Acetyl choline, synthesis

A great many organic quaternary bases can inhibit the action of acetyl choline in organ systems activated by that neurotransmitter and thus possess anticholinergic-antispasmodic activity. One such agent is methantheline bromide (4), used in the treatment of peptic ulcer and as an antispasmodic agent in intestinal disorders. Its synthesis Involves Friedel-Crafts cyclization of o-... 

Dihydropteridine reductase is an important enzyme in the synthesis of several important neurotransmitters, such as tyrosine and acetyl choline. They found that erythrocyte levels of dihydropteridine reductase activity were less than predicted values, and correlated with plasma aluminum levels (Altmann et ah, 1987). After treatment with desferrioxamine, red cell dihydropteridine reductase activity levels doubled. Although brain levels of dihydropteridine reductase activity were not evaluated, it was suggested that high brain aluminum levels might lead to decreased availability of dihydropteridine reductase in the brain. It has been suggested that the mere presence of an increased body aluminum burden has an adverse effect on overall mortality (Chazan et al, 1988). More specifically, an increased body aluminum burden (estimated by the desferrioxamine infusion test) has been associated with memory impairment and increased severity of myoclonus with decreased motor strength (Sprague et al., 1988). 

Phosphatydil choline (lecithin), ethanol amine, inositol, and serine are essential for prop function of cell membranes and brain. They slow down the process of cell aging and prevent high cholesterol. Choline is used for the synthesis of acetyl choline, which is the main neurotransmission. 

The neurotransmitter must be present in presynaptic nerve terminals and the precursors and enzymes necessary for its synthesis must be present in the neuron. For example, ACh is stored in vesicles specifically in cholinergic nerve terminals. It is synthesized from choline and acetyl-coenzyme A (acetyl-CoA) by the enzyme, choline acetyltransferase. Choline is taken up by a high affinity transporter specific to cholinergic nerve terminals. Choline uptake appears to be the rate-limiting step in ACh synthesis, and is regulated to keep pace with demands for the neurotransmitter. Dopamine [51 -61-6] (2) is synthesized from tyrosine by tyrosine hydroxylase, which converts tyrosine to L-dopa (3,4-dihydroxy-L-phenylalanine) (3), and dopa decarboxylase, which converts L-dopa to dopamine. 

The chlorohydrin process (24) has been used for the preparation of acetyl-P-alkylcholine chloride (25). The preparation of salts may be carried out mote economically by the neutralization of choline produced by the chlorohydrin synthesis. A modification produces choline carbonate as an intermediate that is converted to the desired salt (26). The most practical production procedure is that in which 300 parts of a 20% solution of trimethyl amine is neutralized with 100 parts of concentrated hydrochloric acid, and the solution is treated for 3 h with 50 parts of ethylene oxide under pressure at 60°C (27). 

Figure 6.1 Synthesis and metabolism of acetylcholine. Choline is acetylated by reacting with acetyl-CoA in the presence of choline acetyltransferase to form acetylcholine (1). The acetylcholine binds to the anionic site of cholinesterase and reacts with the hydroxy group of serine on the esteratic site of the enzyme (2). The cholinesterase thus becomes acetylated and choline splits off to be taken back into the nerve terminal for further ACh synthesis (3). The acetylated enzyme is then rapidly hydrolised back to its active state with the formation of acetic acid (4)...

The reaction of choline with mitochondrial bound acetylcoenzyme A is catalysed by the cytoplasmic enzyme choline acetyltransferase (ChAT) (see Fig. 6.1). ChAT itelf is synthesised in the rough endoplasmic reticulum of the cell body and transported to the axon terminal. Although the precise location of the synthesis of ACh is uncertain most of that formed is stored in vesicles. It appears that while ChAT is not saturated with either acetyl-CoA or choline its synthesising activity is limited by the actual availability of choline, i.e. its uptake into the nerve terminal. No inhibitors of ChAT itself have been developed but the rate of synthesis of ACh can, however, be inhibited by drugs like hemicholinium or triethylcholine, which compete for choline uptake into the nerve. 

Acetylcholine synthesis and neurotransmission requires normal functioning of two active transport mechanisms. Choline acetyltransferase (ChAT) is the enzyme responsible for ACh synthesis from the precursor molecules acetyl coenzyme A and choline. ChAT is the neurochemical phenotype used to define cholinergic neurons although ChAT is present in cell bodies, it is concentrated in cholinergic terminals. The ability of ChAT to produce ACh is critically dependent on an adequate level of choline. Cholinergic neurons possess a high-affinity choline uptake mechanism referred to as the choline transporter (ChT in Fig. 5.1). The choline transporter can be blocked by the molecule hemicholinium-3. Blockade of the choline transporter by hemicholinium-3 decreases ACh release,... 

