Thiamin function

The cavity of p-CD, with a diameter of about 7 A, provides an attractive binding site for the substrate on the side of the primary OH groups. Benzaldehyde enclosed in the hydrophobic cavity of a thiamine-functionalized p-CD was first converted to a thiazolium adduct having a similarity to a cyanohydrin (Figure 4). This adduct readily formed a benzylic anion, as evidenced by fhe anion s characteristic reactions such as deuterium exchange and oxidation. 

Figure 30-9 Principal urinary catabolites of thiamine. Functions...

Thiamine functions metabolically as the coenzyme cocaiboxylase thiamine p3rrophosphate (TPP) (/5). TPP is enzjrmically mthesized from thiamine and adenocdne triphosphate (ATP) 16). 

Thiamin functions as the coenzyme TDP in the metabolism of carbohydrates and branched-chain amino acids (a-keto-isocaproic, a-keto-yS-methyl valeric, and a-keto-isovaleric acids). In association... 

The exact mode of action of pyrithiamin is thus still obscure what is clear is that it must be closely concerned with interference ivith thiamin function, and this inhibition is due to structural similarity with the essential metabolite with which it interferes. 

Takamizawa et al. developed a general ring-expansion reaction of heterocycles that, applied to thiazolium salts, yields 1,4-thiazines (496, 497) thiamine (220) reacts with dialkyl acylphosphonates (221) to give the tricyclic 1,4-thiazine (222) (498), which is easily hydrolyzed to dihydro-1,4-thiazinone (223) (499) (Scheme 106). In the case of thiazolium slats containing no functional groups (224), 1,4-thiazine derivatives (226) were directly obtained in fairly good yields (Scheme 107). 

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. 

Physical Chemical Characterization. Thiamine, its derivatives, and its degradation products have been fully characterized by spectroscopic methods (9,10). The ultraviolet spectmm of thiamine shows pH-dependent maxima (11). H, and nuclear magnetic resonance spectra show protonation occurs at the 1-nitrogen, and not the 4-amino position (12—14). The H spectmm in D2O shows no resonance for the thiazole 2-hydrogen, as this is acidic and readily exchanged via formation of the thiazole yUd (13) an important intermediate in the biochemical functions of thiamine. Recent work has revised the piC values for the two ionization reactions to 4.8 and 18 respectively (9,10,15). The mass spectmm of thiamine hydrochloride shows no molecular ion under standard electron impact ionization conditions, but fast atom bombardment and chemical ionization allow observation of both an intense peak for the patent cation and its major fragmentation ion, the pyrimidinylmethyl cation (16). 

Thiamine forms the expected derivatives of the thia zole alcohol function, such as carboxyUc and phosphate esters. Eew reactions at the pyrimidine 4-amino function have been reported. Most of the usual conditions used for formation of amides, for example, lead to destmction of the thiazolium ring. 

A number of the genes involved in the biosynthesis of thiamine in E. coli (89—92), i hium meliloti (93), B. suhtilis (94), and Schi saccharomycespomhe (95,96) have been mapped, cloned, sequenced, and associated with biosynthetic functions. Thiamine biosynthesis is tightly controlled by feedback and repression mechanisms limiting overproduction (97,98). A cost-effective bioprocess for production of thiamine will require significant additional progress. 

Nevertheless, the isolation of these metabolites was interesting in two respects. First, the structure of the thiazole glycol stimulated the research of functionalized carbohydrate chains as precursors of thiazole. Second, the thiazolecar-boxylic acid 40 can be secreted by derepressed cells in relatively high amounts, 0.24 nmol per mg of dried cells, which is nearly half the amount of synthesized thiamine. The presence of this free thiazolic derivative in the cells contrasts with... 

NAD and NADP and FMN and FAD, respectively. Pantothenic acid is a component of the acyl group carrier coenzyme A. As its pyrophosphate, thiamin participates in decarboxylation of a-keto acids and folic acid and cobamide coenzymes function in one-carbon metabolism. 

The water-soluble vitamins comprise the B complex and vitamin C and function as enzyme cofactors. Fofic acid acts as a carrier of one-carbon units. Deficiency of a single vitamin of the B complex is rare, since poor diets are most often associated with multiple deficiency states. Nevertheless, specific syndromes are characteristic of deficiencies of individual vitamins, eg, beriberi (thiamin) cheilosis, glossitis, seborrhea (riboflavin) pellagra (niacin) peripheral neuritis (pyridoxine) megaloblastic anemia, methyhnalonic aciduria, and pernicious anemia (vitamin Bjj) and megaloblastic anemia (folic acid). Vitamin C deficiency leads to scurvy. 

B, Thiamin Coenzyme in pyruvate and a-ketoglutarate, dehydrogenases, and transketolase poorly defined function in nerve conduction Peripheral nerve damage (beriberi) or central nervous system lesions (Wernicke-Korsakoff syndrome)... 

