3-hydroxy-3-methylglutaryl-CoA lyase

3-Hydroxy-3-methylglutaryl-CoA lyase
250px Structure of 3-Hydroxy-3-methylglutaryl-CoA lyase
Identifiers
EC number	4.1.3.4
CAS number	9025-54-1
Databases
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB structures	RCSB PDB PDBe PDBsum
Gene Ontology	AmiGO / QuickGO
Search PMC articles PubMed articles NCBI proteins

3-Hydroxy-3-methylglutaryl-CoA lyase (HMG-CoA lyase) is an enzyme that plays a crucial role in the metabolic pathways of ketogenesis and leucine catabolism. It catalyzes the cleavage of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) to produce acetyl-CoA and acetoacetate. This reaction is essential for the production of ketone bodies, which serve as an important energy source during periods of fasting or carbohydrate restriction.

Function

HMG-CoA lyase is primarily located in the mitochondria of liver cells, where it facilitates the conversion of HMG-CoA into acetoacetate and acetyl-CoA. Acetoacetate can be further reduced to beta-hydroxybutyrate or spontaneously decarboxylate to acetone, both of which are ketone bodies. These ketone bodies are then released into the bloodstream and transported to peripheral tissues, such as the brain and muscle, where they are used as an alternative energy source.

In addition to its role in ketogenesis, HMG-CoA lyase is involved in the breakdown of the amino acid leucine. During leucine catabolism, HMG-CoA is an intermediate, and its cleavage by HMG-CoA lyase is a critical step in the pathway.

Clinical Significance

Deficiency of HMG-CoA lyase, a rare genetic disorder known as HMG-CoA lyase deficiency, results in the inability to properly produce ketone bodies and metabolize leucine. This condition can lead to severe metabolic crises, especially during periods of fasting or illness, characterized by hypoglycemia, metabolic acidosis, and lethargy. Early diagnosis and management, including dietary modifications and avoidance of fasting, are crucial for affected individuals.

Structure

HMG-CoA lyase is a homodimeric enzyme, meaning it consists of two identical subunits. Each subunit contains an active site where the cleavage of HMG-CoA occurs. The enzyme requires magnesium ions as cofactors for its activity. The structure of HMG-CoA lyase has been elucidated through X-ray crystallography, providing insights into its catalytic mechanism and substrate binding.

Also see

• Ketogenesis
• Leucine metabolism
• Acetyl-CoA
• Acetoacetate
• HMG-CoA reductase