Affinage

ACACB

Acetyl-CoA carboxylase 2 · UniProt O00763

Length
2458 aa
Mass
276.5 kDa
Annotated
2026-06-09
15 papers in source corpus 5 papers cited in narrative 5 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ACACB (ACC2/ACCbeta) is an acetyl-CoA carboxylase whose activity governs fatty acid beta-oxidation, positioning it as a metabolic control point across muscle, astrocytic, and vascular tissues (PMID:12413941, PMID:42063966). During exercise in human skeletal muscle, the AMPK alpha2 subunit phosphorylates ACCbeta at Ser221, although phosphorylation state can dissociate from AMPK activity over prolonged exertion (PMID:12413941). In astrocytes, ACACB operates within a PKA/ACACB/CPT1A axis: oleic acid acting through PKA modulates ACACB to increase CPT1A-dependent beta-oxidation, reduce lipid droplet accumulation, and restore mitochondrial membrane potential (PMID:42063966). Transcriptionally, a -368 C/T polymorphism in the ACACB promoter P-II alters promoter activity in an allele-specific manner dependent on SREBP-1a, with differential nuclear protein binding to the two alleles (PMID:20799892). ACACB protein is also a direct cellular binding target of the environmental pollutant PFOA, an interaction associated with abnormal fatty acid metabolism (PMID:30134650).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 2002 Medium

    Established the regulatory phosphorylation event linking energy sensing to ACCbeta by identifying AMPK alpha2-mediated phosphorylation at Ser221, and revealed that phosphorylation state can uncouple from kinase activity during prolonged exercise.

    Evidence Phospho-specific immunoblotting of human muscle biopsies with AMPK activity time-course during prolonged exercise

    PMID:12413941

    Open questions at the time
    • Mechanism causing dissociation of Ser221 phosphorylation from AMPK activity is unresolved
    • Functional consequence on malonyl-CoA output and beta-oxidation not directly measured here
  2. 2010 Medium

    Addressed how ACACB transcription is regulated by showing a promoter polymorphism alters activity in an SREBP-1a-dependent, allele-specific manner with differential nuclear protein binding.

    Evidence Luciferase reporter assays in HepG2 cells, EMSA competition, and mass spectrometry of shifted bands

    PMID:20799892

    Open questions at the time
    • Identity of the allele-specific binding proteins (GATA, c-Myb, GR implicated) not confirmed by mass spectrometry
    • Whether SREBP-1a binds the promoter directly or acts indirectly is unresolved
  3. 2018 Medium

    Identified ACACB protein as a direct cellular target of an environmental contaminant, providing a molecular basis for PFOA-associated lipid metabolism disruption.

    Evidence Competitive cysteine-reactive chemical proteomics (IAA/EBX probes), PRM targeted proteomics, and thermal shift assay with targeted metabolomics

    PMID:30134650

    Open questions at the time
    • Functional effect of PFOA binding on carboxylase catalytic activity not quantified
    • Specific cysteine residue(s) engaged not pinpointed
  4. 2025 Low

    Placed ACACB downstream of GPER1 in a pathway influencing vascular endothelial cell senescence.

    Evidence siRNA knockdown of GPER1 in cultured endothelial cells with ACACB expression and senescence marker readouts

    PMID:40131497

    Open questions at the time
    • Single knockdown experiment reported in abstract with limited mechanistic detail
    • Whether ACACB regulation is direct or how it mediates senescence is unknown
  5. 2026 Medium

    Defined a PKA/ACACB/CPT1A signaling axis in astrocytes, connecting ACACB activity to beta-oxidation, lipid droplet clearance, and mitochondrial function.

    Evidence ACACB knockdown/overexpression and CPT1A overexpression in Abeta1-42-induced astrocytes plus APP/PS1 mouse model with mitochondrial and lipid readouts

    PMID:42063966

    Open questions at the time
    • Direct PKA phosphorylation of ACACB not demonstrated biochemically
    • Relationship to AMPK/Ser221 regulation not addressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple regulatory inputs (AMPK phosphorylation, PKA signaling, SREBP-1a transcriptional control, PFOA binding) are integrated to set ACACB catalytic output and malonyl-CoA levels in vivo remains unresolved.
  • No structural model of ACACB regulation in the corpus
  • Quantitative coupling between phosphorylation state and carboxylase activity not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016874 ligase activity 2
Pathway
R-HSA-1430728 Metabolism 3
Partners
AMPKCPT1ASREBP-1A