Another observation on oxalate formation is that other a-keto acids, such as oxalosuccinic acid (74) and a-ketoglutaric acid (106) do not seem to yield oxalate directly but indirectly (123). This appears to be due to the fact that only oxaloacetic acid can function as an acetate donor. In this connection the intervention of Coenzyme A may be considered, since it is reported to function in the acetylation of sulfanilamide and choline (73) and recently was shown to take part in the enzymatic synthesis of citric acid. This concept may be illustrated as follows ... 

The answers are 333-c, 334-a, 335-d. (Katzung, pp 77-80. Hardman, pp 116, 132, 147—148.) Acetylcholine is synthesized from acetyl-CoA and choline. Choline is taken up into the neurons by an active transport system. Ilemicholinium blocks this uptake, depleting cellular choline, so that synthesis of ACh no longer occurs. 

The synthesis reaction is a single step catalyzed by the enzyme choline acetyl transferase (ChAT) ... 

Brain ChAT has a KD for choline of approximately 1 mmol/1 and for acetyl coenzyme A (CoA) of approximately 10pmol/l. The activity of the isolated enzyme, assayed in the presence of optimal concentrations of cofactors and substrates, appears far greater than the rate at which choline is converted to ACh in vivo. This suggests that the activity of ChAT is repressed in vivo. Surprisingly, inhibitors of ChAT do not decrease ACh synthesis when used in vivo this may reflect a failure to achieve a sufficient local concentration of inhibitor, but also suggests that this step is not rate-limiting in the synthesis of ACh [18-20]. 

The effect of Li+ upon the synthesis and release of acetylcholine in the brain is equivocal Li+ is reported to both inhibit and stimulate the synthesis of acetylcholine (reviewed by Wood et al. [162]). Li+ appears to have no effect on acetyl cholinesterase, the enzyme which catalyzes the hydrolysis of acetylcholine [163]. It has also been observed that the number of acetylcholine receptors in skeletal muscle is decreased by Li+ [164]. In the erythrocytes of patients on Li+, the concentration of choline is at least 10-fold higher than normal and the transport of choline is reduced [165] the effect of Li+ on choline transport in other cells is not known. A Li+-induced inhibition of either choline transport and/or the synthesis of acetylcholine could be responsible for the observed accumulation of choline in erythrocytes. This choline is probably derived from membrane phosphatidylcholine which is reportedly decreased in patients on Li+ [166],... 

Synthesis of noradrenaline (norepinephrine) is shown in Figure 4.7. This follows the same route as synthesis of adrenaline (epinephrine) but terminates at noradrenaline (norepinephrine) because parasympathetic neurones lack the phenylethanolamine-N-methyl transferase required to form adrenaline (epinephrine). Acetylcholine is synthesized from acetyl-Co A and choline by the enzyme choline acetyltransferase (CAT). Choline is made available for this reaction by uptake, via specific high-affinity transporters, within the axonal membrane. Following their synthesis, noradrenaline (norepinephrine) or acetylcholine are stored within vesicles. Release from the vesicle occurs when the incoming nerve impulse causes an influx of calcium ions resulting in exocytosis of the neurotransmitter. 

Figure 14.9 Axonal transport of enzymes, neurotransmitter synthesis, storage in vesicles, release and uptake by presynaptic neurone or enzymic degradation. The neurotransmitter in the synaptic cleft may be removed by the presynaptic neurone (i.e. recycling), by the postsynaptic neurone or by glial cells (not shown). Alternatively, the neurotransmitter may be degraded, and therefore inactivated, by enzyme action. For example, acetylcholine is degraded by acetylcholinesterase in the synaptic cleft (Chapter 3). One of the products, choline, is transported back into the neurone to be reacted with acetyl-CoA to re-form acetylcholine. The vesicle, once empty, may also be recycled for re-packaging (Figure 14.8).

Acetylcholine is synthesized from acetyl-CoA and choline in the cytoplasm of the presynap-tic axon [1] and is stored in synaptic vesicles, each of which contains around 1000-10 000 ACh molecules. After it is released by exocy-tosis (see p. 228), the transmitter travels by diffusion to the receptors on the postsynaptic membrane. Catalyzed by acetylcholinesterase, hydrolysis of ACh to acetate and choline immediately starts in the synaptic cleft [2], and within a few milliseconds, the ACh released has been eliminated again. The cleavage products choline and acetate are taken up again by the presynaptic neuron and reused for acetylcholine synthesis [3j. 

The processes involved in neurochemical transmission in a cholinergic neuron are shown in Figure 9.2. The initial substrates for the synthesis of acetylcholine are glucose and choline. Glucose enters the neuron by means of facilitated transport. There is some disagreement as to whether choline enters cells by active or facilitated transport. Pyruvate derived from glucose is transported into mitochondria and converted to acetylcoenzyme A (acetyl-CoA). The acetyl-CoA is transported back into the cytosol. With the aid of the enzyme choline acetyl-transferase, acetylcholine is synthesized from acetyl-CoA and choline. The acetylcholine is then transported into and stored within the storage vesicles by as yet unknown mechanisms. 

C) Inhibition of synthesis of acetylcholine by inhibiting choline acetyl transferase... 

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