PC

Summary

PC (pyruvate carboxylase, HGNC:8636) is a protein-coding gene on chromosome 11q13.2, encoding Pyruvate carboxylase, mitochondrial (P11498). Pyruvate carboxylase catalyzes a 2-step reaction, involving the ATP-dependent carboxylation of the covalently attached biotin in the first step and the transfer of the carboxyl group to pyruvate in the second.

This gene encodes pyruvate carboxylase, which requires biotin and ATP to catalyse the carboxylation of pyruvate to oxaloacetate. The active enzyme is a homotetramer arranged in a tetrahedron which is located exclusively in the mitochondrial matrix. Pyruvate carboxylase is involved in gluconeogenesis, lipogenesis, insulin secretion and synthesis of the neurotransmitter glutamate. Mutations in this gene have been associated with pyruvate carboxylase deficiency. Alternatively spliced transcript variants with different 5’ UTRs, but encoding the same protein, have been found for this gene.

Source: NCBI Gene 5091 — RefSeq curated summary.

At a glance

• Gene–disease (curated): pyruvate carboxylase deficiency disease (Definitive, GenCC) — +3 more curated relationships
• GWAS associations: 16
• Clinical variants (ClinVar): 1,506 total — 67 pathogenic, 99 likely-pathogenic
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_001040716

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8636
Approved symbol	PC
Name	pyruvate carboxylase
Location	11q13.2
Locus type	gene with protein product
Status	Approved
Aliases	PCB
Ensembl gene	ENSG00000173599
Ensembl biotype	protein_coding
OMIM	608786
Entrez	5091

Gene structure

Transcript identifiers

Ensembl transcripts: 58 — 50 protein_coding, 5 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay, 1 retained_intron

ENST00000393955, ENST00000393958, ENST00000393960, ENST00000524491, ENST00000525476, ENST00000528224, ENST00000528403, ENST00000529047, ENST00000530187, ENST00000530259, ENST00000531614, ENST00000534194, ENST00000628663, ENST00000651036, ENST00000651469, ENST00000651831, ENST00000651854, ENST00000652125, ENST00000652387, ENST00000882252, ENST00000882253, ENST00000882254, ENST00000882255, ENST00000882256, ENST00000882257, ENST00000882258, ENST00000882259, ENST00000882260, ENST00000882261, ENST00000882262, ENST00000882263, ENST00000882264, ENST00000882265, ENST00000882266, ENST00000882267, ENST00000882268, ENST00000882269, ENST00000882270, ENST00000882271, ENST00000882272, ENST00000882273, ENST00000882274, ENST00000882275, ENST00000882276, ENST00000882277, ENST00000882278, ENST00000939721, ENST00000951198, ENST00000951199, ENST00000951200, ENST00000951201, ENST00000951202, ENST00000951203, ENST00000951204, ENST00000951205, ENST00000951206, ENST00000951207, ENST00000951208

RefSeq mRNA: 3 — MANE Select: NM_001040716 NM_000920, NM_001040716, NM_022172

CCDS: CCDS8152

Canonical transcript exons

ENST00000393960 — 23 exons

Exon	Start	End
ENSE00001187533	66849611	66849859
ENSE00001187545	66849937	66850116
ENSE00001187554	66850220	66850464
ENSE00001187559	66850674	66850923
ENSE00001187585	66852747	66852836
ENSE00001187592	66853239	66853383
ENSE00001187600	66863774	66863956
ENSE00001187606	66866187	66866349
ENSE00001187614	66868846	66868964
ENSE00001187622	66870302	66870453
ENSE00001187629	66870775	66870892
ENSE00001187634	66871052	66871197
ENSE00001187644	66871315	66871480
ENSE00001517005	66848420	66849147
ENSE00001517020	66952430	66952468
ENSE00001517021	66954249	66954436
ENSE00002165818	66958322	66958383
ENSE00003470798	66872024	66872159
ENSE00003481177	66852439	66852660
ENSE00003522560	66851790	66851946
ENSE00003592953	66851040	66851280
ENSE00003605697	66871687	66871871
ENSE00003616604	66849230	66849370

Expression profiles

Bgee: expression breadth ubiquitous, 204 present calls, max score 97.47.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 19.6186 / max 310.1853, expressed in 1734 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
120873	17.7503	1722
120872	0.7882	494
120868	0.6272	108
120866	0.2019	59
120853	0.1577	65
120867	0.0302	16
120854	0.0241	8
120869	0.0207	6
120865	0.0183	9

