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  • Propionyl coenzyme A (CoA)—formed in the catabolism of several essential amino acids (isoleucine, valine, methionine, threonine), odd-chain fatty acids, and cholesterol—is metabolized primarily by enzymatic conversion to methylmalonyl CoA, which is subsequently isomerized to succinyl CoA. This sequence depends on the activity of several enzymes (see Fig. 123-2): propionyl CoA carboxylase, methylmalonyl CoA racemase, and methylmalonyl CoA mutase. Propionyl CoA carboxylase requires biotin as a cofactor, whereas methylmalonyl CoA mutase requires adenosylcobalamin (AdoCbl), a cobalamin (Cbl; vitamin B12) coenzyme.

  • Propionyl CoA carboxylase and methylmalonyl CoA mutase are oligomeric enzymes. Propionyl CoA carboxylase is composed of nonidentical subunits (α and β); biotin binds to the α subunit. The holocarboxylase contains six α and six β subunits (α6β6). The α subunit is encoded by a gene on chromosome 13 (NM_000282) in humans, the β subunit by a gene on chromosome 3 (NM_000532). Methylmalonyl CoA mutase is a dimer of identical subunits (α2), encoded by a gene on chromosome 6 (NM_000255).

  • Inherited deficiency of propionyl CoA carboxylase activity in humans results from genetically distinct defects at four loci. Isolated deficiency is caused by mutations at the α and β loci coding for the carboxylase subunits. Deficiency of multiple biotin-dependent carboxylases occurs in two forms: one resulting from deficiency of holocarboxylase synthase (the enzyme that attaches biotin to apocarboxylase subunits), the other from deficiency of biotinidase (the enzyme that cleaves biotin from the lysine residue in the carboxylase to which the biotin is attached). Multiple carboxylase deficiency is discussed in detail in Hartnup Disorder.

  • Isolated deficiency of propionyl CoA carboxylase, a major cause of the ketotic hyperglycinemia syndrome, results in the accumulation of propionate in blood and of 3-hydroxypropionate, methylcitrate, tiglylglycine, and unusual ketone bodies in urine. Two complementation groups, pccA (MIM 232000) and pccBC (MIM 232050) have been defined among propionyl CoA carboxylase–deficient patients. These groups correspond to mutations affecting genes coding for the α subunit and the β subunit, respectively, of the carboxylase apoprotein. Clinically, the disorder is characterized by severe metabolic ketoacidosis, which often appears in the neonatal period and requires vigorous alkali therapy and protein restriction. Oral antibiotic therapy to reduce gut propionate production also may prove useful.

  • Multiple carboxylase deficiency (MIM 253270) leads to impaired activity of four biotin-dependent enzymes: acetyl CoA carboxylase, propionyl CoA carboxylase, 3-methylcrotonyl CoA carboxylase, and pyruvate carboxylase. The clinical hallmarks of this disorder include ketoacidosis, a diffuse erythematous rash, alopecia, seizures, hypotonia, and developmental retardation (see Disorders of Biotin Metabolism).

  • Inherited deficiency of methylmalonyl CoA mutase activity in humans is caused by mutations at many different loci. Isolated deficiency results from mutations at the apomutase locus (MIM 251000) and at two loci coding for gene products required, specifically for the biosynthesis of AdoCbl. Combined deficiency of mutase and of the other major Cbl-dependent enzyme in mammalian cells, methionine synthase (formally, N5-methyltetrahydrofolate:homocysteine methyltransferase), results from inherited defects in Cbl transport and from three ...

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