Carboxylases biotin metabolism

Makes propionyl-CoA, which is metabolized by propionyl-CoA carboxylase (biotin) and methylmalonyl-CoA mutase (B12) to give succinyl-CoA. 

Baumgartner ER, Suormala T (1997) Multiple carboxylase deficiency inherited and acquired disorders of biotin metabolism. Int J Vitam Nutr Res 67 377-384... 

Biotin is a colactor for the synthesis of oxaloacetate from pyruvate by pyruvate carboxylase. Therefore, metabolic conversions, which require pyruvate carboxylase, will be inhibited. These will include only reaction (e) pyruvate —> oxaloacetate, and conversion... 

Biotin deficiency causes disturbances in a variety of carboxylase-mediated metabolic reactions. As a result, such a deficiency may induce ketolactic acidosis and organic aciduria (Zempleni et al. 2008). Organic acids such as 3-methylcrotonylglycine, 3-hydroxyvaleric acid or methylcitric acid are excreted in urine in case of biotin deficiency (Figure 43.2). 

MANTHEY, K. C GRIFFIN, J. B ZEMPFENI, I. (2002) Biotin supply affects expression of biotin transporters, biotinylation of carboxylases, and metabolism of interleukin-2 in Jurkat cells. J. Nutr., 132, 887-892. 

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. 

Biotin is involved in carboxylation and decarboxylation reactions. It is covalently bound to its enzyme. In the carboxylase reaction, C02 is first attached to biotin at the ureido nitrogen, opposite the side chain in an ATP-dependent reaction. The activated C02 is then transferred from carboxybiotin to the substrate. The four enzymes of the intermediary metabolism requiring biotin as a prosthetic group are pyruvate carboxylase (pyruvate oxaloacetate), propionyl-CoA-carboxylase (propionyl-CoA methylmalonyl-CoA), 3-methylcroto-nyl-CoA-carboxylase (metabolism of leucine), and actyl-CoA-carboxylase (acetyl-CoA malonyl-CoA) [1]. 

Pantothenic acid is present in coenzyme A and acyl carrier protein, which act as carriers for acyl groups in metabolic reactions. Pyridoxine, as pyridoxal phosphate, is the coenzyme for several enzymes of amino acid metabolism, including the aminotransferases, and of glycogen phosphorylase. Biotin is the coenzyme for several carboxylase enzymes. 

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. 

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. 

Figure 12-2. Metabolic pathways involving the four biotin-dependent carboxylases. The solid rectangular blocks indicate the locations of the enzymes ACC, acetyl-CoA carboxylase PMCC, P-methylcrotonyl-CoA carboxylase PC, pyruvate carboxylase PCC, propionyl-CoA carboxylase. Isolated deficiencies of the first three carboxylases (mitochondrial) have been established (isolated ACC deficiency has not been confirmed). At least the activities of the three mitochondrial carboxylases can be secondarily deficient in the untreated multiple carboxylase deficiencies, biotin holocarboxylase synthetase deficiency and biotinidase deficiency. Lowercase characters indicate metabolites that are frequently found at elevated concentrations in urine of children with both multiple carboxylase deficiencies. The isolated deficiencies have elevations of those metabolites directly related to their respective enzyme deficiency.

Inherited isolated deficiencies of the three mitochondrial biotin-dependent carboxylases were described during the 1970s (Fig. 12-2). Children with each of the isolated deficiencies exhibit neurological symptoms during infancy or early childhood associated with metabolic compromise caused by the accumulation of abnormal metabolites resulting from the respective enzyme block. Each isolated deficiency is due to a structural abnormality in the respective mitochondrial enzyme, whereas the activities of... 

In 1971, a child with biotin-responsive (J-methylcrotonylglycinuria was reported.This individual had metabolic ketoacidosis and elevated concentrations of urinary P-methylcrotonic acid and 5-methylcrotonylglycine. Several days after being given oral biotin, his symptoms resolved, and the urinary metabolites cleared. He subsequently was shown to have deficient activities of all three mitochondrial carboxylases in his peripheral blood leukocytes and skin fibroblasts. This was the first child to be diagnosed with what was called multiple carboxylase deficiency. 

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 activity of propionyl CoA carboxylase in lymphocytes falls, and the activation of the apoenzyme on incubation with biotin rises, in patients receiving total parenteral nutrition before there is any change in the plasma concentration of biotin (Velazquez et al., 1990). In experimental animals, the activity of lymphocyte propionyl CoA carboxylase falls early during biotin depletion, at the same time as the activity of the hepatic enzyme. There is not the expected increase in urinary excretion of hydroxypropionic acid, presumably because propionyl CoA carboxylase is not rate-limiting for propionate metabolism (Mock and Mock, 2002). 

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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