Top tissues by expression

275 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	97.47	gold quality
liver	UBERON:0002107	95.12	gold quality
right frontal lobe	UBERON:0002810	91.48	gold quality
prefrontal cortex	UBERON:0000451	91.27	gold quality
caudate nucleus	UBERON:0001873	90.63	gold quality
right hemisphere of cerebellum	UBERON:0014890	90.49	gold quality
right adrenal gland	UBERON:0001233	90.35	gold quality
putamen	UBERON:0001874	90.25	gold quality
ganglionic eminence	UBERON:0004023	90.23	gold quality
nucleus accumbens	UBERON:0001882	90.13	gold quality
right adrenal gland cortex	UBERON:0035827	90.08	gold quality
cingulate cortex	UBERON:0003027	90.04	gold quality
anterior cingulate cortex	UBERON:0009835	89.94	gold quality
left adrenal gland cortex	UBERON:0035825	89.91	gold quality
left adrenal gland	UBERON:0001234	89.66	gold quality
cerebellar hemisphere	UBERON:0002245	89.61	gold quality
cerebellar cortex	UBERON:0002129	89.57	gold quality
adipose tissue	UBERON:0001013	89.48	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	88.98	gold quality
subcutaneous adipose tissue	UBERON:0002190	88.94	gold quality
frontal cortex	UBERON:0001870	88.92	gold quality
Brodmann (1909) area 9	UBERON:0013540	88.87	gold quality
neocortex	UBERON:0001950	88.68	gold quality
adipose tissue of abdominal region	UBERON:0007808	88.58	gold quality
adrenal cortex	UBERON:0001235	88.57	gold quality
adult mammalian kidney	UBERON:0000082	88.52	gold quality
cranial nerve II	UBERON:0000941	88.48	gold quality
omental fat pad	UBERON:0010414	88.35	gold quality
cerebellum	UBERON:0002037	88.28	gold quality
amygdala	UBERON:0001876	88.25	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	14.99
E-MTAB-7381	no	473.03

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

17 targeting PC, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-6126	99.62	68.09	996
HSA-MIR-143-3P	99.49	69.05	1457
HSA-MIR-4770	99.49	69.09	1451
HSA-MIR-889-5P	99.41	68.75	1025
HSA-MIR-6088	99.29	68.45	1284
HSA-MIR-361-3P	99.19	66.45	1381
HSA-MIR-6840-3P	98.68	65.95	1923
HSA-MIR-31-5P	98.58	68.35	1239
HSA-MIR-1267	98.24	69.05	837
HSA-MIR-6748-3P	97.20	65.66	836
HSA-MIR-6858-3P	96.37	64.41	771
HSA-MIR-2861	95.24	65.47	1056

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 27)

• IVS15+2-5delTAGG results in the retention of intron 15 during pre-mRNA splicing and frameshift mutations. (PMID:12112657)
• expression and characterization of a variant by retroviral gene transfer (PMID:12437512)
• 1 deficiency patient survived from neonatal lactic acidemia and shows an unusual subcortical leucodystrophic process. (PMID:16325442)
• The crystal structures at 2.8-A resolution of full-length PC from Staphylococcus aureus and the C-terminal region (missing only the BC domain) of human PC, is reported. (PMID:18297087)
• Eight novel mutations were identified in PC from 8 pyruvate carboxylase deficiency patients. (PMID:18676167)
• The activities of pyruvate carboxylase (PC) were decreased by 65% in pancreatic islets of patients with type 2 diabetes. (PMID:19296078)
• Nine novel mutations of the PC gene, in five unrelated patients, are reported. (PMID:19306334)
• PC protein is easily detectable by streptavidin blot and the presence of considerable amounts of PC in cultured human myotubes and in human muscle tissue was shown. (PMID:20807508)
• Increased PC expression is correlated with the malignant progression of GC, which might be a potential target for GC biotherapy. (PMID:23294723)
• characterization of PC distal promoter (PMID:23383084)
• PC and PDH may be an important part of cellular adaptation to the IDH1 mutation and may serve as potential therapeutic targets (PMID:25243911)
• These findings indicate that PC-mediated anaplerosis in early-stage NSCLC is required for tumor survival and proliferation. (PMID:25607840)
• Pyruvate carboxylase activates the RIG-I-like receptor-mediated antiviral immune response by targeting the MAVS signalosome. (PMID:26906558)
• breast cancer cells proliferating as lung metastases activate PC-dependent anaplerosis in response to the lung microenvironment. (PMID:27732858)
• PC enzyme activity is much higher in the highly invasive breast cancer cell line MDA-MB-231 than in less invasive breast cancer cell lines. Strong PC suppression lowered glucose incorporation into downstream metabolites of oxaloacetate, the product of the PC reaction, including malate, citrate and aspartate. (PMID:27890529)
• Our studies indicate that PC is specifically required for the growth of breast cancer that has disseminated to the lungs. Overall, these findings point to the potential of targeting PC for the treatment of pulmonary metastatic breast cancer (PMID:30005601)
• Study compares type A and type C patients with pyruvate carboxylase deficiency (PCD). Type C PCD is not associated to homozygous variants in PC. In silico modeling found that variants lead to type A or type C phenotype based on the destabilization between the two major enzyme conformers. (PMID:30870574)
• Overexpression of Pyruvate Carboxylase Is Correlated With Colorectal Cancer Progression and Supports Growth of Invasive Colon Cancer HT-29 Cell Line. (PMID:33109566)
• Integrated analysis of transcriptomic and metabolomic data demonstrates the significant role of pyruvate carboxylase in the progression of ovarian cancer. (PMID:33177242)
• Rethinking the Citric Acid Cycle: Connecting Pyruvate Carboxylase and Citrate Synthase to the Flow of Energy and Material. (PMID:33435350)
• Expression of pyruvate carboxylase in cultured human astrocytoma, glioblastoma and neuroblastoma cells. (PMID:33880999)
• Pyruvate carboxylase supports basal ATP-linked respiration in human pluripotent stem cell-derived brown adipocytes. (PMID:34245978)
• Protective effects of all-trans retinoic acid against gastric premalignant lesions by repressing exosomal LncHOXA10-pyruvate carboxylase axis. (PMID:34632533)
• Fibroblast pyruvate carboxylase is required for collagen production in the tumour microenvironment. (PMID:34764457)
• The ubiquitous expression of pyruvate carboxylase among human prostate tumors. (PMID:35907054)
• In silico Analysis of Two Novel Variants in the Pyruvate Carboxylase (PC) Gene Associated with the Severe Form of PC Deficiency. (PMID:37873728)
• Leat-associated seizures the possible role of EAAT2, pyruvate carboxylase and glutamine synthetase. (PMID:38086219)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	pcxb	ENSDARG00000051939
danio_rerio	pcxa	ENSDARG00000098766
mus_musculus	Pcx	ENSMUSG00000024892
rattus_norvegicus	Pc	ENSRNOG00000019372
drosophila_melanogaster	PCB	FBGN0027580
caenorhabditis_elegans		WBGENE00004258

