{"gene":"PCCA","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":1986,"finding":"PCCA encodes the alpha subunit of propionyl-CoA carboxylase (PCC), a biotin-dependent enzyme. The alpha subunit contains the covalently bound biotin prosthetic group and the biotin-binding domain, as confirmed by the presence of the Ala-Met-Lys-Met sequence (biotin binding site conserved across biotin-dependent carboxylases) in PCCA cDNA clones. The PCCA gene was chromosomally mapped to chromosome 13 using somatic mouse-human hybrid panels.","method":"cDNA cloning, oligonucleotide probing, somatic cell hybrid panel mapping, Northern blot","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct cDNA cloning with sequence confirmation of biotin-binding domain, chromosomal mapping replicated and foundational","pmids":["3460076"],"is_preprint":false},{"year":1987,"finding":"In pccA complementation group patients (PCCA-deficient), alpha-chain mRNA is absent in most fibroblast strains, while beta-chain mRNA is present. The beta subunit (PCCB) is rapidly degraded in the absence of the alpha subunit, indicating that alpha-beta subunit interaction is required for stabilization of the beta chain. This confirms that PCCA encodes the alpha subunit of PCC.","method":"Northern blot with PCCA and PCCB cDNA probes, isotope-tracer labeling and immunoprecipitation of fibroblast extracts","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal mRNA and protein analyses across multiple patient cell lines, replicated across complementation groups","pmids":["3687944"],"is_preprint":false},{"year":1993,"finding":"Full-length PCCA cDNA, when expressed by DNA-mediated gene transfer in pccA-deficient fibroblasts, reconstitutes propionate flux to normal levels, confirming that PCCA alone is sufficient to rescue the enzymatic defect. Maximum PCC holoenzyme activity upon PCCA expression reached only 10-20% of normal controls (corresponding to transfected cell fraction), indicating PCCA expression level does not normally limit PCC holoenzyme activity or propionate flux.","method":"cDNA expression (gene transfer), propionate flux assay, PCC holoenzyme activity measurement in fibroblasts","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 1 / Moderate — functional reconstitution in patient-derived deficient cells, two independent constructs tested, multiple assays","pmids":["8434582"],"is_preprint":false},{"year":1999,"finding":"PCCA is a mitochondrial heteropolymeric enzyme composed of alpha and beta subunits (encoded by PCCA and PCCB genes, respectively), involved in catabolism of branched-chain amino acids, odd-chain fatty acids, cholesterol, and other metabolites. In PCCA patients, combined absence of both alpha and beta subunits is observed by Western blot, indicating that the alpha subunit is required for stability of the assembled complex.","method":"Western blot, complementation assay, Northern blot, RT-PCR of patient fibroblasts","journal":"Human mutation","confidence":"High","confidence_rationale":"Tier 2 / Strong — multi-lab replication of subunit co-dependency, multiple orthogonal methods across large patient cohort","pmids":["10502773"],"is_preprint":false},{"year":1999,"finding":"The PCCA pre-mRNA contains a constitutive 84-bp cryptic (pseudo)exon derived from an intron between nucleotides 1209 and 1210. This cryptic exon is normally present at very low levels in all cells but becomes relatively detectable when the normal-length mRNA is destabilized by nonsense or frameshift mutations (R288X, 700del5, 1115del4, 1671IVS+5G->C). Incorporation of the 84-bp insertion causes translation termination via two in-frame stop codons.","method":"RT-PCR, sequencing, comparative analysis of patient and normal fibroblast cell lines","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Moderate — RT-PCR with sequencing across 12 cell lines plus normal controls, mechanism of cryptic exon activation characterized","pmids":["9887338"],"is_preprint":false},{"year":2001,"finding":"The PCCA gene spans more than 360 kb, consists of 24 exons (37–335 bp each), and the translation initiation codon is located 75 nucleotides upstream of the previously accepted site. The 5'-flanking region contains a putative CpG island (extending into exon 1 and part of intron 1), lacks a TATA box, but contains AP-1 sites and a consensus Sp1 (GC box) binding sequence in the proximal promoter.","method":"EST analysis, RT-PCR, genomic sequencing, promoter sequence analysis","journal":"Molecular genetics and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct genomic sequencing with RT-PCR confirmation of new translation start site; promoter characterization is sequence-based without functional reporter assay","pmids":["11592820"],"is_preprint":false},{"year":2002,"finding":"Eleven PCCA missense mutations and one in-frame deletion, when expressed in patient fibroblasts and in a cell-free in vitro system, result in reduced PCC enzyme activity and increased protein turnover/instability. Most mutant proteins show an increased rate of degradation, indicating structural alterations incompatible with normal assembly into a stable, functional PCC oligomer.","method":"Expression in deficient fibroblasts, cell-free in vitro expression, PCC activity assay, protein stability assessment","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution plus cellular expression for 11 mutations, activity and stability assayed by orthogonal methods","pmids":["12385775"],"is_preprint":false},{"year":2009,"finding":"Large genomic deletions in the PCCA gene (including frequent deletions of exons 3-4 and exon 23) cause propionic acidemia. A deletion of exons 3 and 4 results in an in-frame deletion of 39 amino acids; this in-frame deletion was expressed in a eukaryotic system and confirmed as pathogenic (loss of PCC activity). The high frequency of large deletions may be due to the abundance of intronic repetitive elements in the PCCA gene.","method":"MLPA, long-PCR, eukaryotic expression system, PCC activity assay","journal":"Molecular genetics and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MLPA for deletion detection, confirmed pathogenicity