The Metabolic Functions of Biotin

It is possibly incorrect to consider biotin synthase an enzyme in the true sense of the word it has a turnover number of 1. It only catalyzes the synthesis of a single molecule of biotin from dethiohiotin before being inactivated. This is because the iron-sulfur cluster of the protein is the source of the sulfur that is incorporated into biotin. There is some evidence that the enzyme can be reactivated by incorporation of sulfur from cysteine, but in vitro addition of the enzymes believed to catalyze this reaction has no effect on the turnover number of the enzyme (Frey, 2001 Marquet et al., 2001). 

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. 

The biotin-dependent decarboxylases of anerobic microorganisms are transmembrane proteins. In addition to their roles in the metabolism of ox-aloacetate, methylmalonyl CoA, and glutaconyl CoA, they serve as energy transducers. They transport 2 mol of sodium out of the cell for each mole of substrate decarboxylated. The resultant sodium gradient is then used for active transport of substrates by sodium cotranspoit systems, or maybe used to drive ATP synthesis in a similar manner to the proton gradient in mammalian mitochondria (Buckel, 2001). 

The biotin-dependent carboxylases catalyze a two-step reaction  

enzyme-biotin - - ATP - - HCO3 -s- enzyme-biotin-COOH + ADP + Pi 

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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). 

The biological function of biotin is to regulate important metabolic pathways and enable critical enzyme functions. 

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). 

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). 

The most important carriers of one-carbon groups in biosynthetic pathways are folic acid and S-adenosylmethionine. The metabolism of each is described briefly. (The function of biotin, a carrier of COz groups, is discussed in Section 8.2.)... 

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. 

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. 

Mammals cannot synthesize biotin and depend on a regular dietary supply of this water-soluble vitamin (Zempleni et al., 2009). The Adequate Intake for biotin in adults is 30 pg/d (National Research Council, 1998). The classical role of biotin in mammalian intermediary metabolism is to serve as a covalently bound coenzyme in five carboxylases (Zanpleni et al., 2D09). Both the cytoplasmic acetyl-CoA carboxylase 1 (ACCl) and the mitochondrial acetyl-CoA carboxylase 2 (ACC2) catalyze the binding of bicarbonate to acetyl-CoA to generate malonyl-CoA, but the two isoforms have distinct functions in intermediary metabolism (Kim et al., 1997). ACCl produces malonyl-CoA for the synthesis of fatty acid synthesis in the cytoplasm ACC2... 

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. 

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 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. 

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