Paralogs (4): ACACB (ENSG00000076555), MCCC1 (ENSG00000078070), PCCA (ENSG00000175198), ACACA (ENSG00000278540)

Protein

Protein identifiers

Pyruvate carboxylase, mitochondrial — P11498 (reviewed: P11498)

Alternative names: Pyruvic carboxylase

All UniProt accessions (6): P11498, A0A494BZT5, A0A494C016, A0A494C0T2, A0A494C101, E9PRE7

UniProt curated annotations — full annotation on UniProt →

Function. Pyruvate carboxylase catalyzes a 2-step reaction, involving the ATP-dependent carboxylation of the covalently attached biotin in the first step and the transfer of the carboxyl group to pyruvate in the second. Catalyzes in a tissue specific manner, the initial reactions of glucose (liver, kidney) and lipid (adipose tissue, liver, brain) synthesis from pyruvate.

Subunit / interactions. Homotetramer. Interacts (via the biotin carboxylation domain) with SIRT4.

Subcellular location. Mitochondrion matrix.

Post-translational modifications. Acetylation of Lys-748 might play a role in catalytic activity regulation.

Disease relevance. Pyruvate carboxylase deficiency (PC deficiency) [MIM:266150] Leads to lactic acidosis, intellectual disability and death. It occurs in three forms: mild or type A, severe neonatal or type B, and a very mild lacticacidemia. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 1 Mn(2+) ion per subunit.

Pathway. Carbohydrate biosynthesis; gluconeogenesis.

Isoforms (2)

UniProt ID	Names	Canonical?
P11498-1	1	yes
P11498-2	2

RefSeq proteins (3): NP_000911, NP_001035806, NP_071504 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000089	Biotin_lipoyl	Domain
IPR000891	PYR_CT	Domain
IPR001882	Biotin_BS	Binding_site
IPR003379	Carboxylase_cons_dom	Domain
IPR005479	CPAse_ATP-bd	Domain
IPR005481	BC-like_N	Domain
IPR005482	Biotin_COase_C	Domain
IPR005930	Pyruv_COase	Family
IPR011053	Single_hybrid_motif	Homologous_superfamily
IPR011054	Rudment_hybrid_motif	Homologous_superfamily
IPR011761	ATP-grasp	Domain
IPR011764	Biotin_carboxylation_dom	Domain
IPR013785	Aldolase_TIM	Homologous_superfamily
IPR016185	PreATP-grasp_dom_sf	Homologous_superfamily
IPR055268	PCB-like	Family

Pfam: PF00289, PF00364, PF00682, PF02436, PF02785, PF02786

Enzyme classification (BRENDA):

• EC 6.4.1.1 — pyruvate carboxylase (BRENDA: 57 organisms, 74 substrates, 105 inhibitors, 126 Km, 98 kcat entries)

Substrate kinetics (BRENDA)

8 substrates with measured Km, best-characterized 8. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
PYRUVATE	0.039–16.2	47
ATP	0.009–9.2	37
HCO3-	0.22–400	27
CARBAMOYL PHOSPHATE	1.7–12.3	4
ADP	0.0028–0.008	2
BIOTIN	3.3–18	2
OXAMATE	4.1	1
OXALOACETATE	—	0

Catalyzed reactions (Rhea), 1 shown:

• hydrogencarbonate + pyruvate + ATP = oxaloacetate + ADP + phosphate + H(+) (RHEA:20844)

