HMG-CoA lyase

3-Hydroxy-3-methylglutaryl-CoA lyase (HMG-CoA lyase) is an enzyme that plays a crucial role in the metabolism of ketone bodies and in the leucine catabolic pathway. This enzyme catalyzes the cleavage of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) to acetyl-CoA and acetoacetate, a critical step in the production of ketone bodies in the liver. Ketone bodies serve as an important energy source during periods of fasting or strenuous exercise. HMG-CoA lyase is encoded by the HMGCL gene in humans.

Function

HMG-CoA lyase is involved in the breakdown of fatty acids and amino acids for energy production. Specifically, it functions in the mitochondria to process HMG-CoA, which is derived from both the degradation of leucine – an essential amino acid – and the synthesis of ketone bodies. The enzyme's action facilitates the use of fat as an energy source by converting fats into ketones, which can be used by the brain and muscles as energy, especially when glucose levels are low.

Clinical Significance

Mutations in the HMGCL gene can lead to HMG-CoA lyase deficiency, a rare genetic disorder that disrupts normal ketone body production and leucine degradation. This condition can lead to hypoglycemia, metabolic acidosis, and a buildup of toxic substances within the body. Symptoms often present in infancy or early childhood and can include vomiting, lethargy, seizures, and developmental delay. Management typically involves a diet low in leucine and fats and high in carbohydrates, along with emergency treatment for metabolic crises.

Genetic

The HMGCL gene is located on chromosome 1p36.22 and consists of 9 exons. Variants in this gene are associated with HMG-CoA lyase deficiency. Genetic testing can confirm a diagnosis and guide treatment and management decisions.

See Also

• Ketogenesis
• Metabolic pathway
• Leucine metabolism
• Inborn error of metabolism