The Synthesis of Acetylcholine

Tuček, Stanislav

doi:10.1007/978-1-4899-1881-9_10

Cited by 17 publications

(9 citation statements)

References 306 publications

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“…Thiamine deficiency (TD) in rats caused inhibition of metabolic flux of pyruvate through PDHC, reductions of ACL-dependent fractions of cytoplasmic acetyl-CoA, and quantal ACh release from their brain nerve terminals ( Jankowska-Kulawy et al, 2010 ). When taken together, these data indicate that ACL is preferentially expressed in cholinergic neurons, where it plays a crucial role in adequate provision of acetyl-CoA to the site of ACh synthesis ( Gibson and Shimada, 1980 ; Szutowicz et al, 1982 , 1996 , 2013 ; Tuček, 1983 ; Beigneux et al, 2004 ).…”

Section: Acetyl-coa Precursors In the Brainmentioning

confidence: 82%

“…On the other hand, averaged concentration of free choline in the brain was assessed to be ca. 60 μmol/L ( Shea and Aprison, 1973 ; Brunello et al, 1982 ; Tuček, 1983 , 1985 ; Klein et al, 1993 ), and that of acetyl-CoA to be close to 7 μmol/L, respectively ( Table 2 ). Kinetic studies on ChAT preparations purified from rat brain revealed that in medium containing high phosphate – low chloride concentrations, characteristic for intracellular compartment, the Km’s for acetyl-CoA and choline were equal to about 40 and 1000 μmol/L, respectively ( Table 1 ) ( Rossier et al, 1977 ; Ryan and McClure, 1980 ).…”

Section: Acetyl-coa Levels In the Brainmentioning

confidence: 88%

“…Accordingly, K/Ca-induced rates of ACh synthesis in differentiated SN56 were found to vary from 1.9 to 3.5% of maximal ChAT activities, being close to its calculated in situ activities ( Jankowska et al, 2000 ; Szutowicz et al, 2004 , 2006 ; Bielarczyk et al, 2015 ). In such conditions the availability of acetyl-CoA in cytoplasmic compartment may be a primary factor limiting rate of ACh synthesis through concentration-dependent regulation ChAT activity ( Figures 1E,F , 2 ) ( Tuček, 1983 , 1985 ; Szutowicz et al, 2013 , 2017 ). It is also certain that pyruvate, through PDHC step, is a main source of acetyl moieties for ACh synthesis ( Lefresne et al, 1973 ; Gibson and Shimada, 1980 ; Sterling et al, 1981 ; Bielarczyk and Szutowicz, 1989 ).…”

Section: Acetyl-coa Levels In the Brainmentioning

confidence: 99%

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The Regulatory Effects of Acetyl-CoA Distribution in the Healthy and Diseased Brain

Ronowska

Szutowicz

Bielarczyk

et al. 2018

Front. Cell. Neurosci.

