Conversion of 3-methylcrotonyl CoA to 3-methylglutaconyl CoA is a metabolic step in leucine catabolism pathway that is catalysed by the enzyme methylglutaconyl CoA carboxylase (MCC). Biotin is required as a cofactor for the MCC enzyme, and marginal biotin deficiency reduces the flux through the pathway by reducing the activity of MCC. Marginal biotin deficiency is teratogenic and is thought to develop in a substantial number of pregnant women during the first trimester. Because the conversion of 3-methylcrotonyl CoA to 3-methylglutaconyl CoA occurs in the mitochondria, low activity of MCC causes a build-up of 3-methylcrotonyl CoA. Accumulating 3-methylcrotonyl CoA is converted to 3-hydroxyisovaleric acid (3HIA) by the enzyme enoyl CoA hydratase which disrupts the normal esterified to free CoA ratios and causes mitochondrial toxicity. Binding of 3HIA to carnitine for transfer across the inner mitochondrial membrane forms 3-hydroxyisovaleryl carnitine (3HIA carnitine).
Reduced activity of the MCC enzyme causes increased urinary excretion of 3HIA and 3HIA carnitine and this can be used to assess the biotin status of individuals by administration of leucine to stimulate the activity of the pathway. Those individuals with high urinary excretion of 3HIA and 3HIA carnitine can be considered to have low MCC activity due to insufficient biotin status. For example, researchers1 created biotin deficiency in a group of individuals by administration of raw egg white for a period of 28 days. Egg white contains a protein, avidin, that binds biotin in the gut and prevents absorption. The results showed that urinary excretion of 3HIA and 3HIA carnitine increased 2-fold by day 14 in response to an oral leucine challenge. Therefore measuring 3HIA and 3HIA carnitine in response to a leucine challenge may be a useful clinical test for marginal biotin deficiency.
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