Thiamin acetylcholine

Naturally occurring quaternary ammonium compounds have been reviewed (179). Many types of aliphatic, heterocycHc, and aromatic derived quaternary ammonium compounds are produced both in plants and invertebrates. Examples include thiamine (vitamin B ) (4) (see Vitamins) choline (qv) [62-49-7] (5) and acetylcholine (6). These have numerous biochemical functions. Several quaternaries are precursors for active metaboUtes. 

Vagusstoff, m. vagus substance, acetylcholine or (2.Vaguasto F) thiamine. 

Barclay LL, Gibson GE, and Blass JP (1981) Impairment of behavior and acetylcholine metabolism in thiamine Aeficleucy. Journal of Pharmacology and Experimental Therapeutics 217, 537-43. 

The metabolic functions of pantothenic acid in human biochemistry are mediated through the synthesis of CoA. Pantothenic acid is a structural component of CoA. which is necessary for many important metabolic processes. Pantothenic acid is incorporated into CoA by a. series of five enzyme-catalyzed reactions. CoA is involved in the activation of fatty acids before oxidation, which requires ATP to form the respective fatty ocyl-CoA derivatives. Pantothenic acid aI.so participates in fatty acid oxidation in the final step, forming acetyl-CoA. Acetyl-CoA is also formed from pyruvate decarboxylation, in which CoA participates with thiamine pyrophosphate and lipoic acid, two other important coenzymes. Thiamine pyrophosphate is the actual decarboxylating coenzyme that functions with lipoic acid to form acetyidihydrolipoic acid from pyruvate decarboxylation. CoA then accepts the acetyl group from acetyidihydrolipoic acid to form acetyl-CoA. Acetyl-CoA is an acetyl donor in many processes and is the precursor in important biosyntheses (e.g.. those of fatty acids, steroids, porphyrins, and acetylcholine). 

An inherited pyruvate dehydrogenase deficiency, a thiamine deficiency, or hypoxia deprives the brain of a source of acetyl CoA for acetylcholine synthesis, as well as a source of acetyl CoA for ATP generation from the TCA cycle. 

Thiamin potentiates CNS effects of acetylcholine. improved cognitive functioning in patients with Alzheimer s or age-related memory loss taking 3-8g/day. chronic thiamin diphosphate deficiency may contribute to cognitive impairment in Alzheimer"s Diseas. 

With such an extensive knowledge base, what is the present state of our understanding of the mechanisms of this disorder Not unexpectedly, initial studies, primarily in experimental animal models, focused on the known metabolic pathways which involve thiamine. Indeed, the classical studies of Peters in 1930 (Peters, 1969) showed lactate accumulation in the brainstem of thiamine deficient birds with normalization of this in vitro when thiamine was added to the tissue. This led to the concept of the biochemical lesion of the brain in thiamine deficiency. The enzymes which depend on thiamine are shown in Fig. 14.1. They are transketolase, pyruvate and a-ketoglutarate dehydrogenase. Transketolase is involved in the pentose phosphate pathway needed to form nucleic acids and membrane lipids, including myelin. The ketoacid dehydrogenases are key enzymes of the Krebs cycle needed for energy (ATP) synthesis and also to form acetylcholine via Acetyl CoA synthesis. Decrease in activity of this cycle would result in anaerobic metabolism and lead to lactate formation (i.e., tissue acidosis) (Fig. 14.1). 

Data on the role of acetylcholine deficit in thiamine deficiency are conflicting, but most recent studies do not favor a significant decrease in the synthesis of this neurotransmitter (Hazell et al, 1998 Vorhees et al, 1977). This would be consistent with normal pyruvate dehydrogenase activity in experimental thiamine deficiency, which should not, therefore, result in a lower Acetyl CoA level as a precursor to acetylcholine. 

How far the acetylcholine-like activity of thiamine, postulated by Kalz (1942), can be used to explain the observed anaphylactoid phenomena has not been discussed in the literature. The same applies to its curare-like effects, as reported by Barazzone and Lambelet (1954), as well as to its effects on nervous tissue (Cooper and PiNCUS 1979). Neither does the literature consider the role thiaminases... 

Table 33.3 Thiamine diphosphate deficits reduce acetyl-CoA levels in sub-cellular compartments of the brain neurons, suppressing their viability and cholinergic neurotransmission. Data from Bielarczyk et al. (2005), Bizon-Zygmanska et al. (2011) and Jankowska-Kulawy et al. (2010) expressed as means SEM in pmol/mg protein ( = 5-20 experiments). Italics refer to fractions of acetyl-CoA and acetylcholine provided through the ATP itrate lyase pathway (see Figure 33.1). Bold numbers refer to nonviable cell fractions assayed by trypan blue exclusion assay and expressed as a percentage of the whole cell population.

Heinrich, C.P., Stadler, H., and Weiser, H., 1973. The effect of thiamine deficiency on the acetylcoenzymeA and acetylcholine levels in the rat brain. Journal of Neurochemistry. 21 1273-1281. 

Jankowska-Kulawy, A., Bielarczyk, H., Pawelczyk, T., Wroblewska, M., and Szutowicz A., 2010. Acetyl-CoA and acetylcholine metabolism in nerve terminal compartment of thiamine deficient rat brain. Journal of Neurochemistry. 115 333-342. 

Reynolds, S.F., and Blass, J.P., 1975. Normal levels of acetyl coenzyme A and of acetylcholine in the brains of thiamin-deficient rats. Journal of neurochemistry. 24 183-186. 

---