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).

The HMGCL gene encodes a 34.5-kDa protein that is localized to the and peroxisome. Multible isoforms of the proteins are known due to alternative splicing. The major isoform (isoform 1) is most highly expressed in the liver whereas isoform 2 is found in energy-demanding tissues including the brain, heart, and skeletal muscle.

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. 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.

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.

The enzyme is required for ketogenesis in the liver, and is also responsible for processing the amino acid leucine inside the

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