary restriction of this amino acid however, these patients still develop progressive neurologic symptoms and seizures and usually die within the first 2 years of life ("malignant" hyperphenylalaninemia). These infants exhibit normal phenylalanine hydroxylase (PAH) activity but have a deficiency in dihy-dropteridine reductase (DHPR), an enzyme required for the regeneration of tetrahydro-biopterin (BH4), a cofactor of PAH (see Fig. 39.18). Less frequently, DHPR activity is normal but a defect in the biosynthesis of BH4 exists. In either case, dietary therapy corrects the hyperphenylalaninemia. However, BH4 is also a cofactor for two other hydroxy-lations required in the synthesis of neurotransmitters in the brain the hydroxylation of tryptophan to 5-hydroxytryptophan and of tyrosine to L-dopa (see Chapter 48). It has been suggested that the resulting deficit in central nervous system neurotransmitter activity is, at least in part, responsible for the neurologic manifestations and eventual death of these patients. 

The nervous system consists of various cell types that are functionally interconnected so as to allow efficient signal transmission throughout the system (see Chapter 48). The cells of the central nervous system are protected from potentially toxic compounds by the blood-brain barrier, which restricts entry of compounds into the nervous system (ammonia, however, is a notable exception). The brain cells communicate with each other and with other organs, through the synthesis of neurotransmitters and neuropeptides. Many of the neurotransmitters are derived from amino acids, most of which are synthesized within the nerve cell. Because the pathways of amino acid and neurotransmitter biosynthesis require cofactors (such as pyridoxal phosphate, thiamine pyrophosphate, and vitamin BI2), deficiencies of these cofactors can lead to neuropathies (dysfunction of specific neurons within the nervous system). 

Elevated levels of phenylalanine have been shown to inhibit transport of other amino acids besides tyrosine. This might result in an imbalance of amino acids in the brain that could disrupt protein synthesis or control of the synthesis of neurotransmitters. Several enzymes, including tyrosine hydroxylase, tryptophan, and pyruvate kinase, are inhibited in vitro by phenylalanine. Irrespective of such phenomena in a patient who died with PKU, catecholamine concentration and serotonin levels were much lower than those in control brains from patients suffering mental retardation from other causes, a finding consistent with such a possible role in vivo (Ikeda et al., 1967). 

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