Year: 2023
Type: article
Abstract: ATP citrate lyase (ACLY) is the predominant nucleocytosolic source of acetyl-CoA and is aberrantly regulated in many diseases making it an attractive therapeutic target. Structural studies of ACLY reveal a central homotetrameric core citrate synthase homology (CSH) module flanked by acyl-CoA synthetase homology (ASH) domains, with ATP and citrate binding the ASH domain and CoA binding the ASH-CSH interface to produce acetyl-CoA and oxaloacetate products. The specific catalytic role of the CSH module and an essential D1026A residue contained within it has been a matter of debate. Here, we report biochemical and structural analysis of an ACLY-D1026A mutant demonstrating that this mutant traps a (3S)-citryl-CoA intermediate in the ASH domain in a configuration that is incompatible with the formation of acetyl-CoA, is able to convert acetyl-CoA and OAA to (3S)-citryl-CoA in the ASH domain, and can load CoA and unload acetyl-CoA in the CSH module. Together, this data support an allosteric role for the CSH module in ACLY catalysis.
Source: Nature Communications
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,290
Awards: G1379664177, Epigenetics of Aging and Age-Associated Diseases, Quantification of compartmentalized metabolism in eukaryotic systems, G3203067401, G3372464033, Resource for Biocomputing Visualization and Informatics, G3875392519, G4815039349, G9000310355, Molecular Mechanisms, Pathways and Inhibition of Acetyl-Transfer Reactions, Predoctoral Training at the Chemistry-Biology Interface, Metabolic regulation and inhibition of ATP-citrate lyase
OpenAlex ID: W4366387096