Methylcrotonyl-CoA carboxylase

Methylcrotonyl-CoA carboxylase (MCC) is an enzyme that plays a crucial role in the metabolism of leucine, an essential amino acid. This enzyme catalyzes the carboxylation of 3-methylcrotonyl-CoA to 3-methylglutaconyl-CoA, a critical step in the leucine degradation pathway. The importance of MCC in human health is underscored by its association with a metabolic disorder known as 3-Methylcrotonyl-CoA carboxylase deficiency (MCCD), which can lead to various clinical manifestations ranging from benign to severe metabolic acidosis and developmental delay.

Function

Methylcrotonyl-CoA carboxylase is a biotin-dependent enzyme that facilitates the conversion of 3-methylcrotonyl-CoA to 3-methylglutaconyl-CoA. This reaction is essential for the catabolism of leucine, an amino acid that cannot be synthesized by the body and must be obtained from the diet. The proper functioning of MCC is critical for maintaining energy homeostasis and for the elimination of toxic compounds that can accumulate during leucine breakdown.

Structure

MCC is a multimeric enzyme composed of alpha and beta subunits, which are encoded by the genes MCCC1 (encoding the alpha subunit) and MCCC2 (encoding the beta subunit), respectively. The enzyme's activity is dependent on the presence of biotin, a coenzyme that is attached to the enzyme via a lysine residue. The structure of MCC allows it to catalyze the carboxylation reaction efficiently, a process that is essential for the further breakdown of leucine.

Clinical Significance

Deficiencies in methylcrotonyl-CoA carboxylase activity can lead to 3-Methylcrotonyl-CoA carboxylase deficiency (MCCD), a genetic disorder that can present with a wide range of symptoms, from asymptomatic conditions to severe metabolic crises. Symptoms may include feeding difficulties, developmental delay, hypotonia, and metabolic acidosis. MCCD is inherited in an autosomal recessive manner, meaning that two copies of the defective gene, one from each parent, are required for the disease to manifest.

Diagnosis of MCCD typically involves biochemical tests to detect elevated levels of 3-methylcrotonylglycine and 3-hydroxyisovaleric acid in urine, as well as genetic testing to identify mutations in the MCCC1 and MCCC2 genes. Treatment focuses on dietary management to restrict leucine intake and to prevent metabolic crises.

Genetics

The genes responsible for encoding the subunits of methylcrotonyl-CoA carboxylase, MCCC1 and MCCC2, are located on chromosomes 3 and 5, respectively. Mutations in either of these genes can reduce or eliminate the activity of MCC, leading to MCCD. To date, numerous mutations have been identified, contributing to the variability in clinical presentation and severity of the disorder.

See Also

• Leucine
• Metabolic pathway
• Inborn errors of metabolism
• Biotin