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Official Full Name
acetylcholinesterase
Background
Acetylcholinesterase hydrolyzes the neurotransmitter, acetylcholine at neuromuscular junctions and brain cholinergic synapses, and thus terminates signal transmission. It is also found on the red blood cell membranes, where it constitutes the Yt blood group antigen. Acetylcholinesterase exists in multiple molecular forms which possess similar catalytic properties, but differ in their oligomeric assembly and mode of cell attachment to the cell surface. It is encoded by the single ACHE gene, and the structural diversity in the gene products arises from alternative mRNA splicing, and post-translational associations of catalytic and structural subunits. The major form of acetylcholinesterase found in brain, muscle and other tissues is the hydrophilic species, which forms disulfide-linked oligomers with collagenous, or lipid-containing structural subunits. The other, alternatively spliced form, expressed primarily in the erythroid tissues, differs at the C-terminal end, and contains a cleavable hydrophobic peptide with a GPI-anchor site. It associates with the membranes through the phosphoinositide (PI) moieties added post-translationally.
Synonyms
ACHE; acetylcholinesterase (Yt blood group); YT; ACEE; ARACHE; N-ACHE; acetylcholinesterase; zgc:92550; zim; ziehharmonika

The basic function of acetylcholinesterase (ACHE) is to catalyze the hydrolysis of the neurotransmitter acetylcholine. It mainly exists in the synaptic cleft of cholinergic nerve endings, especially in the wrinkles of the synaptic membrane of motor nerve endplates. In addition, it is also widely expressed in human erythrocytes, epithelial cells, endothelial cells, thymocytes, hepatocytes and even osteoblasts. ACHE has the strongest effect on physiological concentration of acetylcholine (ACh).

The human ACHE gene is located on chromosome 7q22.1 and contains seven exons. Different splicing of ACHE genes at the RNA level can produce at least three ACHE mRNA variants, translating three ACHE variants with different carboxy termini, called synaptic, erythrocyte, and read-through. Synaptic (ACHE-S) and read-through (ACHE-R) are frequently expressed in the mammalian central nervous system. In addition to similar catalytic functions, the two subtypes of ACHE differ in other functions. ACHE-R promotes repair and slows down neurodegeneration, while ACHE-S enhances neurotoxicity and promotes neurodegeneration.

Catalytic Function of ACHE

The catalytic function of ACHE is that ACHE rapidly hydrolyzes the neurotransmitter ACh at the cholinergic synapse, thereby terminating the transmission of cholinergic nerve signals. The process of ACHE hydrolysis of ACh can be divided into three steps: 1. positively charged quaternary ammonium cation head in the molecular structure of ACh, combined with the anion site of ACHE by electrostatic attraction. At the same time, the hydroxyl carbon of ACh molecule and the serine hydroxyl group of the ACHE enzymatic site are covalently bonded to form a complex of ACh and ACHE; 2. ACh and ACHE complexes are cleaved into choline and acetylated ACHE; 3. acetylated ACHE is rapidly hydrolyzed, and the acetic acid is separated and the activity of the enzyme is restored. Anticholinergic drugs, like ACh, can also bind to ACHE. However, the combination is more robust and the hydrolysis is slower, which inhibits ACHE activity. Clinically, this feature is used to treat myasthenia gravis and glaucoma with reversible anti-cholinesterase drugs (such as neostigmine and physostigmine).

ACHE's Non-catalytic Function

The non-catalytic function of ACHE refers to non-enzymatic functions other than its catalytic hydrolysis function, including induction of axon growth and synapse formation, involvement in cell migration, adhesion and apoptosis, promotion of blood cell formation and aggregation of amyloid. These non-catalytic functions of ACHE may be related to the interaction between proteins and proteins mediated by their peripheral anion sites.

The non-classical function that ACHE preferentially distinguishes from its hydrolytical function is its role in axon growth. ACHE can promote axon growth and its active site inhibitors not to attenuate this effect, but peripheral anion site inhibitors can block this effect. Dorsal root ganglia (DRG) showed a transient peak of ACHE expression during axonal growth, indicating a direct correlation between endogenous ACHE and axonal growth of primary DRG neurons. ACHE expressed on the axon surface of DRG neurons may induce DRG axon growth through an adhesion mechanism. It also provides evidence that ACHE is involved in adhesion in the morphogenesis of the central nervous system. In addition, ACHE has an evolutionarily conserved sudden triggering life. This effect is dependent on its ability to hydrolyze and may be related to glutamate receptors. Embryonic ACHE expression is earlier than synapse formation, and its activity will weaken or disappear in some areas as development progresses.