UniProt features (168 total): helix 46, strand 46, modified residue 24, turn 14, sequence variant 11, binding site 10, sequence conflict 7, domain 4, splice variant 2, transit peptide 1, chain 1, mutagenesis site 1, active site 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
8XL9	ELECTRON MICROSCOPY	2.61
3BG3	X-RAY DIFFRACTION	2.8
3BG9	X-RAY DIFFRACTION	3
7WTE	ELECTRON MICROSCOPY	3.3
7WTB	ELECTRON MICROSCOPY	3.7
8J7O	ELECTRON MICROSCOPY	3.83
7WTA	ELECTRON MICROSCOPY	3.9
7WTD	ELECTRON MICROSCOPY	3.9
7WTC	ELECTRON MICROSCOPY	4
8HWL	ELECTRON MICROSCOPY	5.63

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P11498-F1	90.53	0.71

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 328

Ligand- & substrate-binding residues (10): 571–575; 572; 644; 741 (via carbamate group); 771; 773; 908; 152; 236; 271

Post-translational modifications (24): 35, 39, 79, 79, 148, 152, 241, 297, 319, 434, 442, 589, 661, 717, 741, 748, 892, 969, 992, 1003 …

Mutagenesis-validated functional residues (1):

Position	Phenotype
1077	loss of tetramerization and enzyme activity, resulting in an inactive homodimer.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-196780	Biotin transport and metabolism
R-HSA-3371599	Defective HLCS causes multiple carboxylase deficiency
R-HSA-70263	Gluconeogenesis
R-HSA-70268	Pyruvate metabolism

MSigDB gene sets: 257 (showing top): GOBP_NADPPLUS_METABOLIC_PROCESS, IVANOVA_HEMATOPOIESIS_MATURE_CELL, AREB6_01, GOBP_MODULATION_OF_PROCESS_OF_ANOTHER_ORGANISM, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, SARRIO_EPITHELIAL_MESENCHYMAL_TRANSITION_DN, chr11q13, GOBP_HOST_MEDIATED_PERTURBATION_OF_VIRAL_PROCESS, HUMMERICH_SKIN_CANCER_PROGRESSION_DN, GOBP_NADPLUS_METABOLIC_PROCESS, MONNIER_POSTRADIATION_TUMOR_ESCAPE_UP, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, KRASNOSELSKAYA_ILF3_TARGETS_DN, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, MARTINEZ_RB1_TARGETS_UP

GO Biological Process (11): gluconeogenesis (GO:0006094), lipid metabolic process (GO:0006629), NADP+ metabolic process (GO:0006739), negative regulation of gene expression (GO:0010629), viral RNA genome packaging (GO:0019074), viral release from host cell (GO:0019076), NAD+ metabolic process (GO:0019674), host-mediated activation of viral process (GO:0044794), pyruvate metabolic process (GO:0006090), obsolete NADH metabolic process (GO:0006734), small molecule metabolic process (GO:0044281)

GO Molecular Function (10): pyruvate carboxylase activity (GO:0004736), ATP binding (GO:0005524), biotin binding (GO:0009374), identical protein binding (GO:0042802), metal ion binding (GO:0046872), nucleotide binding (GO:0000166), catalytic activity (GO:0003824), protein binding (GO:0005515), ligase activity (GO:0016874), ligase activity, forming carbon-carbon bonds (GO:0016885)

GO Cellular Component (4): cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Metabolism of water-soluble vitamins and cofactors	1
Defects in biotin (Btn) metabolism	1
Glucose metabolism	1
Aerobic respiration and respiratory electron transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
purine nucleotide metabolic process	2
nicotinamide nucleotide metabolic process	2
heterocyclic compound binding	2
cellular anatomical structure	2
cytoplasm	2
glucose metabolic process	1
hexose biosynthetic process	1
primary metabolic process	1
gene expression	1
regulation of gene expression	1
negative regulation of macromolecule biosynthetic process	1
viral genome packaging	1
viral process	1
viral life cycle	1
exit from host cell	1
host-mediated perturbation of viral process	1
monocarboxylic acid metabolic process	1
metabolic process	1
ligase activity, forming carbon-carbon bonds	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
vitamin binding	1
monocarboxylic acid binding	1
sulfur compound binding	1
protein binding	1
cation binding	1
nucleoside phosphate binding	1
molecular_function	1
binding	1
catalytic activity	1
ligase activity	1
intracellular anatomical structure	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

2606 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PC	HLCS	P50747	964
PC	BTD	P43251	903
PC	ME1	P48163	875
PC	PCK2	Q16822	864
PC	CS	O75390	792
PC	G6PD	P11413	784
PC	GLUD1	P00367	780
PC	GPD2	P43304	776
PC	PCK1	P35558	770
PC	G6PC1	P35575	751
PC	ACLY	P53396	748
PC	FH	P07954	744
PC	G6PC3	Q9BUM1	735
PC	G6PC2	Q9NQR9	731
PC	GLUL	P15104	728

IntAct

135 interactions, top by confidence:

