3-hydroxy-3-methylglutaryl-CoA lyase
| Hydroxymethylglutaryl-CoA lyase | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Identifiers | |||||||||
| EC number | 4.1.3.4 | ||||||||
| CAS number | Template:CAS | ||||||||
| 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 / EGO | ||||||||
|
|||||||||
| 3-hydroxymethyl-3-methylglutaryl-Coenzyme A lyase (hydroxymethylglutaricaciduria) | |
|---|---|
| Identifiers | |
| Symbol | HMGCL |
| Entrez | 3155 |
| HUGO | 5005 |
| OMIM | 246450 |
| RefSeq | NM_000191 |
| UniProt | P35914 |
| Other data | |
| EC number | 4.1.3.4 |
| Locus | Chr. 1 p36.1-p35 |
3-hydroxy-3-methylglutaryl-CoA lyase (or HMG-CoA lyase) is an enzyme that in human is encoded by the HMGCL gene located on chromosome 1. It is a key enzyme in ketogenesis (ketone body formation).
Contents
Structure
The HMGCL gene encodes a 34.5-kDa protein that is localized to the mitochondrion and peroxisome.[1] Multible isoforms of the proteins are known due to alternative splicing. The major isoform (isoform 1) is most highly expressed in the liver [2] whereas isoform 2 is found in energy-demanding tissues including the brain, heart, and skeletal muscle.[3]
Structure of the HMGCL protein has been resolved by X-ray crystallography at 2.1-Å resolution, and reveals that the protein may function as a dimer. Substrate access to the active site of the HMGCL enzyme involves substrate binding across a cavity located at the C-terminal end of a beta barrel structure.[4] In addition, the lysine 48 residue which is mutated in patients with 3-hydroxy-3-methylglutaryl-CoA lyase deficiency is also found to be necessary for substrate binding.[5]
Function
The HMGCL protein plays an essential role in breaking down dietary proteins and fats for energy. It catalyzes the reaction:
(S)-3-hydroxy-3-methylglutaryl-CoA = acetyl-CoA + acetoacetate.
and requires a divalent metal ion as co-factor.[6]
The enzyme is required for ketogenesis in the liver, and is also responsible for processing the amino acid leucine inside the mitochondrion
Clinical Significance
Mutations in the HMGCL gene cause 3-hydroxy-3-methylglutaryl-CoA lyase deficiency (HMGCLD), a rare autosomal recessive inborn error of metabolism characterized by disruption of ketogenesis and L-leucine catabolism. To-date more than 30 different mutations including missense mutations of different residues have been associated with patients with HMGCLD in diverse families and ethnicities.[7] HMGCLD typically presents in the first year of the patient's life after a fasting period. Clinical acute symptoms include vomiting, seizures, metabolic acidosis, hypoketotic hypoglycemia, and lethargy.[8]
Interactions
HMGCL interacts with itself to form homodimers and homotetramers. It is also shown in yeast two-hybrid experiments to interact with DNAJA1.
References
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- ↑ http://www.omim.org/entry/246450[full citation needed]
External links
- 3-hydroxy-3-methylglutaryl-coenzyme A lyase at the US National Library of Medicine Medical Subject Headings (MeSH)
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