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Choline acetyltransferase
Choline 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). ChAT is found in high concentration in cholinergic neurons, both in the central nervous system (CNS) and peripheral nervous system (PNS). As with most nerve terminal proteins, ChAT is produced in the body of the neuron and is transported to the nerve terminal, where its concentration is highest. Presence of ChAT in a nerve cell classifies this cell as a "cholinergic" neuron. In humans, the choline acetyltransferase enzyme is encoded by the CHAT gene.
Choline acetyltransferase was first described by David Nachmansohn and A. L. Machado in 1943. 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. Based on prior research showing that "acetylcholine's actions on structural proteins" were responsible for nerve impulses, Nachmansohn and Machado investigated the origin of acetylcholine.
An enzyme has been extracted from brain and nervous tissue which forms acetylcholine. The formation occurs only in presence of adenosinetriphosphate (ATP). The enzyme is called choline acetylase.
— Nachmanson & Machado, 1943
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. It was not until 1945 that Coenzyme A (CoA) was discovered simultaneously and independently by three laboratories, Nachmansohn's being one of these. Subsequently, acetyl-CoA, at the time called “active acetate,” was discovered in 1951. The 3D structure of rat-derived ChAT was not solved until nearly 60 years later, in 2004.
The 3D structure of ChAT has been solved by X-ray crystallography PDB: 2FY2. Choline is bound in the active site of ChAT by non-covalent interactions between the positively charged amine of choline and the hydroxyl group of Tyr552, in addition to a hydrogen bond between choline's hydroxyl group and a histidine residue, His324.
The choline substrate fits into a pocket in the interior of ChAT, while acetyl-CoA fits into a pocket on the surface of the protein. 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.
ChAT is very conserved across the animal genome. Among mammals, in particular, there is very high sequence similarity. Human and cat (Felis catus) ChAT, for example, have 89% sequence identity. Sequence identity with Drosophila is about 30%.
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Choline acetyltransferase
Choline 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). ChAT is found in high concentration in cholinergic neurons, both in the central nervous system (CNS) and peripheral nervous system (PNS). As with most nerve terminal proteins, ChAT is produced in the body of the neuron and is transported to the nerve terminal, where its concentration is highest. Presence of ChAT in a nerve cell classifies this cell as a "cholinergic" neuron. In humans, the choline acetyltransferase enzyme is encoded by the CHAT gene.
Choline acetyltransferase was first described by David Nachmansohn and A. L. Machado in 1943. 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. Based on prior research showing that "acetylcholine's actions on structural proteins" were responsible for nerve impulses, Nachmansohn and Machado investigated the origin of acetylcholine.
An enzyme has been extracted from brain and nervous tissue which forms acetylcholine. The formation occurs only in presence of adenosinetriphosphate (ATP). The enzyme is called choline acetylase.
— Nachmanson & Machado, 1943
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. It was not until 1945 that Coenzyme A (CoA) was discovered simultaneously and independently by three laboratories, Nachmansohn's being one of these. Subsequently, acetyl-CoA, at the time called “active acetate,” was discovered in 1951. The 3D structure of rat-derived ChAT was not solved until nearly 60 years later, in 2004.
The 3D structure of ChAT has been solved by X-ray crystallography PDB: 2FY2. Choline is bound in the active site of ChAT by non-covalent interactions between the positively charged amine of choline and the hydroxyl group of Tyr552, in addition to a hydrogen bond between choline's hydroxyl group and a histidine residue, His324.
The choline substrate fits into a pocket in the interior of ChAT, while acetyl-CoA fits into a pocket on the surface of the protein. 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.
ChAT is very conserved across the animal genome. Among mammals, in particular, there is very high sequence similarity. Human and cat (Felis catus) ChAT, for example, have 89% sequence identity. Sequence identity with Drosophila is about 30%.