Choline acetyltransferase acetylcholine synthesis

Tucek S. Choline acetyltransferase and synthesis of acetylcholine. In Wittaker VP, ed. The Cholinergic Synapse Handbook of Experimental Pharmacology. Berlin Springer-Verlag, 1988, pp. 125-165. 

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)...

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,... 

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. 

Acetylcholine synthesis. Acetylcholine (ACh) is a prominent neurotransmitter, which is formed in cholinergic neurons from two precursors, choline and acetyl coenzyme A (AcCoA) (Fig. 12—8). Choline is derived from dietary and intraneuronal sources, and AcCoA is synthesized from glucose in the mitochondria of the neuron. These two substrates interact with the synthetic enzyme choline acetyltransferase to produce the neurotransmitter ACh. 

Synthesis of acetylcholine Choline is transported from the extracellular fluid into the cytoplasm of the cholinergic neuron by a carrier system that cotransports sodium and can be inhibited by the drug hemicholinium. Choline acetyltransferase (CAT) catalyzes the reaction of choline with acetyl CoA to form acetylcholine in the cytosol. 

Acethylcholine synthesis and release In the presynaptic cholinergic terminal. Ach, acetylcholine ChAT, choline acetyltransferase VAChT, vesicular acetylcholine transporter AChE, acetylcholineesterase CHT, choline transporter... 

Figure 17-6 Ordered synthesis of acetylcholine (ACh) by choline acetyltransferase (ChAT).

S.J. Danishefsky and co-workers developed a synthetic route to the neurotrophic illicinones and a total synthesis of the natural product tricycloillicinone. Illicinones were found to enhance the action of choline acetyltransferase, which catalyzes the synthesis of acetylcholine from its precursors. The application of Corey-Snider oxidative cycHzation and the Barton-McCombie radical deoxygenation provided a direct route to tricycloillicinone. 

In contrast to the biosynthetic systems for catecholamines and serotonin discussed earlier, there appear to be no posttranslational modifications such as protein phosphorylation or proteolytic activation that regulate the catalytic state of choline acetyltransferase. A more detailed discussion of acetylcholine synthesis may be found in Blusztajn and Wurtman (1983). 

Molecular Properties of Choline Acetyltransferase and Their Importance for the Compartmentation of Acetylcholine Synthesis... 

Choline acetyltransferase (ChAc) is responsible for the synthesis of the chemical transmitter acetylcholine (ACh) and is therefore an important enzyme in nervous tissue. There is an excellent correlation between the level of ACh and the level of ChAc in different parts of the nervous system (Silver, 1967), indicating that this enzyme governs the level of ACh. The localization of ChAc is therefore synonymous with the site of synthesis of ACh and knowledge of this site gives important information as to the further processes necessary for the uptake and storage of the neurotransmitter. 

Evidence that acetylcholine is a chemical mediator of synaptic transmission elsewhere in the central nervous system is circumstantial but convincing. Acetylcholine is the transmitter substance from motor nerves, preganglionic autonomic fibres and the postganglionic fibres of the parasympathetic system to their respective effector cells. In all these fibres, the activity of choline acetyltransferase (choline acetylase), the enzyme responsible for the synthesis of acetylcholine, is high. Conversely, its activity is negligibly low in sensory nerve fibres and transmission from these fibres is demonstrably non-cholinergic in nature . It is reasonable, therefore, to... 

The enzyme choline acetyltransferase (EC 2.3.1.6) is the key enzyme in the synthesis of acetylcholine, whereas AChE is essential for the inactivation and regulation of acetylcholine at localized sites of neurotransmission. The mechanism of action of AChE involves an initial reaction where acetylcholine forms a complex with the enzyme, leading to acetylation and the release of choline. The reaction is reversible with the regeneration of de-acetylated enzyme. 

The synthesis of acetylcholine from acetyl CoA and choline is catalyzed by the enzyme choline acetyltransferase (ChAT) (Fig. 48.9). This synthetic step occurs in the presynaptic terminal. The compound is stored in vesicles and later released through calcium-mediated exocytosis. Choline is taken up by the presynaptic terminal from the blood via a low-affinity transport system (high and from the synaptic cleft via a high-affmity transport mechanism (low K. It is also derived from the hydrolysis of phosphatidylcholine (and possibly sphingomyelin) in membrane lipids. Thus, membrane lipids may form a storage site for choline, and their hydrolysis, with the subsequent release of choline, is highly regulated. 

Figure 2.4B Synthesis, release and degradation of acetylcholine. 1). The enzyme choline acetyltransferase catalyzes the acetylation of choline by acetyl CoA to form acetylcholine.

Not fully understood, but it has been shown that quinidine can inhibit the enzyme (choline acetyltransferase), which is concerned with the synthesis of acetylcholine at nerve endings. Neuromuscular transmission would be expected to be reduced if the synthesis of acetylcholine is reduced. Quinidine also inhibits the activity of plasma cholinesterase, which is concerned with the metabolism of suxamethonium. ... 

Acetylcholine (Sec. 11.11) is synthesized in the body s neurons. The enzyme choline acetyltransferase catalyzes its synthesis from acetyl-CoA (see A Word About... Thioesters, Nature s Acyl-Activating Groups on page 312) and choline. Write an equation for the reaction, using the formula CH3C—S—CoA for acetyl-CoA. 

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