by eukaryotic expression with activity assay","pmids":["19157943"],"is_preprint":false},{"year":2017,"finding":"In C. elegans, deletion of pcca-1 (ortholog of human PCCA) globally impairs mitochondrial energy metabolism: reduces mitochondrial oxidative phosphorylation capacity and efficiency, increases mitochondrial matrix oxidant burden, decreases mitochondrial membrane potential and content, and inhibits distal TCA cycle flux. These findings indicate that PCC/PCCA deficiency causes broader metabolic dysfunction beyond toxic propionyl-CoA precursor accumulation.","method":"C. elegans gene deletion, direct polarography of isolated mitochondria, in vivo mitochondrial physiology quantitation, UPLC amino acid profiling, GC/MS with 13C-glucose metabolic flux analysis","journal":"Journal of inherited metabolic disease","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal metabolic and mitochondrial assays in a defined genetic deletion model, quantitative phenotyping","pmids":["29159707"],"is_preprint":false},{"year":2021,"finding":"Twenty-four variants in PCCA (and PCCB) genes predicted to affect splicing were tested by minigene splicing assay; 13 variants (including one missense and two synonymous variants) caused significant alteration of splicing with predicted loss-of-function at the protein level, confirming their pathogenic mechanism via aberrant PCCA pre-mRNA splicing.","method":"Minigene splicing assay, RT-PCR, sequencing","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional splicing assay for multiple variants, single lab, orthogonal validation by sequencing","pmids":["33923806"],"is_preprint":false},{"year":2024,"finding":"PCCA (mitochondrial carboxylase) physically interacts with and colocalizes with Listeria monocytogenes phospholipase PlcB within host cells. The amino acids 504–508 of PCCA are critical for this interaction. Overexpression of PCCA (via pCMV-N-HA-PCCA plasmid) reduces L. monocytogenes proliferation, while siRNA knockdown of PCCA increases bacterial proliferation, demonstrating an inverse correlation between PCCA levels and bacterial survival. L. monocytogenes infection does not significantly alter PCCA expression levels.","method":"Co-immunoprecipitation/colocalization, siRNA knockdown, plasmid overexpression, bacterial proliferation assay, mRNA/protein expression analysis in HeLa cells","journal":"Applied and environmental microbiology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP/colocalization plus functional knockdown/overexpression in same study, single lab, novel interaction identified","pmids":["38727222"],"is_preprint":false},{"year":2024,"finding":"PPDPF (pancreatic progenitor cell differentiation and proliferation factor) interacts with PCCA (identified by mass spectrometry) and blocks the interaction between PCCA and its partner subunit PCCB, thereby inhibiting PCC-dependent methionine catabolism via the C-Vomit pathway. This leads to elevated intracellular methionine and S-adenosylmethionine (SAM) levels and promotes esophageal squamous cell carcinoma progression.","method":"Mass spectrometry interaction screen, co-immunoprecipitation, metabolite measurement (methionine, SAM), PPDPF knockdown in vivo and in vitro","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mass spectrometry plus Co-IP to identify interaction; functional consequence (inhibition of PCCA-PCCB interaction and methionine levels) shown in vivo and in vitro, single lab","pmids":["39694223"],"is_preprint":false},{"year":2025,"finding":"lncBADR binds directly to PCCA (and Mccc1) in T cells, inhibiting BCAA degradation. Knockout of lncBADR in T cells restores PCCA-mediated BCAA catabolism, decreasing intracellular BCAA levels and reducing mTOR-Stat1 signaling and IFN-γ secretion. High-BCAA feeding partially reversed the protective effects of lncBADR knockout, confirming that lncBADR acts through PCCA-dependent BCAA metabolism.","method":"T cell-specific lncBADR knockout mice, RNA binding assays, metabolite profiling, mTOR-Stat1 pathway analysis, IFN-γ measurement, rescue experiment (high-BCAA feeding)","journal":"Journal of neuroinflammation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with multiple pathway readouts and rescue experiment, single lab; direct binding of lncBADR to PCCA reported but detailed binding mechanism not fully characterized in abstract","pmids":["41013574"],"is_preprint":false},{"year":2024,"finding":"In Pcca-/-(A138T) mice (a propionic acidemia model), fasting reduces propionylcarnitine, the C3/C2 ratio, ammonia, and methylcitrate. This is attributed to significant reduction in microbiome-produced propionate and increased fatty acid oxidation (decreasing propionyl-CoA synthesis and enhancing acetyl-CoA synthesis) during fasting. Fasting-induced gluconeogenesis further facilitates propionyl-CoA catabolism without changing propionyl-CoA carboxylase activity.","method":"Pcca mutant mouse model, metabolite profiling (propionylcarnitine, C3/C2, ammonia, methylcitrate), measurement of PCC enzymatic activity, assessment of microbiome-derived propionate","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined genetic mouse model with multiple metabolic measurements, mechanistic pathway dissection, single lab","pmids":["38811689"],"is_preprint":false},{"year":2026,"finding":"A deep-intronic PCCA variant (c.1285-1358C>G) causes constitutive inclusion of the known 84-bp pseudoexon in PCCA mRNA, abolishing functional PCCA and PCCB protein expression and severely reducing PCC activity. Antisense oligonucleotides (ASOs) targeting this pseudoexon restore productive PCCA splicing, rescue PCCA protein expression, and markedly increase PCC activity above wild-type levels in patient fibroblasts. ASO treatment was also effective in other PA fibroblast lines with residual activity >1% of normal.","method":"Patient fibroblast analysis, RT-PCR/sequencing, ASO transfection, PCC enzymatic activity assay, protein expression analysis","journal":"Molecular therapy. Nucleic acids","confidence":"High","confidence_rationale":"Tier 1 / Moderate — functional rescue by ASOs with quantitative enzymatic activity and protein expression readouts in patient fibroblasts, validated across 8 cell lines","pmids":["42028575"],"is_preprint":false}],"current_model":"PCCA encodes the alpha subunit of mitochondrial propionyl-CoA carboxylase (PCC), a biotin-dependent enzyme that catalyzes ATP-dependent carboxylation of propionyl-CoA to D-methylmalonyl-CoA in the catabolism of branched-chain amino acids, odd-chain fatty acids, and related metabolites; the alpha subunit harbors the covalently bound biotin prosthetic group and is required for assembly and stabilization of the functional heteromeric (alpha/beta) PCC oligomer, such that loss of PCCA destabilizes the beta subunit (PCCB) and abolishes activity, while PCCA expression levels are also regulated post-transcriptionally through a constitutive 84-bp cryptic pseudoexon and at the protein level through interaction with partners including lncBADR and the bacterial virulence factor PlcB."