Structural and functional investigations on human acetyl-CoA synthetase (ACSS2)

Metabolic reprogramming is a hallmark of cancer progression and therapeutic resistance. In recognition of these disrupted pathways, acetate metabolism has emerged as a key adaptive mechanism, especially in nutrient-limited environments and under hypoxic conditions. The enzyme acetyl-CoA synthetase 2 (ACSS2) is an ATP-dependent enzyme that enables cancer cells to convert acetate into acetyl-CoA, which fuels lipid synthesis and epigenetic regulations via histone acetylation. While ACSS2 is critical in lipid metabolism and its inhibition is associated with tumour suppression, its structural and mechanistic roles remain unclear. Our project addresses this by integrating structural biology and lipidomics to explore ACSS2’s function and develop anticancer inhibitors that target lipid metabolism in tumor cells. Our research highlights the dimerization and oligomerization of ACSS2, which makes this protein suitable for Cryo-EM analysis.