A	B	Type	Score
IFIT1	IFIT3	psi-mi:“MI:0914”(association)	0.920
DYNLL1	BLTP3B	psi-mi:“MI:0914”(association)	0.730
PC	PC	psi-mi:“MI:0407”(direct interaction)	0.720
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
ME1	PC	psi-mi:“MI:0403”(colocalization)	0.670
ME1	PC	psi-mi:“MI:0914”(association)	0.670
ME1	PC	psi-mi:“MI:0915”(physical association)	0.670
PC	ME1	psi-mi:“MI:2364”(proximity)	0.670
IFT88	IFT56	psi-mi:“MI:0914”(association)	0.640
LYRM7	NDUFAB1	psi-mi:“MI:0914”(association)	0.640
	PC	psi-mi:“MI:0915”(physical association)	0.630
PC		psi-mi:“MI:0403”(colocalization)	0.630
BPNT1	GTPBP10	psi-mi:“MI:0914”(association)	0.530
ANTXR1	POTEF	psi-mi:“MI:0914”(association)	0.530
DEFA5	NUDT19	psi-mi:“MI:0914”(association)	0.530
LRP1	NME4	psi-mi:“MI:0914”(association)	0.530

BioGRID (243): PC (Affinity Capture-MS), PC (Affinity Capture-MS), PC (Affinity Capture-MS), PC (Affinity Capture-MS), PC (Affinity Capture-MS), PC (Affinity Capture-MS), PC (Affinity Capture-MS), PC (Affinity Capture-MS), PC (Affinity Capture-MS), PC (Affinity Capture-MS), CAD (Co-fractionation), CCT6A (Co-fractionation), COPB1 (Co-fractionation), CYP27A1 (Co-fractionation), FASN (Co-fractionation)

ESM2 similar proteins: A2XKU9, A3KMV5, A4FUZ6, A4IHJ3, A7RHL5, A7RWP6, A9NK39, B4YYA9, B5X8A5, O42130, O42131, O46374, P10871, P11498, P17248, P22314, P23489, P52873, Q02880, Q05920, Q1JQD4, Q29504, Q29RK2, Q2T9S3, Q3ZBN0, Q40073, Q498C5, Q498D9, Q558Y7, Q5U300, Q64399, Q64511, Q66KC4, Q6AVK1, Q6DI37, Q6P5L8, Q6PAY8, Q6TGV7, Q6V289, Q7X923

Diamond homologs: A0A0H3JRU9, A0A4P8DJE6, A2C2S8, A5H0J2, A6ZMR9, B3LM95, B8G187, B9HBA8, B9N843, C0H419, C7GRE4, C8ZF72, D3DJ41, D3DJ42, E9Q4Z2, I3R7G3, O00763, O04983, O17732, O27179, O27939, O30019, O34544, O52058, O93918, P05115, P05165, P06959, P0A509, P0DTA4, P10802, P11154, P11497, P11498, P13187, P14882, P24182, P29337, P32327, P32528

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
MAFA	“up-regulates quantity by expression”	PC	“transcriptional regulation”
PC	“up-regulates quantity”	oxaloacetate(2-)	“chemical modification”
PC	“down-regulates quantity”	pyruvate	“chemical modification”
PDK4	“down-regulates activity”	PC	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

1506 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	67
Likely pathogenic	99
Uncertain significance	296
Likely benign	884
Benign	24

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1068572	NM_001040716.2(PC):c.2328_2329del (p.Ala778fs)	Pathogenic
1068973	NM_001040716.2(PC):c.2953del (p.Leu985fs)	Pathogenic
1071460	NM_001040716.2(PC):c.2581del (p.Val861fs)	Pathogenic
1071602	NM_001040716.2(PC):c.3102dup (p.Thr1035fs)	Pathogenic
1073534	NM_001040716.2(PC):c.1042C>T (p.Gln348Ter)	Pathogenic
1075366	NM_001040716.2(PC):c.3288+1G>T	Pathogenic
1076206	NM_001040716.2(PC):c.2156_2159del (p.Ser719fs)	Pathogenic
1323416	NM_001040716.2(PC):c.1186-1G>T	Pathogenic
1359632	NM_001040716.2(PC):c.3190del (p.Ala1064fs)	Pathogenic
1370133	NM_001040716.2(PC):c.1702_1706del (p.Thr568fs)	Pathogenic
1379662	NM_001040716.2(PC):c.3164del (p.Gly1055fs)	Pathogenic
1416961	NM_001040716.2(PC):c.1918C>T (p.Gln640Ter)	Pathogenic
1424155	NM_001040716.2(PC):c.913G>T (p.Glu305Ter)	Pathogenic
1425937	NM_001040716.2(PC):c.3288+2T>C	Pathogenic
1433419	NM_001040716.2(PC):c.1084del (p.Leu362fs)	Pathogenic
1454180	NM_001040716.2(PC):c.1023-1G>A	Pathogenic
1454797	NM_001040716.2(PC):c.366dup (p.Glu123Ter)	Pathogenic
1456444	NM_001040716.2(PC):c.1123C>T (p.Gln375Ter)	Pathogenic
1457904	NM_001040716.2(PC):c.321+1G>T	Pathogenic
1458437	NM_001040716.2(PC):c.1067_1070delinsTCCACGTGGCTGAGGGCAGGCAG (p.Ser356fs)	Pathogenic
1691506	NM_001040716.2(PC):c.1513+1G>A	Pathogenic
1919134	NM_001040716.2(PC):c.1405C>T (p.Gln469Ter)	Pathogenic
1926728	NM_001040716.2(PC):c.2874dup (p.Phe959fs)	Pathogenic
2014330	NM_001040716.2(PC):c.2253del (p.Cys752fs)	Pathogenic
203922	NM_001040716.2(PC):c.797C>A (p.Ser266Tyr)	Pathogenic
2085442	NM_001040716.2(PC):c.1465del (p.Gln489fs)	Pathogenic
2086463	NM_001040716.2(PC):c.2613C>A (p.Tyr871Ter)	Pathogenic
2094	NM_001040716.2(PC):c.1828G>A (p.Ala610Thr)	Pathogenic
2095	NM_001040716.2(PC):c.2229G>T (p.Met743Ile)	Pathogenic
2096	NM_001040716.2(PC):c.434T>C (p.Val145Ala)	Pathogenic

