Affinage

PCCB

Propionyl-CoA carboxylase beta chain, mitochondrial · UniProt P05166

Length
539 aa
Mass
58.2 kDa
Annotated
2026-06-10
35 papers in source corpus 9 papers cited in narrative 9 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 4/5 claims corpus-supported (80%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PCCB encodes the beta subunit of mitochondrial propionyl-CoA carboxylase (PCC), a biotin-dependent enzyme (EC 6.4.1.3) that carboxylates propionyl-CoA to methylmalonyl-CoA and which assembles as a dodecameric heteropolymer of alpha (PCCA) and beta (PCCB) subunits (PMID:3460076, PMID:10502773). Within this assembly, the beta subunit's C-terminal region mediates both alpha-beta heteromeric and beta-beta homomeric contacts, while N-terminal regions are required for proper folding, so that C-terminal mutations directly abolish assembly whereas N-terminal substitutions act as temperature-sensitive folding defects (PMID:11749052). The great majority of pathogenic PCCB variants abolish catalytic activity, and a subset additionally destabilizes the beta-PCC protein, providing the molecular basis for propionic acidemia (PMID:12757933, PMID:37839763). Beyond propionyl-CoA accumulation, loss of PCCB function globally impairs mitochondrial oxidative phosphorylation and constrains distal TCA cycle flux (PMID:29159707), and PCCB-dependent metabolism feeds GABAergic neurotransmission, since PCCB knockdown lowers GABA levels and dysregulates GABAergic synapse networks with consequent neuronal hyperactivity (PMID:37620341). PCC activity is further regulated by PPDPF, which binds PCCA and blocks the PCCA-PCCB interaction to suppress PCC-mediated methionine catabolism (PMID:39694223).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1986 High

    Established the molecular identity of the PCCB gene product, answering what polypeptide PCCB encodes and where it maps in the genome.

    Evidence cDNA cloning with peptide sequence matching and somatic cell hybrid chromosomal assignment

    PMID:3460076

    Open questions at the time
    • No information on subunit stoichiometry or assembly
    • Catalytic mechanism not addressed beyond EC assignment
  2. 1993 High

    Defined the full-length beta-PCC precursor sequence and demonstrated that splicing mutations abolish functional enzyme, linking PCCB lesions to propionic acidemia at the mRNA and genomic level.

    Evidence Full-length cDNA cloning and sequencing of RT-PCR and genomic DNA products from a PA patient

    PMID:8225321

    Open questions at the time
    • Single patient splice defect; spectrum of mutation types not surveyed
    • No structural mapping of the encoded protein
  3. 1999 High

    Showed that PCC is a dodecameric alpha-beta heteropolymer and that PCCB versus PCCA mutations differ in their effects on subunit stability, establishing distinct subunit interdependencies.

    Evidence Western blot, Northern blot, complementation across patient cell lines

    PMID:10502773

    Open questions at the time
    • Which protein domains mediate assembly not yet mapped
    • Mechanism of differential subunit stability unresolved
  4. 2001 High

    Localized the assembly determinants within the beta subunit, distinguishing C-terminal mutations that directly block assembly from N-terminal mutations acting as folding defects.

    Evidence Mammalian two-hybrid assay at two temperatures with site-directed mutants

    PMID:11749052

    Open questions at the time
    • No atomic structure of the assembly interface
    • Two-hybrid readout is indirect for in vivo dodecamer formation
  5. 2003 High

    Distinguished catalytic loss from protein-instability mechanisms across many PCCB variants, refining genotype-to-mechanism interpretation.

    Evidence Transient expression of 18 variants in PCCB-deficient fibroblasts with activity and stability readouts

    PMID:12757933

    Open questions at the time
    • Does not resolve structural basis of catalytic loss for individual residues
    • Folding/degradation pathway not defined
  6. 2017 High

    Demonstrated that PCCB loss disrupts mitochondrial energy metabolism broadly, beyond simple propionyl-CoA accumulation, including OXPHOS capacity and distal TCA flux.

