Choline acetyltransferase

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Not to be confused with Acetylcholinesterase.
Choline acetyltransferase
Identifiers
ExPASy
NiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
Search
PMCarticles
PubMedarticles
NCBIproteins
CHAT
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
Ensembl

ENSG00000070748

ENSMUSG00000021919

UniProt

P28329

Q8BQV2

RefSeq (mRNA)

NM_009891

RefSeq (protein)

NP_034021

Location (UCSC)Chr 10: 49.61 – 49.67 MbChr 14: 32.13 – 32.19 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Choline acetyltransferase (commonly abbreviated as ChAT, but sometimes CAT) is a

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.[5]

History

Choline acetyltransferase was first described by

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.[7]

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[6]

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.[6] It was not until 1945 that Coenzyme A (CoA) was discovered simultaneously and independently by three laboratories,[8][9][10] Nachmansohn's being one of these. Subsequently, acetyl-CoA, at the time called “active acetate,” was discovered in 1951.[11] The 3D structure of rat-derived ChAT was not solved until nearly 60 years later, in 2004.[12]

Structure

The 3D structure of ChAT has been solved by X-ray crystallography

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.

Structure of choline acetyltransferase binding sites
  • Crystal structure of choline ion bound in choline acetyltransferase. Side chain residues of His324A and Tyr552A shown.PDB: 2FY3​
    Crystal structure of choline ion bound in choline acetyltransferase. Side chain residues of His324A and Tyr552A shown.PDB: 2FY3​
  • Stereoscopic depiction of choline and acetyl-CoA in ChAT active site.(PDB: 2FY3​, PDB: 2FY5​ - overlaid).
    Stereoscopic depiction of choline and acetyl-CoA in ChAT active site.(PDB: 2FY3​, PDB: 2FY5​ - overlaid).
  • Stereoscopic depiction of choline and acetyl-CoA bound in ChAT active site - alternate angle. (PDB: 2FY3​, PDB: 2FY5​ - overlaid).
    Stereoscopic depiction of choline and acetyl-CoA bound in ChAT active site - alternate angle. (PDB: 2FY3​, PDB: 2FY5​ - overlaid).

Homology

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%.[13]

Forms of ChAT

There are two forms of ChAT: Soluble form and membrane-bound form.[14] The soluble form accounts for 80-90% of the total enzyme activity while the membrane-bound form is responsible for the rest of 10-20% activity.[15] However, there has long been a debate on how the latter form of ChAT is bound to the membrane.[16] The membrane-bound form of ChAT is associated with synaptic vesicles.[17]

Common and peripheral isoforms of ChAT

There exist two isoforms of ChAT, both encoded by the same sequence. The common type ChAT (cChAT) is present in both the CNS and PNS. Peripheral type ChAT (pChAT) is preferentially expressed in the PNS in humans, and arises from

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.

Function

synthesis and transportation of ACh in cells[18]

nicotinic – which are each implicated in different physiological responses. The role of acetylcholine at the nicotinic receptor is still under investigation. It is likely implicated in the reward/reinforcement pathways, as indicated by the addictive nature of nicotine, which also binds to the nicotinic receptor. The muscarinic action of acetylcholine in the CNS is implicated in learning and memory. The loss of cholinergic innervation in the neocortex has been associated with memory loss, as is evidenced in advanced cases of Alzheimer's disease. In the peripheral nervous system
, cholinergic neurons are implicated in the control of visceral functions such as, but not limited to, cardiac muscle contraction and gastrointestinal tract function.

It is often used as an immunohistochemical marker for motor neurons (motoneurons).

Mutations

Mutants of ChAT have been isolated in several species, including C. elegans, Drosophila, and humans. Most non-lethal mutants that have a non-wild type phenotype exhibit some activity, but significantly less than wild type.

In C. elegans, several mutations in ChAT have been traced to the cha-1 gene. All mutations result in a significant drop in ChAT activity. Percent activity loss can be greater than 98% in some cases. Phenotypic effects include slowed growth, decreased size, uncoordinated behavior, and lack of sensitivity toward

temperature-sensitive mutants in Drosophila have all been lethal. Prior to death, affected flies show a change in behavior, including uncontrolled movements and a change in electroretinogram activity.[20]

The human gene responsible for encoding ChAT is CHAT. Mutations in CHAT have been linked to congenital myasthenic syndrome, a disease which leads to general motor function deficiency and weakness. Further symptoms include fatal apnea. Out of ten isolated mutants, 1 has been shown to lack activity completely, 8 have been shown to have significantly decreased activity, and 1 has an unknown function.[21]

Clinical significance

Alzheimer's disease

The

Beta amyloid protein, interferes with the metabolism of neurones and further damages the cholinergic axons in the cortex and cholinergic neurones in the basal forebrain.[23]

Amyotrophic lateral sclerosis

The

amyotrophic lateral sclerosis (ALS) is one of the most common motor neuron diseases. A significant loss of ChAT immunoreactivity is found in ALS.[24] It is hypothesized that the cholinergic function is involved in an uncontrolled increase of intracellular calcium concentration whose reason still remains unclear.[25]

Drugs

Neostigmine methylsulfate, an anticholinesterase agent, has been used to target ChAT. In particular, use of neostigmine methylsulfate has been shown to have positive effects against congenital myasthenic syndrome.[26]

Exposure to estradiol has been shown to increase ChAT in female rats.[27]

See also

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000070748 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000021919 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. PMID 1840566
    .
  6. ^
    doi:10.1152/jn.1943.6.5.397
    .
  7. PMID 13115440
    .
  8. doi:10.1016/S0021-9258(17)41419-0
    .
  9. PMID 21066687
    .
  10. PMID 20276121
    .
  11. PMID 5716187
    .
  12. PMID 15477102
    .
  13. S2CID 23621617
    .
  14. S2CID 44586742
    .
  15. S2CID 24196247
    .
  16. S2CID 4336737
    .
  17. S2CID 1139292
    .
  18. ^ Rand, James. "Acetylcholine". WormBook.
  19. PMID 6698395
    .
  20. S2CID 45897606
    .
  21. PMID 11172068
    .
  22. PMID 7046051
    .
  23. PMID 9600198
    .
  24. S2CID 23763400
    .
  25. S2CID 28937351
    .
  26. S2CID 8672902
    .
  27. S2CID 1525252
    .

Further reading

External links

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