7wta

Publication Abstract from PubMed

Pyruvate carboxylase (PC) catalyzes the two-step carboxylation of pyruvate to produce oxaloacetate, playing a key role in the maintenance of metabolic homeostasis in cells. Given its involvement in multiple diseases, PC has been regarded as a potential therapeutic target for obesity, diabetes, and cancer. Albeit acetyl-CoA has been recognized as the allosteric regulator of PC for over 60 years, the underlying mechanism of how acetyl-CoA induces PC activation remains enigmatic. Herein, by using time-resolved cryo-electron microscopy, we have captured the snapshots of PC transitional states during its catalytic cycle. These structures and the biochemical studies reveal that acetyl-CoA stabilizes PC in a catalytically competent conformation, which triggers a cascade of events, including ATP hydrolysis and the long-distance communication between the two reactive centers. These findings provide an integrated picture for PC catalysis and unveil the unique allosteric mechanism of acetyl-CoA in an essential biochemical reaction in all kingdoms of life.

Mechanistic insight into allosteric activation of human pyruvate carboxylase by acetyl-CoA.,Chai P, Lan P, Li S, Yao D, Chang C, Cao M, Shen Y, Ge S, Wu J, Lei M, Fan X Mol Cell. 2022 Nov 3;82(21):4116-4130.e6. doi: 10.1016/j.molcel.2022.09.033. Epub, 2022 Oct 24. PMID:36283412^[1]

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