Molecular and evolutionary insights into the structure and mechanism of ATP citrate lyase

ATP citrate lyase (ACL) is an ancient metabolic enzyme found in different kingdoms of life. In

mammals, ACL catalyses the ATP-dependent cleavage of citrate to generate cytosolic acetyl-CoA,

the building block for fatty acid synthesis, thereby linking energy metabolism from carbohydrates to

the production of fatty acids. In view of the importance of ACL in glucose and lipid metabolism, ACL

is considered as a therapeutic target for the treatment of cancer and metabolic disorders. At the

structural level, ACL functions either as a 500 kDa homotetramer (in animals) or ACL-A/ACL-B

hetero-octamer (in plants, yeast and bacteria). At present, the architecture of the ACL holoenzyme

and a detailed structural understanding of the multistep reaction mechanism and allosteric

regulation of ACL remain elusive.

This timely, interdisciplinary research project in structural biology builds on recent exciting advances

in the host lab and aims to provide molecular and evolutionary insights into the structure and

mechanism of this key metabolic enzyme by combining structural methods as X-ray crystallography

and electron microscopy with methods in enzymology, including site-directed mutagenesis and

activity assays. We believe that our research results will appeal to a broad scientific audience and, in

particular, will provide a molecular framework to support ongoing efforts to develop ACL inhibitors

to treat metabolic diseases and cancer.