3-hydroxy-3-methylglutaryl-CoA lyase (HMGCL)

3-hydroxy-3-methylglutaryl-CoA lyase (HMGCL) is a mitochondrial enzyme essential for the final step in ketogenesis, catalyzing the cleavage of (S)-3-hydroxy-3-methylglutaryl-CoA to yield acetoacetate and acetyl-CoA. This reaction provides ketone bodies as alternative energy substrates, especially vital for the brain during fasting or metabolic stress. HMGCL also plays a crucial role in leucine catabolism. The enzyme is encoded by the HMGCL gene, and mutations lead to HMGCL deficiency, an autosomal recessive disorder characterized by impaired ketogenesis and leucine metabolism. Clinically, deficiency manifests as hypoketotic hypoglycemia, metabolic acidosis, and risk of neurological injury, often presenting in infancy after fasting or illness. Alternative splicing generates isoforms with tissue-specific expression, and structural studies reveal HMGCL to be a (β/α)8 TIM barrel dimer that requires Mg²⁺ for activity.

Other names

Hydroxymethylglutaryl-CoA lyase, mitochondrialHMG-CoA lyaseHLHMGCL13-hydroxy-3-methylglutarate-CoA lyaseHydroxymethylglutaryl-CoA lyaseHydroxymethylglutaricaciduria3-hydroxymethyl-3-methylglutaryl-CoA lyase3-hydroxymethyl-3-methylglutaryl-Coenzyme A lyaseMitochondrial 3-hydroxy-3-methylglutaryl-CoA lyase

Not applicable for classical pharmacological modulation; enzyme deficiency leads to disease, and management is via metabolic support rather than direct enzymatic modulation