protein
Malonate--CoA ligase ACSF3, mitochondrial
Gene
ACSF3
Organism
Homo sapiens(9606)
Length
576 aa
Mass
64,130 Da
ACSF3 (malonate–CoA ligase) is a mitochondrial enzyme that catalyzes activation of malonate and methylmalonate into their CoA thioesters, supporting intramitochondrial fatty acid synthesis (UniProt: Q4G176). The protein may preferentially act on very-long-chain substrates. In humans, ACSF3 mutations cause combined malonic and methylmalonic aciduria (CMAMMA, MIM 614265), a metabolic disorder presenting with neurological manifestations including seizures, cognitive decline, and developmental delay.
ACSF3 is relevant to Alzheimer's disease, where it shows reduced abundance in post-mortem AD brain tissue compared to age-matched controls (Chaparral AD proteomics). The mean log2 fold-change was −0.44 across analyzed subcellular fractions, indicating down-regulation. This reduction may reflect impaired mitochondrial fatty acid metabolism in the AD brain, potentially contributing to metabolic dysfunction associated with neurodegeneration.
Generated from the curated entity record below. May contain errors — verify against source links.
Proteomics Evidence · AD
↓ Down in ADP3
-0.444
P2
not detected
S2
not detected
S3
not detected
Mean log₂FC across detected fractions: -0.4442 (1 of 4 fractions detected)
Human post-mortem AD brain vs age-matched controls, TMT-labeled, 4 subcellular fractions (P2, P3, S2, S3), DDA proteomics.
Related Publications
Browse all →Tau molecular diversity contributes to clinical heterogeneity in Alzheimer's disease.
Dujardin Simon et al.Nature medicine2020PMID 32572268Deep Multilayer Brain Proteomics Identifies Molecular Networks in Alzheimer's Disease Progression.
Bai Bing et al.Neuron2020PMID 31926610A Multi-network Approach Identifies Protein-Specific Co-expression in Asymptomatic and Symptomatic Alzheimer's Disease.
Seyfried Nicholas T et al.Cell systems2017PMID 27989508Large-scale deep multi-layer analysis of Alzheimer's disease brain reveals strong proteomic disease-related changes not observed at the RNA level.
Johnson Erik C B et al.Nature neuroscience2022PMID 35115731Organization and regulation of gene transcription.
Cramer PatrickNature2019PMID 31462772
Function
Catalyzes the initial reaction in intramitochondrial fatty acid synthesis, by activating malonate and methylmalonate, but not acetate, into their respective CoA thioester (PubMed:21841779, PubMed:21846720). May have some preference toward very-long-chain substrates (PubMed:17762044)
Disease associations
Combined malonic and methylmalonic aciduriaCMAMMA
A metabolic disease characterized by malonic and methylmalonic aciduria, with urinary excretion of much larger amounts of methylmalonic acid than malonic acid, in the presence of normal malonyl-CoA decarboxylase activity. Clinical features include coma, ketoacidosis, hypoglycemia, failure to thrive, microcephaly, dystonia, axial hypotonia and/or developmental delay, and neurologic manifestations including seizures, psychiatric disease and/or cognitive decline.
Sources
Last updated 5/8/2026, 6:37:40 AM