Acyl-CoA synthetase family (ACS) (ACS)

The Acyl-CoA synthetase (ACS) family consists of enzymes that catalyze the activation of fatty acids or acetate by converting them into their respective CoA thioesters, a fundamental step for their entry into metabolic pathways like beta-oxidation, lipid synthesis, and protein acetylation (UniProt: Q9NR19; PMID: 21835144). This family is categorized based on the chain length of the fatty acid substrates they prefer, ranging from short-chain (ACSS) to very-long-chain (ACSVL) species (PMID: 28611114). In the context of oncology, ACSS2 has emerged as a significant therapeutic target because many tumors utilize acetate as an alternative carbon source for lipid synthesis and epigenetic signaling under hypoxic or nutrient-deprived conditions (PMID: 30612020). Beyond cancer, members of the ACS family are implicated in metabolic diseases such as obesity, type 2 diabetes, and non-alcoholic fatty liver disease due to their roles in regulating lipid homeostasis (PMID: 24508271). Pharmacological inhibition of these enzymes, particularly ACSS2 and ACSL isoforms, is being explored to disrupt tumor metabolism and manage metabolic dysfunction (PMID: 31515444). However, the high degree of homology between family members and their essential roles in normal physiology present challenges for achieving selectivity and minimizing off-target toxicity (PMID: 29453201).

Other names

Acetyl-CoA synthetaseAcyl-CoA synthetaseFatty acid-CoA ligaseAcetate-CoA ligaseAcyl-activating enzymeShort-chain acyl-CoA synthetaseLong-chain acyl-CoA synthetaseACSSACSLACSMACSVLAcetyl-CoA synthetase / acyl-CoA synthetase family

Inhibition of the ATP-dependent conversion of carboxylic acids to acyl-CoA thioesters, thereby blocking fatty acid and acetate utilization in metabolic and signaling pathways (PMID: 21835144).