    Evidence Genetic deletion of C. elegans pccb-1 with polarography, 13C-glucose GC/MS flux analysis, and lifespan assays

    PMID:29159707

    Open questions at the time
    • Ortholog model; human relevance inferred
    • Mechanism linking propionyl-CoA buildup to TCA inhibition not directly traced
  7. 2023 Medium

    Connected PCCB-dependent mitochondrial metabolism to GABAergic neurotransmission and neural network activity, offering a mechanistic basis for neurological phenotypes.

    Evidence shRNA knockdown in human forebrain organoids with RNA-seq, metabolomics, mitochondrial assays, and multielectrode array recording

    PMID:37620341

    Open questions at the time
    • Link is correlative via knockdown rather than reconstitution
    • Causal step from TCA flux to GABA synthesis not isolated
  8. 2023 Medium

    Validated additional novel PCCB variants as loss-of-function via direct reconstitution, supporting clinical interpretation of compound lesions.

    Evidence Eukaryotic expression of p.G246del and p.S322F with PCC activity and Western blot stability readouts

    PMID:37839763

    Open questions at the time
    • Single lab, only two variants
    • Structural impact on the enzyme not modeled
  9. 2024 Medium

    Identified a regulatory mechanism controlling PCC activity, showing PPDPF binds PCCA and blocks PCCA-PCCB interaction to suppress methionine catabolism.

    Evidence Mass spectrometry interaction screen and PPDPF knockdown metabolomics in esophageal squamous cell carcinoma cells

    PMID:39694223

    Open questions at the time
    • Mechanism of PCCB displacement inferred, not shown by reconstitution
    • PPDPF binds PCCA; direct PCCB contact not demonstrated

Open questions

Synthesis pass · forward-looking unresolved questions
  • The atomic structure of the assembled human PCC dodecamer and the precise residue-level basis by which beta-subunit mutations and PPDPF regulate alpha-beta assembly remain unresolved.
  • No high-resolution structure of the assembly interface in the corpus
  • Direct biochemical reconstitution of PPDPF-mediated disassembly absent

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016874 ligase activity 3 GO:0016740 transferase activity 1
Localization
GO:0005739 mitochondrion 2
Pathway
R-HSA-1430728 Metabolism 2
Partners
PCCAPPDPF
Complex memberships
propionyl-CoA carboxylase (PCC)