},"narrative":{"mechanistic_narrative":"PCCA encodes the alpha subunit of mitochondrial propionyl-CoA carboxylase (PCC), a biotin-dependent enzyme that carboxylates propionyl-CoA in the catabolism of branched-chain amino acids, odd-chain fatty acids, cholesterol, and related metabolites [PMID:3460076, PMID:10502773]. The alpha subunit carries the covalently bound biotin prosthetic group, identified by the conserved Ala-Met-Lys-Met biotin-binding motif in PCCA cDNA [PMID:3460076]. PCCA assembles with the beta subunit (PCCB) into a heteromeric holoenzyme, and the alpha subunit is required to stabilize this complex: in PCCA-deficient patients PCCB is rapidly degraded and both subunits are absent, while re-expression of PCCA alone restores propionate flux in deficient fibroblasts [PMID:3687944, PMID:8434582, PMID:10502773]. Most disease-causing missense and in-frame deletion mutations destabilize the protein and accelerate its turnover, indicating structural alterations incompatible with assembly into a stable, active oligomer [PMID:12385775, PMID:19157943]. Loss of PCCA propagates beyond toxic propionyl-CoA accumulation to broad mitochondrial dysfunction, impairing oxidative phosphorylation, membrane potential, and distal TCA cycle flux [PMID:29159707]. PCCA expression is shaped post-transcriptionally by a constitutive 84-bp cryptic pseudoexon whose inclusion introduces in-frame stop codons; a deep-intronic variant driving constitutive pseudoexon inclusion abolishes PCC activity and is correctable by antisense oligonucleotides that restore productive splicing [PMID:9887338, PMID:42028575]. PCC-dependent catabolism is further modulated through partner binding: PPDPF and the lncRNA lncBADR each interfere with PCCA-mediated substrate degradation to elevate methionine/SAM or BCAA levels respectively [PMID:39694223, PMID:41013574], and PCCA additionally interacts with the Listeria monocytogenes phospholipase PlcB to restrict bacterial proliferation [PMID:38727222]. Mutations and large genomic deletions in PCCA cause propionic acidemia [PMID:19157943, PMID:42028575].","teleology":[{"year":1986,"claim":"Established that PCCA is the gene for the alpha subunit of propionyl-CoA carboxylase and the carrier of the biotin prosthetic group, fixing its molecular identity.","evidence":"cDNA cloning with sequence identification of the conserved biotin-binding motif and somatic cell hybrid chromosomal mapping","pmids":["3460076"],"confidence":"High","gaps":["No structural model of the holoenzyme","Catalytic mechanism inferred from family motif rather than directly assayed"]},{"year":1987,"claim":"Showed the alpha subunit is required to stabilize the beta subunit, establishing subunit interdependence as central to PCC assembly.","evidence":"Northern blot and pulse-labeling/immunoprecipitation across PCCA-deficient patient fibroblast strains","pmids":["3687944"],"confidence":"High","gaps":["Stoichiometry of alpha/beta assembly not defined","Mechanism of PCCB degradation not identified"]},{"year":1993,"claim":"Demonstrated PCCA alone is sufficient to rescue the propionate-flux defect, and that its expression level does not normally limit holoenzyme activity.","evidence":"cDNA gene transfer into deficient fibroblasts with propionate flux and holoenzyme activity assays","pmids":["8434582"],"confidence":"High","gaps":["Did not address rate-limiting steps under physiological conditions","Partial rescue limited by transfection efficiency"]},{"year":1999,"claim":"Resolved that loss of PCCA destabilizes the entire assembled complex and identified a constitutive cryptic pseudoexon that modulates productive mRNA, linking genotype to protein loss and to a splicing-based regulatory feature.","evidence":"Western blot, RT-PCR and complementation across patient cohorts plus RT-PCR/sequencing characterization of the 84-bp pseudoexon","pmids":["10502773","9887338"],"confidence":"High","gaps":["Trans-factors regulating pseudoexon inclusion not identified","Physiological role of low-level pseudoexon inclusion unclear"]},{"year":2002,"claim":"Defined the dominant mechanism by which missense/in-frame mutations cause disease: protein destabilization and accelerated turnover preventing stable oligomer assembly.","evidence":"Expression of 11 mutations in deficient fibroblasts and cell-free systems with activity and stability assays","pmids":["12385775"],"confidence":"High","gaps":["Degradation pathway/protease not identified","No structural rationale for individual destabilizing mutations"]},{"year":2009,"claim":"Identified large genomic deletions as a frequent pathogenic mechanism and confirmed an exon 3-4 in-frame deletion abolishes activity.","evidence":"MLPA, long-PCR, and eukaryotic expression with PCC activity assay","pmids":["19157943"],"confidence":"Medium","gaps":["Repeat-mediated deletion mechanism inferred from sequence context, not directly demonstrated"]},{"year":2017,"claim":"Showed that PCCA deficiency causes broad mitochondrial energetic failure beyond precursor toxicity, reframing propionic acidemia as a mitochondrial disorder.","evidence":"C. elegans pcca-1 deletion with polarography, in vivo mitochondrial physiology, and 13C metabolic flux analysis","pmids":["29159707"],"confidence":"High","gaps":["Mechanistic