Biotin fatty acid metabolism

CO2-biotin-enzyme + acetyl Co A —> malonylCoA -I- biotin-enzyme This enzyme is also the essential regulatory enzyme for fatty acid metabolism (Section 22,5). 

Description. Also known as vitamin Bg or H, this vitamin is of great importance for the biochemistry of the human organism. Biotin is the cofactor for a small group of enzymes that catalyze carboxyla-tion, decarboxylation, and transcarboxylation reactions in carbohydrate and fatty acid metabolism. Deficiency of this vitamin is rare in humans, but can be induced in special circumstances in individuals with inborn errors of biotin metabolism, in individuals taking certain medications, and in some women during pregnancy. ... 

Figure 5. Acetyl-coenzyme-A carboxylase (ACC) has critical roles in fatty acid metabolism. The ACC-catalyzed biotin carboxylase (BC) and carboxyltransferase (CT) reactions [103].

All aspects of the biochemical role of biotin have not yet been clarified. The vitamin has been implicated in the metabolism of carbohydrates, lipids, proteins, and nucleic acids. Available evidence indicates that biotin acts as a CO2 carrier in a number of carboxyla-tion and decarboxylation reactions connected with carbohydrate and fatty acid metabolism. A number of experimental procedures are used to establish the participation of biotin in a given biochemical reaction (1) the study of enzyme activity in biotin-deficient animals (2) the effect of avidin administered in vivo or added to the incubation mixture on the activity of the enzyme under study and (3) purification of the enzyme and demonstration of the existence of enzyme-bound biotin. Studies of this kind have established that biotin is required for the carboxylases of jS-methyl-crotonyl CoA, acetyl-CoA, propionyl CoA, and oxaloacetic transcarboxylase. Only some of the results are presented here [74-76]. 

Several of the B vitamins are essential for normal fatty-acid metabolism (Table 2). Pantothenic acid is a constituent of CoA and is thus required for numerous reactions of fatty acids. Niacin and riboflavin are necessary for the synthesis of oxidized and reduced NAD(P) and FAD, respectively. These compounds play essential roles in fatty-acid oxidation, synthesis, and elongation. Biotin is a constituent of acetyl-CoA carboxylase and pyruvate carboxylase, both of which are involved in the synthesis of fatty acids from glucose. Thiamine is required for activity of the pyruvate dehydrogenase complex, which also participates in fatty-acid synthesis from glucose. 

Fatty acids with odd numbers of carbon atoms are rare in mammals, but fairly common in plants and marine organisms. Humans and animals whose diets include these food sources metabolize odd-carbon fatty acids via the /3-oxida-tion pathway. The final product of /3-oxidation in this case is the 3-carbon pro-pionyl-CoA instead of acetyl-CoA. Three specialized enzymes then carry out the reactions that convert propionyl-CoA to succinyl-CoA, a TCA cycle intermediate. (Because propionyl-CoA is a degradation product of methionine, valine, and isoleucine, this sequence of reactions is also important in amino acid catabolism, as we shall see in Chapter 26.) The pathway involves an initial carboxylation at the a-carbon of propionyl-CoA to produce D-methylmalonyl-CoA (Figure 24.19). The reaction is catalyzed by a biotin-dependent enzyme, propionyl-CoA carboxylase. The mechanism involves ATP-driven carboxylation of biotin at Nj, followed by nucleophilic attack by the a-carbanion of propi-onyl-CoA in a stereo-specific manner. 

H Biotin Coenzyme in carboxylation reactions in gluco-neogenesis and fatty acid synthesis Impaired fat and carbohydrate metabolism, dermatitis... 

Biotin cannot be synthesized by mammals. The contribution of the biotin synthesized by intestinal bacteria to the hnman reqnirements is still controversial. Biotin is an essential cofactor for carboxylases involved in prodnction of fatty acids, cell growth, and metabolism of fats and amino acids. 

The reaction involves biotin as a carrier of activated HCO3 (Fig. 14-18). The reaction mechanism is shown in Figure 16-16. Pyruvate carboxylase is the first regulatory enzyme in the gluconeogenic pathway, requiring acetyl-CoA as a positive effector. (Acetyl-CoA is produced by fatty acid oxidation (Chapter 17), and its accumulation signals the availability of fatty acids as fuel.) As we shall see in Chapter 16 (see Fig. 16-15), the pyruvate carboxylase reaction can replenish intermediates in another central metabolic pathway, the citric acid cycle. 

Biotin is involved in many carboxylation and decarboxylation reactions in carbohydrate, fatty acid, protein, and nucleic acid metabolism. Milk is a fairly good source of this vitamin, generally providing about 3/xg/100 g. Pasteurization has a minimal effect on the biotin content of milk. 

Eight enzyme-catalyzed reactions are involved in the conversion of acetyl-CoA into fatty acids. The first reaction is catalyzed by acetyl-CoA carboxylase and requires ATP. This is the reaction that supplies the energy that drives the biosynthesis of fatty acids. The properties of acetyl-CoA carboxylase are similar to those of pyruvate carboxylase, which is important in the gluconeogenesis pathway (see chapter 12). Both enzymes contain the coenzyme biotin covalently linked to a lysine residue of the protein via its e-amino group. In the last section of this chapter we show that the activity of acetyl-CoA carboxylase plays an important role in the control of fatty acid biosynthesis in animals. Regulation of the first enzyme in a biosynthetic pathway is a strategy widely used in metabolism. 

PC requires biotin for activity. Biotin is bound to the enzyme via a peptide-like linkage involving e-NH2 groups of certain lysine residues. This type of biotin complex is biocytin (see Chapter 6). Another compound necessary for PC activity is acetyl-CoA, a positive effector. PC is activated as cellular levels of acetyl-CoA increase, as when extensive lipolysis takes place. Acetyl-CoA is produced in large amounts from fatty acids via the /8-oxidation reaction (see Chapter 19). PC can also be considered an anaplerotic reaction, those reactions that replenish crucial intermediates for metabolic pathways. In this case, oxaloacetate, an important intermediate in the Krebs cycle, is replenished by a reaction catalyzed by PC. 

Biotin is important in a number of metabolic reactions, especially in fatty acid synthesis. The biotin supply of the human organism is only partly derived from the diet. 

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). 

Propionyl-CoA is an intermediary product in the metabo-hsm of four essential amino acids (isoleucine, valine, threonine, and methionine), the aliphatic side-chain of cholesterol, pyrimidines (uracd and thymine), and the final product of the [3-oxidation of odd-chain fatty acids. Under normal circumstances, propionyl-CoA first is converted by a biotin-dependent carboxylase to methylmalonyi-CoA, then to succinyl-CoA by an adenosylcobalamin-dependent mutase, leading to oxidation in the tricarboxylic acid cycle. Primary or secondary defects of these two enzymes were among the first organic acidurias to be discovered, and their natural history has been characterized perhaps better than any other inborn error of organic acid metabolism. 

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