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1986 PCCB encodes the beta subunit of propionyl-CoA carboxylase (PCC), a biotin-dependent enzyme (EC 6.4.1.3) that catalyzes carboxylation of propionyl-CoA; the beta-chain cDNA was isolated and confirmed to encode beta-PCC by peptide sequence matching, and the PCCB gene was chromosomally assigned to chromosome 3 by somatic cell hybrid analysis. cDNA cloning, oligonucleotide probing, peptide sequencing, somatic cell hybrid panel blot hybridization Proceedings of the National Academy of Sciences of the United States of America High 3460076
1993 The beta-PCC precursor cDNA encodes a polypeptide of 539 amino acids (molecular mass ~58,202 Da) sharing 91% amino acid identity with rat beta-PCC; an 8-bp intronic deletion disrupts the 5' splice signal, causing exon skipping in a PA patient, establishing that splicing mutations in PCCB can abolish functional enzyme. cDNA cloning, sequencing of RT-PCR products, genomic DNA PCR sequencing Human genetics High 8225321
1999 PCC is a dodecameric heteropolymeric mitochondrial enzyme composed of alpha (PCCA-encoded) and beta (PCCB-encoded) subunits; PCCB mutations cause loss of beta-PCC subunit detectable by Western blot, while many PCCA mutations lead to combined absence of both subunits, establishing distinct subunit-stability dependencies. Western blot, complementation assay, Northern blot, RT-PCR sequencing Human mutation High 10502773
2001 Mutations in the C-terminal region of PCCB (R512C, L519P, W531X, N536D) directly inhibit alpha-beta heteromeric and/or beta-beta homomeric assembly of PCC at both normal and reduced temperatures, indicating a primary structural role of the C-terminus in subunit assembly; N-terminal mutations (R67S, S106R, G131D, R165W, E168K, G198D) impair assembly only at elevated temperature, suggesting they act as folding defects that indirectly disrupt assembly. Mammalian two-hybrid system assay at two temperatures, site-directed mutagenesis Molecular genetics and metabolism High 11749052
2003 Expression of 18 PCCB missense variants in PCCB-deficient human fibroblasts showed: L17M and A497V substitutions retain wild-type PCC activity (non-pathogenic); K218R, R410W and N536D retain substantial residual activity; 13 others show null/very low activity; L519P, R512C and G112D mutations cause beta-PCC protein instability by Western blot, establishing that most PCCB pathogenic variants abolish activity with a subset also destabilizing the protein. Transient transfection of PCCB-deficient fibroblasts, PCC enzyme activity assay, Western blot protein stability analysis Biochimica et biophysica acta High 12757933
2017 Deletion of the C. elegans pccb-1 gene (ortholog of PCCB) globally impairs mitochondrial oxidative phosphorylation capacity and efficiency (measured by direct polarography of isolated mitochondria), inhibits distal TCA cycle flux (reduced +1 malate by GC/MS with 13C-glucose), and reduces animal lifespan, establishing that PCCB/pccb-1 loss disrupts mitochondrial energy metabolism beyond simple propionyl-CoA accumulation. Genetic deletion, direct polarography of isolated mitochondria, GC/MS isotopic flux analysis with 13C-glucose, lifespan assay, UPLC amino acid profiling Journal of inherited metabolic disease High 29159707
2023 PCCB knockdown in human forebrain organoids reduces TCA cycle activity, resulting in decreased GABA levels (confirmed by metabolomics), and dysregulates GABAergic synapse gene networks; multielectrode array recording showed PCCB-knockdown organoids exhibit hyper-neuroactivity and decreased neural network synchronization, establishing a functional link between PCCB-dependent mitochondrial metabolism and GABAergic pathway activity. shRNA knockdown in human forebrain organoids, RNA sequencing, metabolomics, mitochondrial function assays, multielectrode array recording Nature communications Medium 37620341
2024 PPDPF protein interacts with PCCA (the alpha subunit of PCC) as identified by mass spectrometry, and PPDPF inhibits the interaction between PCCA and PCCB, thereby suppressing PCC-mediated methionine catabolism and elevating methionine and SAM levels in esophageal squamous cell carcinoma cells. Mass spectrometry interaction screen, co-immunoprecipitation (implied by interaction identification), PPDPF knockdown metabolomics Cancer letters Medium 39694223
2023 Two novel PCCB missense/deletion variants (p.G246del and p.S322F) identified in cis in a PA patient each individually reduce PCC enzyme activity and/or beta-PCC protein levels when expressed in a eukaryotic system; the double mutant shows no residual PCC activity, confirming both variants are pathogenic loss-of-function changes affecting protein stability or catalytic function. Eukaryotic expression system, PCC enzyme activity assay, Western blot for protein levels Gene Medium 37839763