Rice bran is the richest natural source of B-complex vitamins. Considerable amounts of thiamin (Bl), riboflavin (B2), niacin (B3), pantothenic acid (B5) and pyridoxin (B6) are available in rice bran (Table 17.1). Thiamin (Bl) is central to carbohydrate metabolism and kreb s cycle function. Niacin (B3) also plays a key role in carbohydrate metabolism for the synthesis of GTF (Glucose Tolerance Factor). As a pre-cursor to NAD (nicotinamide adenine dinucleotide-oxidized form), it is an important metabolite concerned with intracellular energy production. It prevents the depletion of NAD in the pancreatic beta cells. It also promotes healthy cholesterol levels not only by decreasing LDL-C but also by improving HDL-C. It is the safest nutritional approach to normalizing cholesterol levels. Pyridoxine (B6) helps to regulate blood glucose levels, prevents peripheral neuropathy in diabetics and improves the immune function. 

In most cases, management of intoxication is supportive. The most important goal is to maintain cardiopulmonary function. If consciousness is impaired, obtain blood chemistries and administer intravenous glucose and thiamine (100 to 250 mg). 

These enzymes catalyse the non-hydrolytic cleavage of bonds in a substrate to remove specific functional groups. Examples include decarboxylases, which remove carboxylic acid groups as carbon dioxide, dehydrases, which remove water, and aldolases. The decarboxylation of pyruvic acid (10.60) to form acetaldehyde (10.61) takes place in the presence of pyruvic decarboxylase (Scheme 10.13), which requires the presence of thiamine pyrophosphate and magnesium ions for activity. 

The water-soluble vitamins generally function as cofactors for metabolism enzymes such as those involved in the production of energy from carbohydrates and fats. Their members consist of vitamin C and vitamin B complex which include thiamine, riboflavin (vitamin B2), nicotinic acid, pyridoxine, pantothenic acid, folic acid, cobalamin (vitamin B12), inositol, and biotin. A number of recent publications have demonstrated that vitamin carriers can transport various types of water-soluble vitamins, but the carrier-mediated systems seem negligible for the membrane transport of fat-soluble vitamins such as vitamin A, D, E, and K. 

The PDHC catalyzes the irreversible conversion of pyruvate to acetyl-CoA (Fig. 42-3) and is dependent on thiamine and lipoic acid as cofactors (see Ch. 35). The complex has five enzymes three subserving a catalytic function and two subserving a regulatory role. The catalytic components include PDH, El dihydrolipoyl trans-acetylase, E2 and dihydrolipoyl dehydrogenase, E3. The two regulatory enzymes include PDH-specific kinase and phospho-PDH-specific phosphatase. The multienzyme complex contains nine protein subunits, including... 

Straightforward thiamine deficiency in man, beri-beri, is characterized by accumulation of pyruvic and lactic acids in the blood and brain, and impairment of cardiovascular, nervous, and gastrointestinal function (DIO, G17, P4, Yl). Neurological lesions characterize thiamine deficiency in growing rats (B40), guinea pigs (M6), mice (M13), chicks, and pigeons (B30). The effects of thiamine deficiency on the central nervous system of animals have been reviewed (DIO). 

The clinical significance of thiamine and its necessity for pyruvic acid oxidation has been discussed. Recent reports concerning the coenzyme function of thiamine in pentose (H13), tryptophan (D2), and lipoic acid metabolism (R6) have increased our knowledge of thiamine in metabolism and lend added interest to the role of thiamine in clinical problems. This method has also been used to assay thiamine in liver and brain. 

Coenzymes complement the catalytic action of the amino-acid functional groups. They are bound to apoenzymes (apoproteins) either covalently or non-covalently. It is interesting to note that non-covalently-bound coenzymes are polyanions at neutral pH as exemplified by the structures of glutathione (GSH) [17] and thiamine pyrophosphate [18]. Shinkai and Kunitake (1976b, 1977a) demonstrated the efficient binding of glutathione and coenzyme A (a polyphosphate) to cationic micelles and cationic polysoaps. Thus, the combina- ... 

The way in which thiamine participated in the oxidation of pyruvate became clearer when Lohmann and Schuster (1937) showed vitamin Bj to be present intracellularly as thiamine pyrophosphate. In yeast, decarboxylation of pyruvate yielded ethanal which was reduced by alcohol dehydrogenase to give ethanol. A cofactor was needed for this decarboxylation, co-carboxylase. Like the cofactor needed in animal cells for the decarboxylation of pyruvate, cocarboxylase was found to be identical to thiamine pyrophosphate. Vitamin Bj thus became the first vitamin whose intracellular function as a coenzyme had been established in vitro. Another aphorism therefore arose about vitamins—B vitamins are (parts of) coenzymes—an idea that was to be completely confirmed. 

Although we will not discuss further the question of requirements and deficiencies involving vitamin B6, much of what has been said, both with respect to thiamine and pantothenic acid, applies in principle to vitamin B6 as well. It, like the other B vitamins, functions in every cell of the body. 

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