Acetoacetyl-CoA synthetase

Acetoacetyl-CoA synthetase (AACS) is a cytosolic enzyme that converts acetoacetate to acetoacetyl-CoA, catalyzing a key step in ketone body utilization and supporting the biosynthesis of cholesterol and fatty acids (UniProt: Q86V21). The protein localizes to the cytoplasm and participates in metabolic pathways essential for cellular energy metabolism and lipid homeostasis. No baseline disease associations are documented in UniProt for this protein.

AACS is relevant to Alzheimer's Disease based on proteomics evidence from post-mortem AD brain tissue. Analysis of human AD brain versus age-matched controls using tandem mass tag (TMT) labeling and data-dependent acquisition (DDA) mass spectrometry across four subcellular fractions (P2, P3, S2, S3) showed that AACS is consistently downregulated in AD (mean log2 fold-change: −0.27; Chaparral AD proteomics). This reduction in ketone body-metabolizing capacity may reflect disrupted energy metabolism in Alzheimer's pathology, potentially contributing to mitochondrial dysfunction and impaired neuronal bioenergetics observed in the disease.