Source papers

Stage 0 corpus · 35 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1986 Isolation of cDNA clones coding for the alpha and beta chains of human propionyl-CoA carboxylase: chromosomal assignments and DNA polymorphisms associated with PCCA and PCCB genes. Proceedings of the National Academy of Sciences of the United States of America 110 3460076
1999 Overview of mutations in the PCCA and PCCB genes causing propionic acidemia. Human mutation 70 10502773
2023 Human forebrain organoid-based multi-omics analyses of PCCB as a schizophrenia associated gene linked to GABAergic pathways. Nature communications 34 37620341
2004 Mutation spectrum of the PCCA and PCCB genes in Japanese patients with propionic acidemia. Molecular genetics and metabolism 31 15059621
2003 Functional analysis of PCCB mutations causing propionic acidemia based on expression studies in deficient human skin fibroblasts. Biochimica et biophysica acta 30 12757933
1990 Two distinct mutations at the same site in the PCCB gene in propionic acidemia. Genomics 27 2249848
1993 Three independent mutations in the same exon of the PCCB gene: differences between Caucasian and Japanese propionic acidaemia. Journal of inherited metabolic disease 24 8411997
2001 Effect of PCCB gene mutations on the heteromeric and homomeric assembly of propionyl-CoA carboxylase. Molecular genetics and metabolism 21 11749052
1993 The molecular defect in propionic acidemia: exon skipping caused by an 8-bp deletion from an intron in the PCCB allele. Human genetics 18 8225321
2017 Propionyl-CoA carboxylase pcca-1 and pccb-1 gene deletions in Caenorhabditis elegans globally impair mitochondrial energy metabolism. Journal of inherited metabolic disease 17 29159707
2002 Molecular analysis of PCCB gene in Korean patients with propionic acidemia. Molecular genetics and metabolism 15 12409268
2016 Seventeen Novel Mutations in PCCA and PCCB Genes in Indian Propionic Acidemia Patients, and Their Outcomes. Genetic testing and molecular biomarkers 11 27227689
2002 Transfection screening for defects in the PCCA and PCCB genes encoding propionyl-CoA carboxylase subunits. Molecular genetics and metabolism 8 11914040
1995 A novel splicing mutation in propionic acidemia associated with a tetranucleotide direct repeat in the PCCB gene. Human genetics 8 7789958
1999 Identification of novel mutations in the PCCB gene in European propionic acidemia patients. Mutation in brief no. 253. Online. Human mutation 7 10447268
2022 Case Report: Novel Mutations in the PCCB Gene Causing Late-Onset Propionic Acidemia. Frontiers in genetics 6 35368667
2021 Functional Analysis of the PCCA and PCCB Gene Variants Predicted to Affect Splicing. International journal of molecular sciences 6 33923806
2019 Generation and characterization of a human iPSC line (UAMi004-A) from a patient with propionic acidemia due to defects in the PCCB gene. Stem cell research 6 31132581
2015 [Analysis of PCCA and PCCB gene mutations in patients with propionic acidemia]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 6 25636094
2022 Novel compound heterozygous variants in the PCCB gene causing adult-onset propionic acidemia presenting with neuropsychiatric symptoms: a case report and literature review. BMC medical genomics 5 35296328
2001 cDNA cloning, mapping and expression of the mouse propionyl CoA carboxylase beta (pccb), the gene for human type II propionic acidaemia. Gene 5 11245989
2020 Generation of a gene-corrected human isogenic line (UAMi006-A) from propionic acidemia patient iPSC with an homozygous mutation in the PCCB gene using CRISPR/Cas9 technology. Stem cell research 4 33128956
2021 Novel variants of the PCCB gene in Chinese patients with propionic acidemia. Clinica chimica acta; international journal of clinical chemistry 3 33798502
2020 Case reports: three novel variants in PCCA and PCCB genes in Chinese patients with propionic acidemia. BMC medical genetics 3 32252659
2020 Biochemical phenotype and its relationship to treatment in 16 individuals with PCCB c.1606A > G (p.Asn536Asp) variant propionic acidemia. Molecular genetics and metabolism 3 33127324
2015 A novel PCCB mutation in a Thai patient with propionic acidemia identified by exome sequencing. Human genome variation 3 27081542
2023 A common benign intronic deletion masking a pathogenic deep intronic PCCB variant - genome sequencing and RNA studies to the rescue. Molecular genetics and metabolism 2 37776842
2025 Novel CRISPR-Cas9 iPSC knockouts for PCCA and PCCB genes: advancing propionic acidemia research. Human cell 1 40044943
2023 Human forebrain organoids-based multi-omics analyses reveal PCCB's regulation on GABAergic system contributing to schizophrenia. Research square 1 37034773
2023 Functional analysis of novel variants identified in cis in the PCCB gene in a patient with propionic acidemia. Gene 1 37839763
2021 [Identification of two novel variants of the PCCB gene in a pedigree affected with propionic acidemia]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 1 33751535
2020 Generation of isogenic Propionyl-CoA carboxylase beta subunit (PCCB) deficient induced pluripotent stem cell lines. Stem cell research 1 32822967
2026 Identification of novel compound heterozygote variants in the PCCB gene in a fetus with undetectable fetal phenotype. BMC medical genomics 0 41776507
2024 Establishment of a non-integrated iPSC line (SDQLCHi043-A) from a male infant with propionic acidemia carrying compound heterozygote mutations in PCCB gene. Stem cell research 0 38394970
2024 PPDPF promotes esophageal squamous cell carcinoma progression by blocking PCCA binding to PCCB and inhibiting methionine catabolism. Cancer letters 0 39694223

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