Evidence

Reading pass · 5 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 AMPK (alpha2 subunit) phosphorylates ACCbeta at Ser221 during exercise in human skeletal muscle, but ACCbeta Ser221 phosphorylation peaked at 1h and returned to resting levels at exhaustion despite continued increases in alpha2 AMPK activity, demonstrating a dissociation between AMPK activity and ACCbeta phosphorylation state during prolonged exercise. Phospho-specific immunoblotting of muscle biopsies during prolonged exercise; measurement of alpha1 and alpha2 AMPK activity Biochemical and biophysical research communications Medium 12413941
2010 A single-nucleotide polymorphism -368 C/T (rs16939972) in the ACACB promoter P-II affects promoter activity in an allele-specific manner; the T-allele construct showed significantly lower activity than the C-allele only in the presence of SREBP-1a overexpression, and EMSA showed higher affinity nuclear protein binding to the T-allele probe. Competition assays implicated GATA, c-Myb, and GR binding sites, though these proteins were not detected by mass spectrometry of shifted bands. Luciferase reporter transfection in HepG2 cells; EMSA with competition assays; mass spectrometry of gel extracts DNA and cell biology Medium 20799892
2018 PFOA directly binds Acacb (and Acaca) protein in a cellular context, as identified by competitive cysteine-reactive chemical proteomics using iodoacetamide alkyne and EBX probes, verified by parallel reaction monitoring targeted proteomics and thermal shift assay; this binding was associated with abnormal fatty acid metabolism. Competitive cysteine-targeting chemical proteomics (IAA and EBX probes), PRM-based targeted proteomics, thermal shift assay, targeted metabolomics Analytical chemistry Medium 30134650
2026 Oleic acid modulates ACACB (ACC2) activity through PKA signaling in astrocytes, leading to increased CPT1A-dependent fatty acid beta-oxidation, reduced lipid droplet accumulation, and restored mitochondrial membrane potential; ACACB knockdown/overexpression and CPT1A overexpression experiments confirmed the PKA/ACACB/CPT1A pathway axis. ACACB knockdown/overexpression and CPT1A overexpression in Abeta1-42-induced astrocytes; APP/PS1 mouse model with dietary OA supplementation; mitochondrial membrane potential assay; ATP measurement; lipid droplet quantification Frontiers in neuroscience Medium 42063966
2025 GPER1 silencing decreased ACACB expression and accelerated endothelial cell senescence in vitro, placing ACACB downstream of GPER1 in a pathway regulating vascular endothelial cell senescence. siRNA knockdown of GPER1 in cultured vascular endothelial cells with measurement of ACACB expression and senescence markers Neurosurgical review Low 40131497

Source papers

Stage 0 corpus · 15 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Dissociation of AMPK activity and ACCbeta phosphorylation in human muscle during prolonged exercise. Biochemical and biophysical research communications 106 12413941
2011 Association of ACACB polymorphisms with obesity and diabetes. Molecular genetics and metabolism 40 21908218
2012 ACACβ gene (rs2268388) and AGTR1 gene (rs5186) polymorphism and the risk of nephropathy in Asian Indian patients with type 2 diabetes. Molecular and cellular biochemistry 35 23081748
2010 The acetyl-coenzyme A carboxylase beta (ACACB) gene is associated with nephropathy in Chinese patients with type 2 diabetes. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 34 20519229
2006 Coordinate expression of the acetyl coenzyme A carboxylase genes, accB and accC, is necessary for normal regulation of biotin synthesis in Escherichia coli. Journal of bacteriology 33 17056747
2018 Integrative Chemical Proteomics-Metabolomics Approach Reveals Acaca/Acacb as Direct Molecular Targets of PFOA. Analytical chemistry 24 30134650
2018 Genetic association of the ACACB gene with milk yield and composition traits in dairy cattle. Animal genetics 17 29521460
2022 ACACB is a novel metabolism-related biomarker in the prediction of response to cetuximab therapy inmetastatic colorectal cancer. Acta biochimica et biophysica Sinica 12 36111743
2010 Functional single-nucleotide polymorphism in acetyl-CoA carboxylase ACACB gene promoter. DNA and cell biology 7 20799892
2015 The ACACB gene rs2268388 polymorphism is associated with nephropathy in Caucasian patients with diabetes: a meta-analysis. Renal failure 6 26030797
2010 Physiogenomic analysis of statin-treated patients: domain-specific counter effects within the ACACB gene on low-density lipoprotein cholesterol? Pharmacogenomics 6 20602615
2022 Crystal structure of Acetyl-CoA carboxylase (AccB) from Streptomyces antibioticus and insights into the substrate-binding through in silico mutagenesis and biophysical investigations. Computers in biology and medicine 4 35344865
2024 Improving the substrate binding of acetyl-CoA carboxylase (AccB) from Streptomyces antibioticus through computational enzyme engineering. Biotechnology and applied biochemistry 3 38287712
2025 GPER1/ACACB are potential target genes associated with intracranial aneurysm and vascular endothelial cell senescence. Neurosurgical review 1 40131497
2026 Oleic acid improves pathological changes in Aβ1-42-induced astrocytes and Alzheimer's disease mouse models through PKA/ACACB/CPT1A. Frontiers in neuroscience 0 42063966

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