The ATP-citrate Lyase (ACLY) Project

Updated Jan. 2020

ATP-citrate lyase (ACLY) catalyzes the ATP-dependent conversion of citrate and CoA to oxaloacetate and acetyl-CoA. It is one of the major sources of cytosolic acetyl-CoA, and is a central metabolic enzyme. The acetyl-CoA product is crucial for fatty acid metabolism, cholesterol biosynthesis, and post-translational modification of proteins (acetylation and prenylaion).

ACLY activity is required for proliferation by many tumors, making it an attractive target for drug discovery. ACLY is also a target against dyslipidemia and hepatic steatosis. A compound is in phase III clinical trials against dyslipidemia. The currently known inhibitors of ACLY all have weak activity, with IC50 greater than 100 uM.

ACLY is a homotetramer of 500 kD, wich each monomer containing ~1100 residues. The reaction proceeds in four steps, with the formation of a citryl-CoA intermediate.

Crystal structure information is available for the first ~820 residues of the enzyme, but this N-terminal fragment is monomeric and cannot catalyze the overall reaction. The C-terminal ~300 residues have weak homology to citrate synthase (CS).

Major findings from this project

Publications from this project

Funding for this project

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