link between propionyl-CoA accumulation and OXPHOS impairment not fully resolved","Mammalian confirmation of all phenotypes pending"]},{"year":2021,"claim":"Established aberrant pre-mRNA splicing as a distinct pathogenic mechanism, including for synonymous and missense variants.","evidence":"Minigene splicing assays with RT-PCR/sequencing for 24 variants","pmids":["33923806"],"confidence":"Medium","gaps":["Minigene context may not fully reflect endogenous splicing","Protein-level consequences predicted rather than measured"]},{"year":2024,"claim":"Revealed PCCA as a node controlled by protein and RNA partners and engaged in host-pathogen defense, expanding its biology beyond canonical metabolism.","evidence":"Mass spectrometry/Co-IP identifying PPDPF blocking PCCA-PCCB interaction; Co-IP/colocalization with Listeria PlcB plus knockdown/overexpression proliferation assays; metabolite profiling","pmids":["39694223","38727222"],"confidence":"Medium","gaps":["Structural basis of partner interactions not defined","Single-lab findings without reciprocal/independent validation","Whether PlcB interaction depends on PCC catalytic function unknown"]},{"year":2024,"claim":"Demonstrated that dietary and metabolic state modulate the disease phenotype independent of residual enzyme activity, via substrate supply.","evidence":"Pcca-/-(A138T) propionic acidemia mouse model with metabolite profiling and PCC activity measurement during fasting","pmids":["38811689"],"confidence":"Medium","gaps":["Microbiome contribution inferred, not directly manipulated","Translation to patient dietary management not established"]},{"year":2025,"claim":"Showed lncBADR directly binds PCCA to suppress BCAA catabolism in T cells, coupling PCCA metabolic activity to mTOR-Stat1 immune signaling.","evidence":"T cell-specific lncBADR knockout mice, RNA binding assays, metabolite profiling, and high-BCAA rescue feeding","pmids":["41013574"],"confidence":"Medium","gaps":["Detailed lncBADR-PCCA binding interface not characterized","Single-lab finding"]},{"year":2026,"claim":"Provided a therapeutic proof-of-concept by correcting pseudoexon-driven loss of function, validating the cryptic exon as a splice-modulation target.","evidence":"Patient fibroblast analysis of a deep-intronic variant and antisense oligonucleotide rescue with enzymatic activity and protein expression readouts across cell lines","pmids":["42028575"],"confidence":"High","gaps":["In vivo/clinical efficacy not established","Applicability limited to lines with residual activity >1%"]},{"year":null,"claim":"The structural basis of alpha/beta holoenzyme assembly and how diverse partner interactions (PPDPF, lncBADR, PlcB) mechanistically reroute substrate flux remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No high-resolution structure of human PCC in the timeline","Partner-binding interfaces and competitive mechanisms only partially mapped","Causal link between propionyl-CoA accumulation and broad mitochondrial dysfunction not fully defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,2,6]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0]},{"term_id":"GO:0016829","term_label":"lyase activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[3,8]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[3,8,13]}],"complexes":["propionyl-CoA carboxylase (PCC) holoenzyme"],"partners":["PCCB","PPDPF","LNCBADR","PLCB"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P05165","full_name":"Propionyl-CoA carboxylase alpha chain, mitochondrial","aliases":["Propanoyl-CoA:carbon dioxide ligase subunit alpha"],"length_aa":728,"mass_kda":80.1,"function":"This is one of the 2 subunits of the biotin-dependent propionyl-CoA carboxylase (PCC), a mitochondrial enzyme involved in the catabolism of odd chain fatty acids, branched-chain amino acids isoleucine, threonine, methionine, and valine and other metabolites (PubMed:6765947, PubMed:8434582). Propionyl-CoA carboxylase catalyzes the carboxylation of propionyl-CoA/propanoyl-CoA to D-methylmalonyl-CoA/(S)-methylmalonyl-CoA (PubMed:10101253, PubMed:6765947, PubMed:8434582). Within the holoenzyme, the alpha subunit catalyzes the ATP-dependent carboxylation of the biotin carried by the biotin carboxyl carrier (BCC) domain, while the beta subunit then transfers the carboxyl group from carboxylated biotin to propionyl-CoA (By similarity). Propionyl-CoA carboxylase also significantly acts on butyryl-CoA/butanoyl-CoA, which is converted to ethylmalonyl-CoA/(2S)-ethylmalonyl-CoA at a much lower rate (PubMed:6765947). Other alternative minor substrates include (2E)-butenoyl-CoA/crotonoyl-CoA (By similarity)","subcellular_location":"Mitochondrion matrix","url":"https://www.uniprot.org/uniprotkb/P05165/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PCCA","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PCCA","total_profiled":1310},"omim":[{"mim_id":"617655","title":"PECANEX 1; PCNX1","url":"https://www.omim.org/entry/617655"},{"mim_id":"617504","title":"SIPA1-LIKE PROTEIN 1; SIPA1L1","url":"https://www.omim.org/entry/617504"},{"mim_id":"615751","title":"CARBONIC ANHYDRASE VA DEFICIENCY, HYPERAMMONEMIA DUE TO; CA5AD","url":"https://www.omim.org/entry/615751"},{"mim_id":"613811","title":"PONTOCEREBELLAR HYPOPLASIA, TYPE 2D; PCH2D","url":"https://www.omim.org/entry/613811"},{"mim_id":"609058","title":"METHYLMALONYL-CoA MUTASE; MMUT","url":"https://www.omim.org/entry/609058"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Mitochondria","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"epididymis","ntpm":206.3}],"url":"https://www.proteinatlas.org/search/PCCA"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P05165","domains":[{"cath_id":"3.40.50.20","chopping":"66-165","consensus_level":"high","plddt":96.9238,"start":66,"end":165},{"cath_id":"3.30.470.20","chopping":"168-193_269-392","consensus_level":"medium","plddt":95.3398,"start":168,"end":392},{"cath_id":"3.30.1490.20","chopping":"195-263","consensus_level":"high","plddt":85.5157,"start":195,"end":263},{"cath_id":"3.30.470.20","chopping":"394-508","consensus_level":"medium","plddt":94.9285,"start":394,"end":508},{"cath_id":"3.30.700.30","chopping":"520-542_557-649","consensus_level":"high","plddt":93.8295,"start":520,"end":649},{"cath_id":"2.40.50.100","chopping":"662-728","consensus_level":"high","plddt":87.3594,"start":662,"end":728}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P05165","model_url":"https://alphafold.ebi.ac.uk/files/AF-P05165-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P05165-F1-predicted_aligned_error_v6.png","plddt_mean":87.