SpliceAI

4991 predictions. Top by Δscore:

Variant	Effect	Δscore
11:66849224:CAATA:C	donor_loss	1.0000
11:66849225:AATAC:A	donor_loss	1.0000
11:66849226:ATAC:A	donor_loss	1.0000
11:66849227:TACC:T	donor_loss	1.0000
11:66849228:A:AG	donor_loss	1.0000
11:66849232:T:A	donor_gain	1.0000
11:66849250:TG:T	donor_gain	1.0000
11:66849366:TCCAC:T	acceptor_gain	1.0000
11:66849367:CCAC:C	acceptor_gain	1.0000
11:66849367:CCACC:C	acceptor_gain	1.0000
11:66849368:CAC:C	acceptor_gain	1.0000
11:66849368:CACC:C	acceptor_gain	1.0000
11:66849369:AC:A	acceptor_gain	1.0000
11:66849370:CC:C	acceptor_gain	1.0000
11:66849370:CCT:C	acceptor_loss	1.0000
11:66849371:C:CC	acceptor_gain	1.0000
11:66849371:C:CG	acceptor_loss	1.0000
11:66849374:C:CT	acceptor_gain	1.0000
11:66849606:CTGA:C	donor_loss	1.0000
11:66849607:TGA:T	donor_loss	1.0000
11:66849608:GAC:G	donor_loss	1.0000
11:66849609:A:AC	donor_gain	1.0000
11:66849610:C:CA	donor_loss	1.0000
11:66849610:C:CC	donor_gain	1.0000
11:66849610:CCT:C	donor_gain	1.0000
11:66849614:AAACT:A	donor_gain	1.0000
11:66849726:G:C	donor_gain	1.0000
11:66849855:AGTAC:A	acceptor_gain	1.0000
11:66849856:GTAC:G	acceptor_gain	1.0000
11:66849857:TAC:T	acceptor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000025353 (11:66940782 A>C), RS1000029767 (11:66885868 G>A), RS1000029879 (11:66902200 A>G), RS1000051023 (11:66934882 G>A,C), RS1000108299 (11:66855711 A>G), RS1000113228 (11:66928362 G>A,C), RS1000193996 (11:66850638 G>A,C), RS1000196288 (11:66952635 G>A), RS1000197907 (11:66887580 T>C), RS1000207402 (11:66913091 G>A), RS1000262841 (11:66895555 G>C), RS1000307936 (11:66915276 C>A,G), RS1000310826 (11:66952838 C>G,T), RS1000368271 (11:66915804 A>C,G), RS1000406048 (11:66926870 G>A)

Disease associations

OMIM: gene MIM:608786 | disease phenotypes: MIM:266150, MIM:176860, MIM:612304

GenCC curated gene-disease

Disease	Classification	Inheritance
pyruvate carboxylase deficiency disease	Definitive	Autosomal recessive
pyruvate carboxylase deficiency, infantile form	Supportive	Autosomal recessive
pyruvate carboxylase deficiency, severe neonatal type	Supportive	Autosomal recessive
pyruvate carboxylase deficiency, benign type	Supportive	Autosomal recessive

Mondo (6): pyruvate carboxylase deficiency disease (MONDO:0009949), thrombophilia due to protein C deficiency, autosomal dominant (MONDO:0008316), thrombophilia due to protein C deficiency, autosomal recessive (MONDO:0012860), pyruvate carboxylase deficiency, infantile form (MONDO:0018141), pyruvate carboxylase deficiency, severe neonatal type (MONDO:0018142), pyruvate carboxylase deficiency, benign type (MONDO:0018143)

Orphanet (2): Pyruvate carboxylase deficiency (Orphanet:3008), Severe hereditary thrombophilia due to congenital protein C deficiency (Orphanet:745)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

16 associations (top):

