Enzyme Induction by Biotin

Biotin acts to induce glucokinase, phosphofructokinase, and pyruvate kinase (key enzymes of glycolysis), phosphoenolpyruvate carboxykinase (a key enzyme of gluconeogenesis), and holocarboxylase synthetase, acting via a cell-surface receptor linked to formation of cGMP and increased activity of RNA polymerase. The activity of holocarboxylase synthetase (Section 11.2.2) falls in experimental biotin deficiency and increases with a parallel increase in mRNA during repletion (Chauhan and Dakshinamurti, 1991; Borboni et al., 1996; Rodriguez-Melendez et al., 2001).

Glucokinase is the high-_RTm isoenzyme of hexokinase found in liver and pancreatic f-islet cells. In the liver, its function is to permit rapid uptake and metabolism of glucose when the concentration of glucose in the portal blood is high after a meal. In the pancreas, the increased uptake and metabolism of glucose caused by glucokinase acts as the signal for insulin release. Children with a genetic lack of glucokinase suffer from what has been termed maturity-onset diabetes of the young (MODY); although they can synthesize and secrete normal basal amounts of insulin, they are unable to secrete additional insulin in response to glucose (Froguel et al., 1993). Presumably as a result of increased activity of glucokinase, high doses of biotin have a hypoglycemic effect in insulin-dependent diabetic patients. In non-insulin-dependent spontaneously diabetic mice, the administration of 2 mg of biotin per kg of body weight (considerably in excess of vitamin requirements) lowers blood glucose and improves both oral glucose tolerance and the blood glucose response to insulin (Reddi et al., 1988).

Hyperammonemia occurs in biotin deficiency and the functional deficiency associated with lack of holocarboxylase synthetase (Section 11.2.2.1) andbio-tinidase (Section 11.2.3.1). In deficient rats, the activity of ornithine carbamyl-transferase is two-thirds of that in control animals, as a result of decreased gene expression, although the activities of other urea cycle enzymes are unaffected (Maeda etal., 1996).

In addition to induction of specific proteins, the administration of biotin to deficient rats results in an overall two-fold stimulation of the incorporation of amino acids into proteins. The synthesis of serum albumin in liver is increased two-fold, but at least 10 other proteins show increases in amino incorporation of about five-fold, and some show an eight-fold increase, whereas others show no change (Dakshinamurti and Litvak, 1970; Boeckx and Dakshinamurti, 1974).

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