Biosynthesis of neurotransmitters

The multifimctional CaM kinases are collectively referred to as CaM kinases of type II, whereby further subtypes a, p, y and 6 are differentiated. The a and P subtypes of CaM kinase II only occur in the brain whereas the other subtypes are also found in other organs. The multifunctional CaM kinases regulate many processes (see Table 7.1) such as glycogen metabolism, activity of transcription factors, microfilament formation, synaptic release of neurotransmitters from storage vesicles, biosynthesis of neurotransmitters and many more. An important cellular function is assigned to CaM kinase II in brain, where it makes up 0.25 % of the total protein. 

Nutritionally, humans derive their pyridoxal coenzyme from vitamin B6. Most symptoms of vitamin Be deficiency apparently result from the involvement of the coenzyme in the biosynthesis of neurotransmitters and the niacin group of NAD and NADPH rather than from amino acid deficiency. 

The energy requirements of the neuron needed to maintain the Na" " and K+ gradients are pronounced. The maximal rate of ATP hydrolysis under conditions of maximal cation exchange has been estimated to be between 15 and 30% of the total hydrolysis of ATP within the neuron. In comparison, the combination of protein and lipid turnover and biosynthesis of neurotransmitters appears to require only 10% of the total ATP hydrolysis of the nerve. (The remaining hydrolysis occurs during active transport of other substances and for a variety of enzymatic reactions.)... 

Some enzymatio reaotions that involve PLP include transaminations, which convert amino acids to ketones for use in the citric acid cycle and other pathways decarbox-yiation of amino acids for biosynthesis of neurotransmitters such as histamine, dopamine, and serotonin and inversion of amino acid chirality centers, such as required for the biosynthesis of cell walls in bacteria. 

Important nonheme iron monooxygenases other than sMMO are pterin-dependent enzymes and isopenicillin N synthase. Three enzymes are known as the pterin-dependent monooxygenases phenylalanine hydroxylase (PAH), tyrosine hydroxylase (TH), and tryptophan hydroxylase (TPH). These enzymes perform metabolically important transformations, e,g, for the biosynthesis of neurotransmitters, and catalyze the reactions shown in Fig. 8. 

Late markers are not shared by undifferentiated neuroepithelial cells in their resident or itinerant status, and often not even after neuroblasts settle in their stable niche, but only after they become functional and mature neurons, with regard to the biosynthesis of neurotransmitters, resting membrane potential, membrane receptors, and synaptic contacts. The start of those markers expression should be kept in mind not only with reference to brain sections from the fetal to the neonatal stage but also, with particular attention, when the same tissues are used as starting material for growing cell cultures. For this purpose. Table 1 summarizes the most useful and predictive immunocytochemical markers found in the course of neuronal differentiation. 

Psychoactive drugs can influence neurotransmission at its five different stages (Chapter 2). First, they may modify the biosynthesis of a neurotransmitter. Second, they can increase or decrease their storage within the presynaptic neuron. Third, they may stimulate or inhibit neurotransmitter release from the synaptic bouton. Fourth, they may affect the binding of the neurotransmitters to its receptor. Finally, they can retard the neurotransmitter s inactivation. Some examples of each of these stages will be given below, but it should be noted that many drugs affect several of these processes. 

Biosynthesis See also Anabolism Biosynthesis is also used to describe the conversion of inactive (precursor) molecules into physiologically active ones as in the biosynthesis of a neurotransmitter. 

Cyclic AMP Stimulation or inhibition of the biosynthesis of the second messenger cyclic adenosine-S jS -monophosphate occurs through the activation of Gs or G protein-coupled neurotransmitter receptors, respectively. 

The biosynthesis of neuropeptides is fundamentally different from that of conventional neurotransmitters 321 Many of the enzymes involved in peptide biogenesis have been identified 321... 

The biosynthesis of neuropeptides is fundamentally different from that of conventional neurotransmitters. 

Normal biochemical events surrounding the maintenance and functions of the nervous system centers around energy metabolism, biosynthesis of macromolecules, and neurotransmitter synthesis, storage, release, uptake, and degradation. Measurement of these events is complicated by the sequenced nature of the components of the nervous system and the transient and labile nature of the moieties involved. Use of measurements of alterations in these functions as indicators of neurotoxicity is further complicated by our lack of a complete understanding of the normal operation of these systems and by the multitude of day-to-day occurrences (such as diurnal cycle, diet, temperature, age, sex, and endocrine status) which are constantly modulating the baseline system. For detailed discussions of these difficulties, the reader is advised to see Damstra and Bondy (1980, 1982). 