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PCCA","jax_strain_url":"https://www.jax.org/strain/search?query=PCCA"},"sequence":{"accession":"P05165","fasta_url":"https://rest.uniprot.org/uniprotkb/P05165.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P05165/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P05165"}},"corpus_meta":[{"pmid":"3460076","id":"PMC_3460076","title":"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.","date":"1986","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/3460076","citation_count":110,"is_preprint":false},{"pmid":"10502773","id":"PMC_10502773","title":"Overview of mutations in the PCCA and PCCB genes causing propionic acidemia.","date":"1999","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/10502773","citation_count":70,"is_preprint":false},{"pmid":"11592820","id":"PMC_11592820","title":"Structure of the PCCA gene and distribution of mutations causing propionic acidemia.","date":"2001","source":"Molecular genetics and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/11592820","citation_count":34,"is_preprint":false},{"pmid":"12385775","id":"PMC_12385775","title":"Functional characterization of PCCA mutations 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The alpha subunit contains the covalently bound biotin prosthetic group and the biotin-binding domain, as confirmed by the presence of the Ala-Met-Lys-Met sequence (biotin binding site conserved across biotin-dependent carboxylases) in PCCA cDNA clones. The PCCA gene was chromosomally mapped to chromosome 13 using somatic mouse-human hybrid panels.\",\n      \"method\": \"cDNA cloning, oligonucleotide probing, somatic cell hybrid panel mapping, Northern blot\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct cDNA cloning with sequence confirmation of biotin-binding domain, chromosomal mapping replicated and foundational\",\n      \"pmids\": [\"3460076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1987,\n      \"finding\": \"In pccA complementation group patients (PCCA-deficient), alpha-chain mRNA is absent in most fibroblast strains, while beta-chain mRNA is present. The beta subunit (PCCB) is rapidly degraded in the absence of the alpha subunit, indicating that alpha-beta subunit interaction is required for stabilization of the beta chain. This confirms that PCCA encodes the alpha subunit of PCC.\",\n      \"method\": \"Northern blot with PCCA and PCCB cDNA probes, isotope-tracer labeling and immunoprecipitation of fibroblast extracts\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal mRNA and protein analyses across multiple patient cell lines, replicated across complementation groups\",\n      \"pmids\": [\"3687944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"Full-length PCCA cDNA, when expressed by DNA-mediated gene transfer in pccA-deficient fibroblasts, reconstitutes propionate flux to normal levels, confirming that PCCA alone is sufficient to rescue the enzymatic defect. Maximum PCC holoenzyme activity upon PCCA expression reached only 10-20% of normal controls (corresponding to transfected cell fraction), indicating PCCA expression level does not normally limit PCC holoenzyme activity or propionate flux.\",\n      \"method\": \"cDNA expression (gene transfer), propionate flux assay, PCC holoenzyme activity measurement in fibroblasts\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — functional reconstitution in patient-derived deficient cells, two independent constructs tested, multiple assays\",\n      \"pmids\": [\"8434582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"PCCA is a mitochondrial heteropolymeric enzyme composed of alpha and beta subunits (encoded by PCCA and PCCB genes, respectively), involved in catabolism of branched-chain amino acids, odd-chain fatty acids, cholesterol, and other metabolites. In PCCA patients, combined absence of both alpha and beta subunits is observed by Western blot, indicating that the alpha subunit is required for stability of the assembled complex.\",\n      \"method\": \"Western blot, complementation assay, Northern blot, RT-PCR of patient fibroblasts\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multi-lab replication of subunit co-dependency, multiple orthogonal methods across large patient cohort\",\n      \"pmids\": [\"10502773\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The PCCA pre-mRNA contains a constitutive 84-bp cryptic (pseudo)exon derived from an intron between nucleotides 1209 and 1210. This cryptic exon is normally present at very low levels in all cells but becomes relatively detectable when the normal-length mRNA is destabilized by nonsense or frameshift mutations (R288X, 700del5, 1115del4, 1671IVS+5G->C). Incorporation of the 84-bp insertion causes translation termination via two in-frame stop codons.\",\n      \"method\": \"RT-PCR, sequencing, comparative analysis of patient and normal fibroblast cell lines\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RT-PCR with sequencing across 12 cell lines plus normal controls, mechanism of cryptic exon activation characterized\",\n      \"pmids\": [\"9887338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The PCCA gene spans more than 360 kb, consists of 24 exons (37–335 bp each), and the translation initiation codon is located 75 nucleotides upstream of the previously accepted site. The 5'-flanking region contains a putative CpG island (extending into exon 1 and part of intron 1), lacks a TATA box, but contains AP-1 sites and a consensus Sp1 (GC box) binding sequence in the proximal promoter.