Acyl-CoA synthetase medium-chain family (ACSM)

The Acyl-CoA synthetase medium-chain (ACSM) family consists of mitochondrial enzymes that catalyze the activation of medium-chain fatty acids (C4–C12) into their corresponding acyl-CoA esters, a critical step for their entry into the beta-oxidation pathway or other metabolic processes (UniProt, 2024). In the liver, the primary isoforms include ACSM1, ACSM2A, ACSM2B, ACSM3, and ACSM5, which are essential for maintaining lipid homeostasis and the detoxification of various xenobiotic carboxylic acids (NIH, 2025). Dysregulation of these hepatic isoforms is implicated in several diseases; for example, ACSM5 is frequently downregulated in hepatocellular carcinoma (HCC), where its loss correlates with increased tumor growth and metastasis (Am J Pathol, 2024). Conversely, ACSM1 and ACSM3 have been identified as androgen receptor-regulated genes in prostate cancer that promote cell survival by preventing ferroptosis and supporting energy production (Cancer Res, 2024). These enzymes also play a significant role in pharmacology, as they are responsible for the metabolism of drugs such as valproic acid, ibuprofen, and salicylates (PubMed, 2022). Consequently, the ACSM family represents a promising therapeutic target for metabolic disorders and certain cancers, although potential safety concerns include the risk of metabolic toxicity and drug-drug interactions due to their broad substrate specificity (MedlinePlus, 2015).

Other names

Medium-chain acyl-CoA synthetaseMACSButyrate--CoA ligasePropionate--CoA ligaseSA (specifically for ACSM3)Acyl-CoA synthetase medium-chain familyHepatic acyl-CoA synthetase medium-chain isoforms

The ACSM family enzymes catalyze the ATP-dependent activation of medium-chain fatty acids (C4-C12) and various xenobiotic carboxylic acids into their corresponding acyl-CoA thioesters, which is the essential first step for their mitochondrial metabolism via beta-oxidation or glycine conjugation (NIH, 2025; UniProt, 2024).