Catalyzes the synthesis of acetyl-CoA from short-chain fatty acids (PubMed:11150295, PubMed:16790548). Acetate is the preferred substrate (PubMed:11150295, PubMed:16790548). Can also utilize propionate with a much lower affinity (PubMed:11150295). Provides acetyl-CoA that is utilized mainly for oxidation under ketogenic conditions (PubMed:11150295). Involved in thermogenesis under ketogenic conditions, using acetate as a vital fuel when carbohydrate availability is insufficient (PubMed:19187775). acetate + ATP + CoA = acetyl-CoA + AMP + diphosphate ATP + CoA + propanoate = AMP + diphosphate + propanoyl-CoA Inhibited by acetylation at Lys-635 and activated by deacetylation mediated by the deacetylase SIRT3. Interacts with SIRT3. Highly expressed in heart, testis, kidney, skeletal muscle, lung and spleen. Detected at low levels in brain. By fasting. Reversibly acetylated at Lys-635 (PubMed:16790548). The acetyl-CoA synthase activity is inhibited by acetylation and activated by deacetylation mediated by the deacetylase SIRT3. No visible phenotype at birth, but exhibit significant growth retardation at the time of weaning. Attain normal size and weight when fed normally. Exhibit hypothermia and hypoglycemia when fed high-fat, low-carbohydrate diet, leading to 50% mortality. Display strongly reduced whole-body acetate oxidation when fasting. Fasting adults exhibit hypothermia, reduced capacity to sustain running and low ATP levels. Belongs to the ATP-dependent AMP-binding enzyme family.