Acetyl-CoA carboxylase 1

Acetyl-CoA carboxylase 1 (ACC1, encoded by ACACA) is a cytosolic enzyme that catalyzes the ATP-dependent carboxylation of acetyl-CoA to malonyl-CoA, the first and rate-limiting step of de novo fatty acid biosynthesis (UniProt: Q13085). The reaction proceeds via carboxylation of a biotin cofactor followed by carboxyl group transfer to acetyl-CoA. Mutations in ACACA cause acetyl-CoA carboxylase-alpha deficiency (ACACAD, MIM 613933), a severe autosomal recessive condition characterized by brain damage, myopathy, and growth failure, indicating the critical role of fatty acid synthesis in neurological function (UniProt: Q13085).

In Alzheimer's Disease, ACC1 protein levels are significantly reduced in post-mortem AD brain compared to age-matched controls (mean log2 fold-change −0.35, Chaparral AD proteomics). This downregulation was observed in a quantitative proteomics study of human post-mortem tissue using TMT-labeling across four subcellular fractions (P2, P3, S2, S3) by data-dependent acquisition mass spectrometry. The reduction in ACC1 abundance may reflect altered lipid metabolism in the AD brain, a pathway increasingly implicated in neurodegeneration.