Thiamine metabolic functions

Thiamin was the first of the vitamins to be demonstrated to have a clearly defined metabolic function as a coenzyme indeed, the studies of Peters group in the 1920s and 1930s laid the foundations not only of nutritional biochemistry but also of modern metabolic biochemistry and neurochemistry. Despite this, the mechanism by which thiamin deficiency results in central and peripheral nervous system lesions remains unclear in addition to its established coenzyme role, thiamin regulates the activity of a chloride transporter in nerve cells. 

In higher mammalian organisms, thiamine is transformed to the coenzyme thiamine pyrophosphate by direct pyrophosphate transfer from ATP. This coenzyme performs important metabolic functions, for example, as cocarboxylase in the decarboxylation of rr-keto acids (such as pyruvate to form acctyl-CoA) and in tran.sketolases (such as use of pentoses in the hexose monophosphate shunt). 

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). 

One has only to think of the extraordinarily varied metabolic functions of thiamine, riboflavin, pantothenic acid, pyridoxine, and biotin to realize that it is most unlikely that ascorbic acid could possibly replace every one of these. Moreover, one would have to postulate a quite different mechanism for the large number of other substances, such as sorbitol, sorbose, arabitol, and starch, which spare B vitamins even more readily than ascorbic acid, but which do not have its redox properties. 

Many C. in the wider sense are synthesized from vitamins. The relationships of some C. to vitamins and metabolic function are listed in the table. Strictly speaking, ATP, which commands a special position in metabolism, does not fit the definition of a CThe C. of C -unit transfer are S-Adenosylmethionine (see), Tetrahydrofolic acid (see) and Biotin (see). The C. of C2"transfer are Coenzyme A (see) and Thiamin pyrophosphate (see). Vitamin B[j is involved in various metabolic reactions, in free form, as methyl-vitamin B,2 and as S -Deoxyadenosylcobalamine (see). 

Water-Soluble Vitamins. Vitamin G (ascorbic acid) functions in the formation of collagen, wound healing, metabolic functions, and other roles. Foods high in vitamin G include citrus fruits, strawberries, cantaloupe, and cruciferous vegetables. B vitamins are important in energy metabolism. Thiamin (Bj) is called the antineuritic vitamin. Riboflavin (B ), rarely deficient in the diet, is found most abundantly in milk and dairy products. Niacin (Bj) is prevalent in meats, poultry, fish, peanut butter, and other foods. Other major B vitamins include folic acid (B ), B, and Bj2-... 

TMP), thiamine diphosphate (TDP also known as thiamine pyrophosphate, TPP), and thiamine triphosphate (TTP). TDP, the best characterized form, in its role as a eoenzyme for molecules involved in carbohydrate metabolism e.g. transketolase and pyruvate dehydrogenase) is important for energy production and numerous metabolic functions (Lonsdale 2006). 

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. 

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. 

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 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. 

The first examples of mechanism must be divided into two principal classes the chemistry of enzymes that require coenzymes, and that of enzymes without cofactors. The first class includes the enzymes of amino-acid metabolism that use pyridoxal phosphate, the oxidation-reduction enzymes that require nicotinamide adenine dinucleotides for activity, and enzymes that require thiamin or biotin. The second class includes the serine esterases and peptidases, some enzymes of sugar metabolism, enzymes that function by way of enamines as intermediates, and ribonuclease. An understanding of the mechanisms for all of these was well underway, although not completed, before 1963. 

Vitamins are chemically unrelated organic compounds that cannot be synthesized by humans and, therefore, must must be supplied by the diet. Nine vitamins (folic acid, cobalamin, ascorbic acid, pyridoxine, thiamine, niacin, riboflavin, biotin, and pantothenic acid) are classified as water-soluble, whereas four vitamins (vitamins A, D, K, and E) are termed fat-soluble (Figure 28.1). Vitamins are required to perform specific cellular functions, for example, many of the water-soluble vitamins are precursors of coenzymes for the enzymes of intermediary metabolism. In contrast to the water-soluble vitamins, only one fat soluble vitamin (vitamin K) has a coenzyme function. These vitamins are released, absorbed, and transported with the fat of the diet. They are not readily excreted in the urine, and significant quantities are stored in Die liver and adipose tissue. In fact, consumption of vitamins A and D in exoess of the recommended dietary allowances can lead to accumulation of toxic quantities of these compounds. 

Why do we need vitamins Early clues came in 1935 when nicotinamide was found in NAD+ by H. von Euler and associates and in NADP+ by Warburg and Christian. Two years later, K. Lohman and P. Schuster isolated pure cocarboxylase, a dialyz-able material required for decarboxylation of pyruvate by an enzyme from yeast. It was shown to be thiamin diphosphate (Fig. 15-3). Most of the water-soluble vitamins are converted into coenzymes or are covalently bound into active sites of enzymes. Some lipid-soluble vitamins have similar functions but others, such as vitamin D and some metabolites of vitamin A, act more like hormones, binding to receptors that control gene expression or other aspects of metabolism. 

A reaction that is related to that of transketolase but is likely to function via acetyl-TDP is phosphoketolase, whose action is required in the energy metabolism of some bacteria (Eq. 14-23). A product of phosphoketolase is acetyl phosphate, whose cleavage can be coupled to synthesis of ATP. Phosphoketolase presumably catalyzes an a cleavage to the thiamin-containing enamine shown in Fig. 14-3. A possible mechanism of formation of acetyl phosphate is elimination of HzO from this enamine, tautomerization to 2-acetylthiamin, and reaction of the latter with inorganic phosphate. 

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