Study	Trait	p-value
GCST001241_12	Bipolar disorder	2.000000e-07
GCST001353_7	HIV-1 susceptibility	8.000000e-06
GCST006088_4	Familial squamous cell lung carcinoma	1.000000e-06
GCST008103_30	Bipolar disorder	4.000000e-08
GCST008972_250	Urate levels	5.000000e-08
GCST012226_348	Waist circumference adjusted for body mass index	5.000000e-16
GCST012226_349	Waist circumference adjusted for body mass index	2.000000e-08
GCST012227_666	Hip circumference adjusted for BMI	1.000000e-25
GCST012227_669	Hip circumference adjusted for BMI	2.000000e-10
GCST012465_19	Bipolar disorder	5.000000e-09
GCST90020024_399	A body shape index	8.000000e-13
GCST90020027_1500	Waist-hip index	5.000000e-08
GCST90020028_1914	Hip circumference adjusted for BMI	7.000000e-09
GCST90020028_1915	Hip circumference adjusted for BMI	4.000000e-13
GCST90020029_339	Waist circumference adjusted for body mass index	1.000000e-30
GCST90020029_340	Waist circumference adjusted for body mass index	3.000000e-09

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0000180	HIV-1 infection
EFO:0006953	family history of lung cancer
EFO:0004531	urate measurement
EFO:0007789	BMI-adjusted waist circumference
EFO:0008039	BMI-adjusted hip circumference
EFO:0007788	BMI-adjusted waist-hip ratio

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D015324	Pyruvate Carboxylase Deficiency Disease	C10.228.140.163.100.725; C16.320.565.189.725; C16.320.565.202.810.666; C18.452.132.100.725; C18.452.648.189.725; C18.452.648.202.810.666; C18.452.660.705
C567353	Thrombophilia, Hereditary, Due To Protein C Deficiency, Autosomal Recessive (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5725151 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Carboxylases

Most potent curated ligand interactions (2 total), top 2:

Ligand	Action	Affinity	Parameter
erianin	Inhibition	8.29	pIC50
dendrophenol	Inhibition	7.47	pIC50

ChEMBL bioactivities

8 potent at pChembl≥5 of 8 total, top 8 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.27	IC50	54	nM	CHEMBL5569150
7.24	IC50	58	nM	CHEMBL5566098
7.16	IC50	69	nM	CHEMBL450226
7.14	IC50	73	nM	CHEMBL5574397
6.76	IC50	175	nM	CHEMBL5570469
6.10	IC50	793	nM	CHEMBL5571609
6.05	IC50	894	nM	CHEMBL5570175
5.00	Kd	1.01e+04	nM	CHEMBL5566098

PubChem BioAssay actives

7 with measured affinity, of 38 total; 7 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
7-[4-[6-[[(1R,3aS,5aR,5bR,7aR,8R,9S,11aR,11bR,13aR,13bR)-9-[(2S,3R,4S,5S)-4,5-dihydroxy-3-[(2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxyoxan-2-yl]oxy-8-(hydroxymethyl)-5a,5b,8,11a-tetramethyl-1-prop-1-en-2-yl-1,2,3,4,5,6,7,7a,9,10,11,11b,12,13,13a,13b-hexadecahydrocyclopenta[a]chrysene-3a-carbonyl]amino]hexanoyl]piperazin-1-yl]-1-cyclopropyl-6-fluoro-4-oxoquinoline-3-carboxylic acid	2106543: Inhibition of pyruvate carboxylase (unknown origin) by NADH-malate dehydrogenase based spectrophotometry	ic50	0.0540	uM
methyl 6-[[(1R,3aS,5aR,5bR,7aR,8R,9S,11aR,11bR,13aR,13bR)-9-[(2S,3R,4S,5S)-4,5-dihydroxy-3-[(2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxyoxan-2-yl]oxy-8-(hydroxymethyl)-5a,5b,8,11a-tetramethyl-1-prop-1-en-2-yl-1,2,3,4,5,6,7,7a,9,10,11,11b,12,13,13a,13b-hexadecahydrocyclopenta[a]chrysene-3a-carbonyl]amino]hexanoate	2106543: Inhibition of pyruvate carboxylase (unknown origin) by NADH-malate dehydrogenase based spectrophotometry	ic50	0.0580	uM
[(2S,3R,4S,5S,6R)-6-[[(2R,3R,4R,5S,6R)-3,4-dihydroxy-6-(hydroxymethyl)-5-[(2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxyoxan-2-yl]oxymethyl]-3,4,5-trihydroxyoxan-2-yl] (1R,3aS,5aR,5bR,7aR,8R,9S,11aR,11bR,13aR,13bR)-9-[(2S,3R,4S,5S)-4,5-dihydroxy-3-[(2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxyoxan-2-yl]oxy-8-(hydroxymethyl)-5a,5b,8,11a-tetramethyl-1-prop-1-en-2-yl-1,2,3,4,5,6,7,7a,9,10,11,11b,12,13,13a,13b-hexadecahydrocyclopenta[a]chrysene-3a-carboxylate	2106543: Inhibition of pyruvate carboxylase (unknown origin) by NADH-malate dehydrogenase based spectrophotometry	ic50	0.0690	uM
(1R,3aS,5aR,5bR,7aR,8R,9S,11aR,11bR,13aR,13bR)-9-[(2S,3R,4S,5S)-4,5-dihydroxy-3-[(2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxyoxan-2-yl]oxy-8-(hydroxymethyl)-5a,5b,8,11a-tetramethyl-N-[6-[(4-methyl-2-oxochromen-7-yl)amino]-6-oxohexyl]-1-prop-1-en-2-yl-1,2,3,4,5,6,7,7a,9,10,11,11b,12,13,13a,13b-hexadecahydrocyclopenta[a]chrysene-3a-carboxamide	2106543: Inhibition of pyruvate carboxylase (unknown origin) by NADH-malate dehydrogenase based spectrophotometry	ic50	0.0730	uM
6-[[(1R,3aS,5aR,5bR,7aR,8R,9S,11aR,11bR,13aR,13bR)-9-[(2S,3R,4S,5S)-4,5-dihydroxy-3-[(2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxyoxan-2-yl]oxy-8-(hydroxymethyl)-5a,5b,8,11a-tetramethyl-1-prop-1-en-2-yl-1,2,3,4,5,6,7,7a,9,10,11,11b,12,13,13a,13b-hexadecahydrocyclopenta[a]chrysene-3a-carbonyl]amino]hexanoic acid	2106543: Inhibition of pyruvate carboxylase (unknown origin) by NADH-malate dehydrogenase based spectrophotometry	ic50	0.1750	uM
(1R,3aS,5aR,5bR,7aR,8R,9S,11aR,11bR,13aR,13bR)-N-(2-aminoethyl)-9-[(2S,3R,4S,5S)-4,5-dihydroxy-3-[(2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxyoxan-2-yl]oxy-8-(hydroxymethyl)-5a,5b,8,11a-tetramethyl-1-prop-1-en-2-yl-1,2,3,4,5,6,7,7a,9,10,11,11b,12,13,13a,13b-hexadecahydrocyclopenta[a]chrysene-3a-carboxamide	2106543: Inhibition of pyruvate carboxylase (unknown origin) by NADH-malate dehydrogenase based spectrophotometry	ic50	0.7930	uM
tert-butyl N-[3-[[(1R,3aS,5aR,5bR,7aR,8R,9S,11aR,11bR,13aR,13bR)-9-[(2S,3R,4S,5S)-4,5-dihydroxy-3-[(2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxyoxan-2-yl]oxy-8-(hydroxymethyl)-5a,5b,8,11a-tetramethyl-1-prop-1-en-2-yl-1,2,3,4,5,6,7,7a,9,10,11,11b,12,13,13a,13b-hexadecahydrocyclopenta[a]chrysene-3a-carbonyl]amino]propyl]carbamate	2106543: Inhibition of pyruvate carboxylase (unknown origin) by NADH-malate dehydrogenase based spectrophotometry	ic50	0.8940	uM

