Biotin metabolic functions

M3. Macleod, P. R., and Lardy, H. A., Metabolic functions of biotin. II. The fixation of carbon dioxide by normal and biotin deficient rats. J. Biol. Chem. 179, 733-741 (1949). 

Pantothenic acid and biotin were thus found to be growth factors for yeast. Like riboflavin these molecules are incorporated into larger molecules in order to exert their essential metabolic function. Unlike the other vitamins there has been no evidence of pathological signs in man which can be attributed to dietary deficiencies in biotin or pantothenic acid. 

The main metabolic function of vitamin K is as the coenzyme in the carboxyla-tion ofprotein-incorporated glutamate residues to yield y -carboxyglutamate -a unique type of carboxylation reaction, clearly distinct from the biotin-dependent carboxylation reactions (Section 11.2.1). 

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). 

In the organism that Is required In small amounts In food to sustain the normal metabolic functions of life. The key to this definition Is that this chemical compound must be supplied to the organism because the animal cannot synthesize vitamins. Lack of It produces a specific deficiency syndrome and supplying It cures that deficiency. An exception to this definition Is vitamin D, which can be made In the skin upon adequate exposure to sunlight. However, without adequate exposure, the animal Is dependent on a dietary source. Biotin, panthothenlc acid, and vitamin R are made by bacteria In the human Intestine, based on a symbiotic relation-ship and, thus, are not required by the human. Niacin can also be synthesized In humans from the amino acid tryptophane. 

Biotin is central to the metabolism of carbohydrates, amino acids, and lipids as biotin is the prosthetic group of the carboxylases. In addition to this metabolic function, biotin influences transcription in organisms ranging from bacteria to humans. Biotin exerts complex effects on cell cycle and gene transcription through epigenetic mechanisms. Nuclear biotin holocarboxylase synthetase seems to interact with other chromatin proteins to form a multiprotein gene repressor complex. 

Biotin (referred to as vitamin H in humans) is an essential cofactor for a number of enzymes that have diverse metabolic functions. Almost a dozen different enzymes use biotin. Among the most well-known are acetyl-CoA carboxylase, pyruvate carboxylase, propionyl-CoA carboxylase, urea carboxylase, methylmalonyl-CoA decarboxylase, and oxaloacetate decarboxylase. Biotin serves as a covalent bound CO2 carrier for reactions in which CO 2 is fixed into an acceptor by carboxylases. Then this carboxyl group in an independent reaction can be transferred from the acceptor substrate to a new acceptor substrate by transcarboxylases, or the carboxyl group can be removed as CO 2 by decarboxylases. 

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 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. 

Biotin is the coenzyme in a small number of carboxylation reactions in mammalian metabolism and some decarboxylation and transcarboxylation reactions in bacteria. Although the biotin-dependent enzymes are cytosolic and mitochondrial, about 25% of tissue biotin is found in the nucleus, much of it bound as thioesters to histones. Biotin has two noncoenzyme functions induction of enzyme synthesis and regulation of the cell cycle. 

Biotin deficiency and the functional deficiency associated with lack of holo-carboxylase synthetase (Section 11.2.2.1), or biotinidase (Section 11.2.3.1), causes alopecia (hair loss) and a scaly erythematous dermatitis, especially around the body orifices. The dermatitis is similar to that seen in zinc and essential fatty acid deficiency and is commonly associated with Candida albicans infection. Histology of the skin shows an absence of sebaceous glands and atrophy of the hair follicles. The dermatitis is because of impaired metabolism of polyunsaturated fatty acids as a result of low activity of acetyl CoA carboxylase (Section 11.2.1.1). In biotin-deficient experimental animals, provision of supplements of long-chain 6 polyunsaturated fatty acids prevents the development of skin lesions (Mock et al., 1988a, 1988b Mock, 1991). 

The major functions of pantothenic acid are in CoA (Section 12.2.1) and as the prosthetic group for AGP in fatty acid synthesis (Section 12.2.3). In addition to its role in fatty acid oxidation, CoA is the major carrier of acyl groups for a wide variety of acyl transfer reactions. It is noteworthy that a wide variety of metabolic diseases in which there is defective metabolism of an acyl CoA derivative (e.g., the biotin-dependent carboxylase deficiencies Sections 11.2.2.1 and 11.2.3.1), CoA is spared by formation and excretion of acyl carnitine derivatives, possibly to such an extent that the capacity to synthesize carnitine is exceeded, resulting in functional carnitine deficiency (Section 14.1.2). 

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