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

@article{Wei2019AnAM,
  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},
  journal={Nature},
  year={2019},
  volume={568},
  pages={566-570}
}
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… 
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Discovery of a new ATP-citrate lyase (ACLY) inhibitor identified by a pharmacophore-based virtual screening study
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TLDR
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
TLDR
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.
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    Trends in pharmacological sciences
  • 2019
Exploring the Role of ATP-Citrate Lyase in the Immune System
TLDR
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
TLDR
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.
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