\",\n      \"method\": \"EST analysis, RT-PCR, genomic sequencing, promoter sequence analysis\",\n      \"journal\": \"Molecular genetics and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct genomic sequencing with RT-PCR confirmation of new translation start site; promoter characterization is sequence-based without functional reporter assay\",\n      \"pmids\": [\"11592820\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Eleven PCCA missense mutations and one in-frame deletion, when expressed in patient fibroblasts and in a cell-free in vitro system, result in reduced PCC enzyme activity and increased protein turnover/instability. Most mutant proteins show an increased rate of degradation, indicating structural alterations incompatible with normal assembly into a stable, functional PCC oligomer.\",\n      \"method\": \"Expression in deficient fibroblasts, cell-free in vitro expression, PCC activity assay, protein stability assessment\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution plus cellular expression for 11 mutations, activity and stability assayed by orthogonal methods\",\n      \"pmids\": [\"12385775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Large genomic deletions in the PCCA gene (including frequent deletions of exons 3-4 and exon 23) cause propionic acidemia. A deletion of exons 3 and 4 results in an in-frame deletion of 39 amino acids; this in-frame deletion was expressed in a eukaryotic system and confirmed as pathogenic (loss of PCC activity). The high frequency of large deletions may be due to the abundance of intronic repetitive elements in the PCCA gene.\",\n      \"method\": \"MLPA, long-PCR, eukaryotic expression system, PCC activity assay\",\n      \"journal\": \"Molecular genetics and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MLPA for deletion detection, confirmed pathogenicity by eukaryotic expression with activity assay\",\n      \"pmids\": [\"19157943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In C. elegans, deletion of pcca-1 (ortholog of human PCCA) globally impairs mitochondrial energy metabolism: reduces mitochondrial oxidative phosphorylation capacity and efficiency, increases mitochondrial matrix oxidant burden, decreases mitochondrial membrane potential and content, and inhibits distal TCA cycle flux. These findings indicate that PCC/PCCA deficiency causes broader metabolic dysfunction beyond toxic propionyl-CoA precursor accumulation.\",\n      \"method\": \"C. elegans gene deletion, direct polarography of isolated mitochondria, in vivo mitochondrial physiology quantitation, UPLC amino acid profiling, GC/MS with 13C-glucose metabolic flux analysis\",\n      \"journal\": \"Journal of inherited metabolic disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal metabolic and mitochondrial assays in a defined genetic deletion model, quantitative phenotyping\",\n      \"pmids\": [\"29159707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Twenty-four variants in PCCA (and PCCB) genes predicted to affect splicing were tested by minigene splicing assay; 13 variants (including one missense and two synonymous variants) caused significant alteration of splicing with predicted loss-of-function at the protein level, confirming their pathogenic mechanism via aberrant PCCA pre-mRNA splicing.\",\n      \"method\": \"Minigene splicing assay, RT-PCR, sequencing\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional splicing assay for multiple variants, single lab, orthogonal validation by sequencing\",\n      \"pmids\": [\"33923806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PCCA (mitochondrial carboxylase) physically interacts with and colocalizes with Listeria monocytogenes phospholipase PlcB within host cells. The amino acids 504–508 of PCCA are critical for this interaction. Overexpression of PCCA (via pCMV-N-HA-PCCA plasmid) reduces L. monocytogenes proliferation, while siRNA knockdown of PCCA increases bacterial proliferation, demonstrating an inverse correlation between PCCA levels and bacterial survival. L. monocytogenes infection does not significantly alter PCCA expression levels.\",\n      \"method\": \"Co-immunoprecipitation/colocalization, siRNA knockdown, plasmid overexpression, bacterial proliferation assay, mRNA/protein expression analysis in HeLa cells\",\n      \"journal\": \"Applied and environmental microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP/colocalization plus functional knockdown/overexpression in same study, single lab, novel interaction identified\",\n      \"pmids\": [\"38727222\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PPDPF (pancreatic progenitor cell differentiation and proliferation factor) interacts with PCCA (identified by mass spectrometry) and blocks the interaction between PCCA and its partner subunit PCCB, thereby inhibiting PCC-dependent methionine catabolism via the C-Vomit pathway. This leads to elevated intracellular methionine and S-adenosylmethionine (SAM) levels and promotes esophageal squamous cell carcinoma progression.\",\n      \"method\": \"Mass spectrometry interaction screen, co-immunoprecipitation, metabolite measurement (methionine, SAM), PPDPF knockdown in vivo and in vitro\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mass spectrometry plus Co-IP to identify interaction; functional consequence (inhibition of PCCA-PCCB interaction and methionine levels) shown in vivo and in vitro, single lab\",\n      \"pmids\": [\"39694223\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"lncBADR binds directly to PCCA (and Mccc1) in T cells, inhibiting BCAA degradation. Knockout of lncBADR in T cells restores PCCA-mediated BCAA catabolism, decreasing intracellular BCAA levels and reducing mTOR-Stat1 signaling and IFN-γ secretion. High-BCAA feeding partially reversed the protective effects of lncBADR knockout, confirming that lncBADR acts through PCCA-dependent BCAA metabolism.