An allosteric mechanism for potent inhibition of human ATP-citrate lyase

  title={An allosteric mechanism for potent inhibition of human ATP-citrate lyase},
  author={Jia Wei and Silvana M. Leit and Jun Kuai and Eric Therrien and Salma Rafi and Harold James Harwood and B. Delabarre and Liang Tong},
ATP-citrate lyase (ACLY) is a central metabolic enzyme and catalyses the ATP-dependent conversion of citrate and coenzyme A (CoA) to oxaloacetate and acetyl-CoA1–5. The acetyl-CoA product is crucial for the metabolism of fatty acids6,7, the biosynthesis of cholesterol8, and the acetylation and prenylation of proteins9,10. There has been considerable interest in ACLY as a target for anti-cancer drugs, because many cancer cells depend on its activity for proliferation2,5,11. ACLY is also a target… 
ATP-citrate lyase: a driver of metabolism and histone acetylation.
Inhibition of ACLY mediated acetyl-CoA production blunted de novo acetylation of histones and reduced the expression of pro-inflammatory cytokines including IL-6 and IL-12-p70, whereas expression of anti- inflammatory cytokines IL-10 andIL-1RA was increased.
Discovery of a new ATP-citrate lyase (ACLY) inhibitor identified by a pharmacophore-based virtual screening study
A pharmacophore-based virtual screening protocol with the aid of hierarchical docking, consensus docking, molecular dynamics simulations and ligand-protein binding free energy calculations led to the identification of compound VS1, which showed a moderate but promising inhibitory activity, demonstrating to be 2.5 times more potent than reference inhibitor 2-hydroxycitrate.
ATP-citrate lyase (ACLY) inhibitors as therapeutic agents: a patenting perspective
  • C. Granchi
  • Biology, Chemistry
    Expert opinion on therapeutic patents
  • 2022
The search for new effective ACLY inhibitors is of great significance and has broad application prospects for the treatment of hyperlipidemia and cancer.
Molecular Basis for Acetyl‐CoA Production by ATP‐Citrate Lyase
Cryo‐EM structures of human ACLY alone or bound to substrates or products are reported to challenge previous proposals of the ACLY catalytic mechanism and suggest additional therapeutic possibilities for ACLY‐associated metabolic disorders.
Molecular basis for acetyl-CoA production by ATP-citrate lyase
Cryo-EM structures of human ATP-citrate lyase alone or bound to substrates or products and supportive biochemical and biophysical data reveal the catalytic mechanism of this enzyme, which is the major source of cytosolic acetyl-CoA.
Discovery of Allosteric Inhibition of Human ATP-Citrate Lyase.
  • C. Granchi
  • Biology, Chemistry
    Trends in pharmacological sciences
  • 2019
Exploring the Role of ATP-Citrate Lyase in the Immune System
The role of ACLY is focused on in supporting de novo lipogenesis in immune cells as well as on its impact on epigenetic alterations, and alternative sources of acetyl-CoA are summarized.
Identification of the active site residues in ATP‐citrate lyase's carboxy‐terminal portion
To investigate the roles of residues of ACLY equivalent to active site residues of citrate synthase, these residues in ACLY from Chlorobium limicola were mutated, and the proteins were investigated using kinetics assays and biophysical techniques.


On the catalytic mechanism of human ATP citrate lyase.
ATP citrate lyase (ACL) catalyzes an ATP-dependent biosynthetic reaction which produces acetyl-coenzyme A and oxaloacetate from citrate and coenzyme A (CoA). Studies were performed with recombinant
ATP-citrate lyase: a key player in cancer metabolism.
The present review highlights current knowledge about the role of ACLY in cancer cells, with special reference to the different pathways that are linked by ACLY.
Binding of hydroxycitrate to human ATP-citrate lyase.
Well diffracting crystals showing how the inhibitor binds to human ATP-citrate lyase were grown by modifying the protein by introducing cleavage sites for Tobacco etch virus protease on either side of a disordered linker, and electron density was evident for the loop that contains His760.
ATP-citrate lyase: genetics, molecular biology and therapeutic target for dyslipidemia
The efficacy of bempedoic acid as an LDL-C-lowering agent has validated ACLY inhibition as a therapeutic strategy, and positive results of phase 3 patient studies, together with long-term cardiovascular disease outcome trials are required to establish ACLY as a major new target in cardiovascular medicine.
Identification of the Citrate-binding Site of Human ATP-Citrate Lyase Using X-ray Crystallography*
This is the first structure of any member of the acyl-CoA synthetase (NDP-forming) superfamily in complex with its organic acid substrate, and locating the citrate-binding site is significant for understanding the catalytic mechanism of each member, including the prototype SCS.
ATP-citrate lyase: a mini-review.
ADP-Mg2+ bound to the ATP-grasp domain of ATP-citrate lyase.
  • T. Sun, K. Hayakawa, M. Fraser
  • Chemistry, Biology
    Acta crystallographica. Section F, Structural biology and crystallization communications
  • 2011
The structure shows ADP-Mg(2+) bound to the domain that possesses the ATP-grasp fold and demonstrates that this crystal form could be used to investigate the structures of complexes with inhibitors of ATP-citrate lyase that bind at either the citrate- or ATP-binding site.
ATP-Citrate Lyase Links Cellular Metabolism to Histone Acetylation
It is found that ACL is required for increases in histone acetylation in response to growth factor stimulation and during differentiation, and that glucose availability can affect hist one acetylations in an ACL-dependent manner.
Structure and function of biotin-dependent carboxylases
  • L. Tong
  • Biology, Chemistry
    Cellular and Molecular Life Sciences
  • 2012
Understanding ofiotin-dependent carboxylases has been greatly enhanced over the past few years by the crystal structures of the holoenzymes of PCC, MCC, PC, and UC, which provide a molecular basis for understanding their catalytic mechanism as well as the large collection of disease-causing mutations.