In vivo experiments have demonstrated that stress-induced ACHE-R overexpression stimulates bone marrow hematopoietic cells and platelet production, and both catalytic and non-catalytic functions of ACHE may be involved in this promotion process. The discovery of ACHE's function provides a new way to slow the thrombocytopenia after stem cell transplantation and partly explains the increased risk of leukemia in anti-ACHE pesticide users. Leal et al. found that the characteristics of ACHE may constitute sensitive biomarkers of red blood cell (RBC) aging in the body. This information may help to understand the effects of red blood cell homeostasis and blood transfusion.

Figure 1. Schematic representation of the ACHE–ACh active complex transduction pathway of the NO efflux from human erythrocytes. (Saldanha, et al. 2017).

ACHE and Tumor

In lung, colon and rectal cancer, it is found that the decrease in ACHE activity leads to an increase in ACH levels, enhancing the cholinergic signaling system and promoting tumor growth, which may be related to ACHE involvement in cell growth, proliferation, and apoptosis. In cancer, especially in cancers associated with smoking, the response mechanism of tumor cells to abnormally activated cholinergic signaling is a key issue. Castillogonzález et al. compared the ACHE activity of fifty pairs of laryngeal squamous cell carcinoma and adjacent non-cancerous tissue acetyl and found that low ACHE activity observed in laryngeal squamous cell carcinoma may help predict patient outcomes. Subsequently, the team found that low ACHE activity in head and neck squamous cell carcinoma can also be used to predict survival. Therefore, ACHE activity level can be used as a reliable indicator of tumor prognosis.

Xi et al. found that ACHE antisense RNA (ACHE-AS) plays an important role in the regulation of ACHE expression. Studies have shown that ACHE-AS regulates ACHE expression and exerts an anti-apoptotic effect by directly inhibiting ACHE expression in hepatoma cells (HCC). Thus, natural antisense RNA may play an important role in ACHE regulation by affecting epigenetic modifications in the ACHE promoter region.

ACHE and AD

Alzheimer's disease (AD) is a central nervous system degenerative disease characterized by progressive cognitive functioning, including learning, memory, judgment, and abstract thinking. The neuropathological features of AD are the presence of a large number of senile plaques and neurofibrillary tangles in nerve cells between nerve cells, and its pathogenesis has many theories. Choline acetyltransferase (ChAT) activity is low due to the large lack of neurotransmitter ACh found in the brains of AD patients. In addition, ACHE's promotion of amyloid aggregation may also be a causative factor in AD. Metal (copper, iron)-induced ACHE oxidative stress also plays an important role in the production of AD. Therefore, acetylcholine activation therapy, which regulates the function of the cholinergic system, has become a major direction in the study of AD drugs.

Currently, many drugs that inhibit ACHE activity have been developed. Hamulakova et al. synthesized a novel multifunctional tacrine-7-hydroxycoumarin hybrid to inhibit the activity of acetylcholinesterase. It has been clinically found that changes in ACHE subtypes in cerebrospinal fluid (the ratio of ACHE-R-S) are highly correlated with changes in cognitive function in AD patients. Campanari et al. found a selective change in specific ACHE variants in the AD cortex that was not associated with enzymatic activity. Thus, differential expression of ACHE variants in AD may reflect changes in the pathophysiological effects of ACHE, rather than on cholinergic damage or its role in the degradation of acetylcholine.

Reference:

  1. Leal J K F, Adjobohermans M J W, Brock R, et al. Acetylcholinesterase provides new insights into red blood cell ageing in vivo and in vitro. Blood transfusion = Trasfusione del sangue, 2017, 15(3):232.
  2. Campanari M L, Navarrete F, Ginsberg S D, et al. Increased Expression of Readthrough Acetylcholinesterase Variants in the Brains of Alzheimer's Disease Patients. Journal of Alzheimers Disease Jad, 2016, 53(3).
  3. Hamulakova S, Poprac P, Jomova K, et al. Targeting copper (II)-induced oxidative stress and the acetylcholinesterase system in Alzheimer's disease using multifunctional tacrine-coumarin hybrid molecules. Journal of Inorganic Biochemistry, 2016, 161:52-62.
  4. Castillogonzález A C, Pelegrínhernández J P, Nietocerón S, et al. Unbalanced acetylcholinesterase activity in larynx squamous cell carcinoma. International Immunopharmacology, 2015, 29(1):81-6.
  5. Castillo-González A C, Nieto-Cerón S, Pelegrín-Hernández J P, et al. Dysregulated cholinergic network as a novel biomarker of poor prognostic in patients with head and neck squamous cell carcinoma. Bmc Cancer, 2015, 15(1):385.
  6. Xi Q, Gao N, Zhang X, et al. A natural antisense transcript regulates acetylcholinesterase gene expression via epigenetic modification in Hepatocellular Carcinoma. International Journal of Biochemistry & Cell Biology, 2014, 55(1):242-51.
  7. Saldanha C. Human Erythrocyte Acetylcholinesterase in Health and Disease. Molecules, 2017, 22(9):1499.