Choline acetyltransferase

2FY2, 2FY3, 2FY4, 2FY5110312647ENSG00000070748ENSMUSG00000021919P28329Q8BQV2NM_020984NM_020985NM_009891NP_066265NP_066266NP_034021Choline acetyltransferase (commonly abbreviated as ChAT, but sometimes CAT) is a transferase enzyme responsible for the synthesis of the neurotransmitter acetylcholine.

ChAT catalyzes the transfer of an acetyl group from the coenzyme acetyl-CoA to choline, yielding acetylcholine (ACh).

[6] A German biochemist, Nachmansohn had been studying the process of nerve impulse conduction and utilization of energy-yielding chemical reactions in cells, expanding upon the works of Nobel laureates Otto Warburg and Otto Meyerhof on fermentation, glycolysis, and muscle contraction.

The enzyme is called choline acetylase.The acetyl transferase mode of action was unknown at the time of this discovery, however Nachmansohn hypothesized the possibility of acetylphosphate or phosphorylcholine exchanging the phosphate (from ATP) for choline or acetate ion.

The 3D crystal structure shows the acetyl group of acetyl-CoA abuts the choline binding pocket – minimizing the distance between acetyl-group donor and receiver.

The pChAT isoform was discovered in 2000 based on observations that brain-derived ChAT antibodies failed to stain peripheral cholinergic neurons as they do for those found in the brain.

This gene splicing mechanism which leads to cChAT and pChAT differences has been observed in various species, including both vertebrate mammals and invertebrate mollusks, suggesting this mechanism leads to some yet-unidentified evolutionary advantage.

Acetylcholine acts at two classes of receptors in the central nervous system – muscarinic and nicotinic – which are each implicated in different physiological responses.

Mutants of ChAT have been isolated in several species, including C. elegans, Drosophila, and humans.

Phenotypic effects include slowed growth, decreased size, uncoordinated behavior, and lack of sensitivity toward cholinesterase inhibitors.

Mutations in CHAT have been linked to congenital myasthenic syndrome, a disease which leads to general motor function deficiency and weakness.

The concentrations of acetylcholine and ChAT are remarkably reduced in the cerebral neocortex and hippocampus.

[24] It is hypothesized that the cholinergic function is involved in an uncontrolled increase of intracellular calcium concentration whose reason still remains unclear.