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Brain neurons, to support their neurotransmitter functions, require a several times higher supply of glucose than non-excitable cells. Pyruvate, the end product of glycolysis, through pyruvate dehydrogenase complex reaction, is a principal source of acetyl-CoA, which is a direct energy substrate in all brain cells. Several neurodegenerative conditions result in the inhibition of pyruvate dehydrogenase and decrease of acetyl-CoA synthesis in mitochondria. This attenuates metabolic flux through TCA in the mitochondria, yielding energy deficits and inhibition of diverse synthetic acetylation reactions in all neuronal sub-compartments. The acetyl-CoA concentrations in neuronal mitochondrial and cytoplasmic compartments are in the range of 10 and 7 μmol/L, respectively. They appear to be from 2 to 20 times lower than acetyl-CoA Km values for carnitine acetyltransferase, acetyl-CoA carboxylase, aspartate acetyltransferase, choline acetyltransferase, sphingosine kinase 1 acetyltransferase, acetyl-CoA hydrolase, and acetyl-CoA acetyltransferase, respectively. Therefore, alterations in acetyl-CoA levels alone may significantly change the rates of metabolic fluxes through multiple acetylation reactions in brain cells in different physiologic and pathologic conditions. Such substrate-dependent alterations in cytoplasmic, endoplasmic reticulum or nuclear acetylations may directly affect ACh synthesis, protein acetylations, and gene expression. Thereby, acetyl-CoA may regulate the functional and adaptative properties of neuronal and non-neuronal brain cells. The excitotoxicity-evoked intracellular zinc excess hits several intracellular targets, yielding the collapse of energy balance and impairment of the functional and structural integrity of postsynaptic cholinergic neurons. Acute disruption of brain energy homeostasis activates slow accumulation of amyloid-β1-42 (Aβ). Extra and intracellular oligomeric deposits of Aβ affect diverse transporting and signaling pathways in neuronal cells. It may combine with multiple neurotoxic signals, aggravating their detrimental effects on neuronal cells. This review presents evidences that changes of intraneuronal levels and compartmentation of acetyl-CoA may contribute significantly to neurotoxic pathomechanisms of different neurodegenerative brain disorders.

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Section: Acetyl-coa Precursors In the Brainmentioning

confidence: 82%

Section: Acetyl-coa Levels In the Brainmentioning

confidence: 88%

Section: Acetyl-coa Levels In the Brainmentioning

confidence: 99%

See 1 more Smart Citation

The Regulatory Effects of Acetyl-CoA Distribution in the Healthy and Diseased Brain

Ronowska

Szutowicz

Bielarczyk

et al. 2018

Front. Cell. Neurosci.

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“…Suppressive, chronic effects of Zn on ChAT activity might depend on its interaction with sulfhydryl groups essential for the enzyme activity (Table 1; Fig. 5) (Tucek 1983) and/or on inhibition of acetyl‐CoA provision to cytoplasmic compartment of the cholinergic cells (Table 1; Fig. 3e).…”

Section: Discussionmentioning

confidence: 99%

Effects of zinc on SN56 cholinergic neuroblastoma cells

Ronowska

Gul-Hinc

Bielarczyk

et al. 2007

Journal of Neurochemistry

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Zinc is a trace element necessary for proper development and function of brain cells. However, excessive accumulation of zinc exerts several cytotoxic effects in the brain. The aim of this work was to see whether cytotoxic effects of zinc are quantitatively correlated with changes in acetyl-CoA metabolism. The zinc levels up to 0.20 mmol/L caused concentrationdependent inhibition of pyruvate dehydrogenase (PDH) activity that correlated with the increase in trypan blue-positive fraction and the decrease in cultured cell number (r = 0.96, p = 0.0001). Chronic exposure of cells to 0.15 mmol/L zinc decreased choline acetyltransferase and aconitase activities, cytoplasmic acetyl-CoA and whole cell ATP level by 38%, 57%, 35%, and 62%, respectively but caused no change in mitochondrial acetyl-CoA level and activities of other enzymes of glycolytic and tricarboxylic acid cycle. DL-a-lipoamide when added simultaneously with zinc to cultured cells or their homogenates attenuated its chronic or acute suppressive effects. In homogenates of chronically Zn-treated cells, lipoamide overcame PDH but not aconitase inhibition. Presented data indicate that acute-transient elevation of zinc caused reversible inhibition of PDH, aconitase activities and acetylCoA metabolism, which when prolonged could lead to irreversible enzyme inactivation yielding decrease in cell viability and secondary suppression of their cholinergic phenotype.

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“…Ansell and Spanner, 1982), Tucek (1983), and Lynn Wecker, a participant in this Meeting, it became clear that phospholipid metabolism generates choline, and that, in turn, choline is involved in the formation of membrane phospholipids (see also Blusztajn and Wurtman, 1983).…”

Section: State Of Artmentioning

confidence: 99%