Structure of ATP citrate lyase and the origin of citrate synthase in the Krebs cycle

  title={Structure of ATP citrate lyase and the origin of citrate synthase in the Krebs cycle},
  author={Koen H. G. Verschueren and Clement Blanchet and Jan Felix and Ann Dansercoer and Dirk E. De Vos and Yehudi Bloch and Jozef J. Van Beeumen and Dmitri I. Svergun and Irina Gutsche and Savvas N. Savvides and Kenneth Verstraete},
Across different kingdoms of life, ATP citrate lyase (ACLY, also known as ACL) catalyses the ATP-dependent and coenzyme A (CoA)-dependent conversion of citrate, a metabolic product of the Krebs cycle, to oxaloacetate and the high-energy biosynthetic precursor acetyl-CoA1. The latter fuels pivotal biochemical reactions such as the synthesis of fatty acids, cholesterol and acetylcholine2, and the acetylation of histones and proteins3,4. In autotrophic prokaryotes, ACLY is a hallmark enzyme of the… 
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.
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.
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.
The Drosophila Citrate Lyase Is Required for Cell Division during Spermatogenesis
It is described that depletion of DmATPCL affects spindle organization, cytokinesis, and fusome assembly during male meiosis, revealing an unanticipated role for DmatPCL during spermatogenesis and unveiling for the first time an involvement in the regulation of meiotic cell division in human cells.
Tyrosine phosphorylation is critical for ACLY activity in lipid metabolism and cancer
A novel mechanism for direct ACLY regulation is revealed that is subverted by multiple oncogenically-activated tyrosine kinases in diverse human cancers and has significant implications for novel therapies targeting ACLY in cancer and metabolism.
Anaerobic derivates of mitochondria and peroxisomes in the free-living amoeba Pelomyxa schiedti revealed by single-cell genomics
The successful approach for generating good-quality genome and transcriptome drafts from a peculiar amoeba Pelomyxa schiedti using single-cell methods is demonstrated.
Second distinct conformation of the phosphohistidine loop in succinyl-CoA synthetase.
  • Ji Huang, M. Fraser
  • Chemistry, Biology
    Acta crystallographica. Section D, Structural biology
  • 2021
The first crystal structure of SCS revealing the conformation of the phosphohistidine loop in site II of the porcine GTP-specific enzyme is presented and another magnesium ion was found that interacts with the side chains of Glu141β and Glu204β via water-mediated interactions.


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.
ATP-Citrate Lyase Deficiency in the Mouse*
Acly was expressed ubiquitously but was expressed particularly highly in tissues with high levels of lipogenesis, such as in the livers of mice fed a high-carbohydrate diet, and β-galactosidase staining was intense in the developing brain, in keeping with thehigh levels of de novo lipogenesis of the tissue.
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.
Molecular Characterization of a Heteromeric ATP-Citrate Lyase That Generates Cytosolic Acetyl-Coenzyme A in Arabidopsis1,212
Results indicate that ACL, encoded by theACLA and ACLB genes of Arabidopsis, generates cytosolic acetyl-CoA, a homomeric structure indicating that a evolutionary fusion of the ACLA and ACL B genes probably occurred early in the evolutionary history of this kingdom.
ATP-citrate lyase: a mini-review.
Reversibility of citrate synthase allows autotrophic growth of a thermophilic bacterium
The sulfur-reducing anaerobic deltaproteobacterium Desulfurella acetivorans is capable of both acetate oxidation and autotrophic carbon fixation, with the tricarboxylic acid cycle operating either in the oxidative or reductive direction, respectively.
Structure and mechanism of citrate synthase.
  • S. Remington
  • Biology, Chemistry
    Current topics in cellular regulation
  • 1992
A primordial and reversible TCA cycle in a facultatively chemolithoautotrophic thermophile
Phylometabolic evaluation suggests that the TCA cycle with reversible CS may represent an ancestral mode of the rTCA cycle and raises the possibility of a facultatively chemolithomixotrophic origin of life.