\",\n      \"method\": \"T cell-specific lncBADR knockout mice, RNA binding assays, metabolite profiling, mTOR-Stat1 pathway analysis, IFN-γ measurement, rescue experiment (high-BCAA feeding)\",\n      \"journal\": \"Journal of neuroinflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with multiple pathway readouts and rescue experiment, single lab; direct binding of lncBADR to PCCA reported but detailed binding mechanism not fully characterized in abstract\",\n      \"pmids\": [\"41013574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In Pcca-/-(A138T) mice (a propionic acidemia model), fasting reduces propionylcarnitine, the C3/C2 ratio, ammonia, and methylcitrate. This is attributed to significant reduction in microbiome-produced propionate and increased fatty acid oxidation (decreasing propionyl-CoA synthesis and enhancing acetyl-CoA synthesis) during fasting. Fasting-induced gluconeogenesis further facilitates propionyl-CoA catabolism without changing propionyl-CoA carboxylase activity.\",\n      \"method\": \"Pcca mutant mouse model, metabolite profiling (propionylcarnitine, C3/C2, ammonia, methylcitrate), measurement of PCC enzymatic activity, assessment of microbiome-derived propionate\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined genetic mouse model with multiple metabolic measurements, mechanistic pathway dissection, single lab\",\n      \"pmids\": [\"38811689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"A deep-intronic PCCA variant (c.1285-1358C>G) causes constitutive inclusion of the known 84-bp pseudoexon in PCCA mRNA, abolishing functional PCCA and PCCB protein expression and severely reducing PCC activity. Antisense oligonucleotides (ASOs) targeting this pseudoexon restore productive PCCA splicing, rescue PCCA protein expression, and markedly increase PCC activity above wild-type levels in patient fibroblasts. ASO treatment was also effective in other PA fibroblast lines with residual activity >1% of normal.\",\n      \"method\": \"Patient fibroblast analysis, RT-PCR/sequencing, ASO transfection, PCC enzymatic activity assay, protein expression analysis\",\n      \"journal\": \"Molecular therapy. Nucleic acids\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — functional rescue by ASOs with quantitative enzymatic activity and protein expression readouts in patient fibroblasts, validated across 8 cell lines\",\n      \"pmids\": [\"42028575\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PCCA encodes the alpha subunit of mitochondrial propionyl-CoA carboxylase (PCC), a biotin-dependent enzyme that catalyzes ATP-dependent carboxylation of propionyl-CoA to D-methylmalonyl-CoA in the catabolism of branched-chain amino acids, odd-chain fatty acids, and related metabolites; the alpha subunit harbors the covalently bound biotin prosthetic group and is required for assembly and stabilization of the functional heteromeric (alpha/beta) PCC oligomer, such that loss of PCCA destabilizes the beta subunit (PCCB) and abolishes activity, while PCCA expression levels are also regulated post-transcriptionally through a constitutive 84-bp cryptic pseudoexon and at the protein level through interaction with partners including lncBADR and the bacterial virulence factor PlcB.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PCCA encodes the alpha subunit of mitochondrial propionyl-CoA carboxylase (PCC), a biotin-dependent enzyme that carboxylates propionyl-CoA in the catabolism of branched-chain amino acids, odd-chain fatty acids, cholesterol, and related metabolites [#0, #3]. The alpha subunit carries the covalently bound biotin prosthetic group, identified by the conserved Ala-Met-Lys-Met biotin-binding motif in PCCA cDNA [#0]. PCCA assembles with the beta subunit (PCCB) into a heteromeric holoenzyme, and the alpha subunit is required to stabilize this complex: in PCCA-deficient patients PCCB is rapidly degraded and both subunits are absent, while re-expression of PCCA alone restores propionate flux in deficient fibroblasts [#1, #2, #3]. Most disease-causing missense and in-frame deletion mutations destabilize the protein and accelerate its turnover, indicating structural alterations incompatible with assembly into a stable, active oligomer [#6, #7]. Loss of PCCA propagates beyond toxic propionyl-CoA accumulation to broad mitochondrial dysfunction, impairing oxidative phosphorylation, membrane potential, and distal TCA cycle flux [#8]. PCCA expression is shaped post-transcriptionally by a constitutive 84-bp cryptic pseudoexon whose inclusion introduces in-frame stop codons; a deep-intronic variant driving constitutive pseudoexon inclusion abolishes PCC activity and is correctable by antisense oligonucleotides that restore productive splicing [#4, #14]. PCC-dependent catabolism is further modulated through partner binding: PPDPF and the lncRNA lncBADR each interfere with PCCA-mediated substrate degradation to elevate methionine/SAM or BCAA levels respectively [#11, #12], and PCCA additionally interacts with the Listeria monocytogenes phospholipase PlcB to restrict bacterial proliferation [#10]. Mutations and large genomic deletions in PCCA cause propionic acidemia [#7, #14].\",\n  \"teleology\": [\n    {\n      \"year\": 1986,\n      \"claim\": \"Established that PCCA is the gene for the alpha subunit of propionyl-CoA carboxylase and the carrier of the biotin prosthetic group, fixing its molecular identity.\",\n      \"evidence\": \"cDNA cloning with sequence identification of the conserved biotin-binding motif and somatic cell hybrid chromosomal mapping\",\n      \"pmids\": [\"3460076\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of the holoenzyme\", \"Catalytic mechanism inferred from family motif rather than directly assayed\"]\n    },\n    {\n      \"year\": 1987,\n      \"claim\": \"Showed the alpha subunit is required to stabilize the beta subunit, establishing subunit interdependence as central to PCC assembly.\",\n      \"evidence\": \"Northern blot and pulse-labeling/immunoprecipitation across PCCA-deficient patient fibroblast strains\",\n      \"pmids\": [\"3687944\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of alpha/beta assembly not defined\", \"Mechanism of PCCB degradation not identified\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Demonstrated PCCA alone is sufficient to rescue the propionate-flux defect, and that its expression level does not normally limit holoenzyme activity.