Genes encoding for the biosynthesis and catabolism of neurotransmitters Tryptophan hydroxylase (TPH)... 

D. E. Duggan, S.D. Aster, Selective inhibitors of biosynthesis of aminergic neurotransmitters, Nature 274 (1978) 906-908. 

FIGURE 22-29 Biosynthesis of some neurotransmitters from amino acids. The key step is the same in each case a PLP-dependent decarboxylation (shaded in pink). 

The hereditary absence of phenylalanine hydroxylase, which is found principally in the liver, is the cause of the biochemical defect phenylketonuria (Chapter 25, Section B).430 4308 Especially important in the metabolism of the brain are tyrosine hydroxylase, which converts tyrosine to 3,4-dihydroxyphenylalanine, the rate-limiting step in biosynthesis of the catecholamines (Chapter 25), and tryptophan hydroxylase, which catalyzes formation of 5-hydroxytryptophan, the first step in synthesis of the neurotransmitter 5-hydroxytryptamine (Chapter 25). All three of the pterin-dependent hydroxylases are under complex regulatory control.431 432 For example, tyrosine hydroxylase is acted on by at least four kinases with phosphorylation occurring at several sites.431 433 4338 The kinases are responsive to nerve growth factor and epidermal growth factor,434 cAMP,435 Ca2+ + calmodulin, and Ca2+ + phospholipid (protein kinase C).436 The hydroxylase is inhibited by its endproducts, the catecholamines,435 and its activity is also affected by the availability of tetrahydrobiopterin.436... 

Levodopa (L-dopa) is a natural intermediate in the biosynthesis of catecholamines in the brain and peripheral adrenergic nerve terminals. In the biologic sequence of events it is converted to dopamine, which in turn serves as a substrate of the neurotransmitter norepinephrine. Levodopa is used successfully in the treatment of Parkinson s syndrome, a disease characterized by dopamine deficiency. When levodopa is administered to an individual with this syndrome, the symptoms of Parkinson s disease are ameliorated, presumably because the drug is converted to dopamine and thereby counteracts the deficiency. Individuals treated with levodopa, especially older men, have been observed to experience a sexual rejuvenation. This effect has led to the belief that levodopa stimulates sexual powers. Consequently, studies with younger men complaining of decreased erectile ability have shown that levodopa increases libido and the incidence of penile erections. Overall, however, these effects are short lived and do not reflect continued satisfactory sexual function and potency. Thus, levodopa is not a true aphrodisiac. The increased sexual activity experienced by parkinsonian patients treated with levodopa may reflect improved well-being and partial recovery of normal sexual functions that were impaired by Parkinson s disease. 

The fifth chapter, Tetrahydrobiopterin and Related Biologically Important Pterins by Shizuaki Murata, Hiroshi Ichinose and Fumi Urano, describes a modern aspect of pteridine chemistry and biochemistry. Pteridine derivatives play a very important role in the biosynthesis of amino acids, nucleic acids, neurotransmitters and nitrogenmonooxides, and metabolism of purine and aromatic amino acids. Some pteridines are used in chemotherapy and for the diagnosis of various diseases. From these points of view, this article will attract considerable attention from medicinal and pharmaceutical chemists, and also heterocyclic chemists and biochemists. 

The current RDA for vitamin C is 60 mg/day for a healthy non-smoking adult, Vitamin C is a cofactor for several enzymes involved in the biosynthesis of collagen, neurotransmitters, carnitine (45), hydroxylation of cholesterol (to form bile acids). It is also an important water-soluble antioxidant, which scavenges most of the RS and acts as a coantioxidant by regenerating a-tocopheryl radicals (46). 

In vivo tolerance to copper is quite high, however, deficiency and excess are serious problems. Infants are particularly vulnerable as they take time to assimilate the correct levels and it is known that trace copper from cooking utensils or water pipes can cause childhood cirrhosis. Copper deficiency leads to arterial weakness and heart enlargement. This is probably caused by a decrease in catecholamine neurotransmitters derived from the biosynthesis of adrenaline which requires the copper-containing enzymes phenylalanine hydroxylase, dopamine P-monooxygenase and tyrosinase. 

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