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Publication Abstract from PubMed

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.

Allosteric role of the citrate synthase homology domain of ATP citrate lyase.,Wei X, Schultz K, Pepper HL, Megill E, Vogt A, Snyder NW, Marmorstein R Nat Commun. 2023 Apr 19;14(1):2247. doi: 10.1038/s41467-023-37986-9. PMID:37076498^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.