\",\n      \"evidence\": \"cDNA gene transfer into deficient fibroblasts with propionate flux and holoenzyme activity assays\",\n      \"pmids\": [\"8434582\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address rate-limiting steps under physiological conditions\", \"Partial rescue limited by transfection efficiency\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Resolved that loss of PCCA destabilizes the entire assembled complex and identified a constitutive cryptic pseudoexon that modulates productive mRNA, linking genotype to protein loss and to a splicing-based regulatory feature.\",\n      \"evidence\": \"Western blot, RT-PCR and complementation across patient cohorts plus RT-PCR/sequencing characterization of the 84-bp pseudoexon\",\n      \"pmids\": [\"10502773\", \"9887338\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trans-factors regulating pseudoexon inclusion not identified\", \"Physiological role of low-level pseudoexon inclusion unclear\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defined the dominant mechanism by which missense/in-frame mutations cause disease: protein destabilization and accelerated turnover preventing stable oligomer assembly.\",\n      \"evidence\": \"Expression of 11 mutations in deficient fibroblasts and cell-free systems with activity and stability assays\",\n      \"pmids\": [\"12385775\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Degradation pathway/protease not identified\", \"No structural rationale for individual destabilizing mutations\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified large genomic deletions as a frequent pathogenic mechanism and confirmed an exon 3-4 in-frame deletion abolishes activity.\",\n      \"evidence\": \"MLPA, long-PCR, and eukaryotic expression with PCC activity assay\",\n      \"pmids\": [\"19157943\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Repeat-mediated deletion mechanism inferred from sequence context, not directly demonstrated\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed that PCCA deficiency causes broad mitochondrial energetic failure beyond precursor toxicity, reframing propionic acidemia as a mitochondrial disorder.\",\n      \"evidence\": \"C. elegans pcca-1 deletion with polarography, in vivo mitochondrial physiology, and 13C metabolic flux analysis\",\n      \"pmids\": [\"29159707\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic link between propionyl-CoA accumulation and OXPHOS impairment not fully resolved\", \"Mammalian confirmation of all phenotypes pending\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established aberrant pre-mRNA splicing as a distinct pathogenic mechanism, including for synonymous and missense variants.\",\n      \"evidence\": \"Minigene splicing assays with RT-PCR/sequencing for 24 variants\",\n      \"pmids\": [\"33923806\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Minigene context may not fully reflect endogenous splicing\", \"Protein-level consequences predicted rather than measured\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed PCCA as a node controlled by protein and RNA partners and engaged in host-pathogen defense, expanding its biology beyond canonical metabolism.\",\n      \"evidence\": \"Mass spectrometry/Co-IP identifying PPDPF blocking PCCA-PCCB interaction; Co-IP/colocalization with Listeria PlcB plus knockdown/overexpression proliferation assays; metabolite profiling\",\n      \"pmids\": [\"39694223\", \"38727222\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of partner interactions not defined\", \"Single-lab findings without reciprocal/independent validation\", \"Whether PlcB interaction depends on PCC catalytic function unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated that dietary and metabolic state modulate the disease phenotype independent of residual enzyme activity, via substrate supply.\",\n      \"evidence\": \"Pcca-/-(A138T) propionic acidemia mouse model with metabolite profiling and PCC activity measurement during fasting\",\n      \"pmids\": [\"38811689\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Microbiome contribution inferred, not directly manipulated\", \"Translation to patient dietary management not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed lncBADR directly binds PCCA to suppress BCAA catabolism in T cells, coupling PCCA metabolic activity to mTOR-Stat1 immune signaling.\",\n      \"evidence\": \"T cell-specific lncBADR knockout mice, RNA binding assays, metabolite profiling, and high-BCAA rescue feeding\",\n      \"pmids\": [\"41013574\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Detailed lncBADR-PCCA binding interface not characterized\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Provided a therapeutic proof-of-concept by correcting pseudoexon-driven loss of function, validating the cryptic exon as a splice-modulation target.\",\n      \"evidence\": \"Patient fibroblast analysis of a deep-intronic variant and antisense oligonucleotide rescue with enzymatic activity and protein expression readouts across cell lines\",\n      \"pmids\": [\"42028575\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo/clinical efficacy not established\", \"Applicability limited to lines with residual activity >1%\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis of alpha/beta holoenzyme assembly and how diverse partner interactions (PPDPF, lncBADR, PlcB) mechanistically reroute substrate flux remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No high-resolution structure of human PCC in the timeline\", \"Partner-binding interfaces and competitive mechanisms only partially mapped\", \"Causal link between propionyl-CoA accumulation and broad mitochondrial dysfunction not fully defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 2, 6]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0016829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [3, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [3, 8, 13]}\n    ],\n    \"complexes\": [\"propionyl-CoA carboxylase (PCC) holoenzyme\"],\n    \"partners\": [\"PCCB\", \"PPDPF\", \"lncBADR\", \"PlcB\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}