CTD chemical–gene interactions

63 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases expression, increases methylation, affects methylation, decreases methylation	5
sodium arsenite	increases expression, decreases expression	4
Tetrachlorodibenzodioxin	affects expression, increases expression	4
bisphenol A	decreases methylation, increases expression, affects cotreatment	2
Air Pollutants	affects cotreatment, increases abundance, increases expression, decreases expression	2
Tobacco Smoke Pollution	decreases expression, increases expression	2
Cyclosporine	decreases expression	2
Aflatoxin B1	decreases expression	2
aristolochic acid I	decreases expression	1
bisphenol F	increases expression	1
alpha-pinene	affects cotreatment, increases expression, increases abundance	1
glycidyl methacrylate	decreases expression	1
lead acetate	decreases expression	1
nobiletin	decreases expression, decreases reaction	1
potassium perchlorate	decreases expression	1
sodium arsenate	decreases expression, decreases reaction	1
2,5,2’,5’-tetrachlorobiphenyl	increases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression, increases expression	1
arsenite	increases reaction, affects binding	1
sulforaphane	decreases expression	1
benzo(e)pyrene	affects methylation	1
aflatoxin B2	decreases methylation	1
cupric chloride	decreases expression	1
methacrylaldehyde	affects cotreatment, increases expression, increases abundance	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression	1
CGP 52608	affects binding, increases reaction	1
obeticholic acid	decreases expression	1
bisphenol B	increases expression	1
abrine	increases expression	1
2-amino-14,16-dimethyloctadecan-3-ol	decreases expression	1

ChEMBL screening assays

10 unique, capped per target: 10 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5549392	Binding	Inhibition of pyruvate carboxylase (unknown origin) by NADH-malate dehydrogenase based spectrophotometry	Discovery of a New Anti-Inflammatory Agent from Anemoside B4 Derivatives and Its Therapeutic Effect on Colitis by Targeting Pyruvate Carboxylase. — J Med Chem

Cellosaurus cell lines

3 cell lines: 1 induced pluripotent stem cell, 1 transformed cell line, 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_C0JI	SHCDNi007-A	Induced pluripotent stem cell	Male
CVCL_D9MD	Ubigene HEK293 PC KO	Transformed cell line	Female
CVCL_TC39	HAP1 PC (-)	Cancer cell line	Male

Clinical trials (associated diseases)

1 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT01461304	Not specified	NO_LONGER_AVAILABLE	Compassionate Use of Triheptanoin (C7) for Inherited Disorders of Energy Metabolism