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. It is a selective cancer dependency (DepMap: 19.4% of cell lines).

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): 1,522 total — 66 pathogenic, 100 likely-pathogenic (top 2% of genes corpus-wide)
• GTEx eGene: eQTL in 14 tissues, sQTL in 3 (q < 0.05)
• Phenotypes (HPO): 19
• Cancer dependency (DepMap): dependent in 19.4% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• Constraint (gnomAD): pLI 0.07 (LoF-tolerant), LOEUF 0.54 (moderately constrained)
• MANE Select transcript: NM_001040716
• Interaction hub: 2,164 STRING partners (top 6% of genes corpus-wide)

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: 61 — 52 protein_coding, 5 protein_coding_CDS_not_defined, 3 nonsense_mediated_decay, 1 retained_intron

MANE Select: ENST00000393960

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 3, TSL 2: 3, TSL 3: 3, TSL 5: 4

ENST00000393960, ENST00000393955, ENST00000393958, 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, ENST00001071800, ENST00001071801, ENST00001143496

RefSeq mRNA: 9 — MANE Select: NM_001040716 NM_000920, NM_001040716, NM_001439352, NM_001439353, NM_001439355, NM_001439357, NM_001439358, NM_001439359, 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.

Highest expression (Bgee): lobe of liver, liver, frontal lobe, prefrontal cortex, caudate nucleus.

Genetic regulation across tissues (GTEx eQTL / sQTL)

PC is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 14 tissues and its splicing (sQTL) in 3 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

17 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Esophagus Mucosa	eqtl	3.4e-40	+0.93	11:66906236:G:A
Pancreas	eqtl	1.0e-08	-0.36	11:66918255:T:C
Brain Cerebellar Hemisphere	eqtl	9.8e-07	-0.30	11:66915389:T:C
Brain Cerebellum	eqtl	1.1e-06	-0.32	11:66932151:G:C
Esophagus Mucosa	sqtl	4.7e-05	+0.69	11:66971292:C:T
Muscle Skeletal	eqtl	8.1e-05	+0.16	11:66883030:G:A
Nerve Tibial	eqtl	1.5e-03	-0.11	11:66956900:A:C
Cells Cultured fibroblasts	eqtl	3.7e-03	-0.21	11:66887377:A:G
Colon Sigmoid	eqtl	4.8e-03	+0.35	11:66030528:G:A
Testis	sqtl	5.8e-03	+0.34	11:66856029:C:CCT
Adipose Subcutaneous	eqtl	2.3e-02	+0.08	11:67815476:C:T
Brain Putamen basal ganglia	eqtl	2.5e-02	-0.17	11:66561406:G:A
Cells EBV-transformed lymphocytes	eqtl	3.2e-02	+1.00	11:67807327:G:T
Breast Mammary Tissue	eqtl	3.3e-02	-0.39	11:66010792:C:T
Brain Frontal Cortex BA9	eqtl	4.1e-02	+0.79	11:67889759:G:T
Artery Aorta	sqtl	4.2e-02	+0.58	11:67579272:T:C
Brain Spinal cord cervical c-1	eqtl	4.6e-02	+1.29	11:66755870:T:C

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

showing 100 of 275 tissues 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
peritoneum	UBERON:0002358	88.23	gold quality
adrenal gland	UBERON:0002369	88.14	gold quality
connective tissue	UBERON:0002384	87.96	gold quality
telencephalon	UBERON:0001893	87.60	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	87.58	gold quality
cerebral cortex	UBERON:0000956	87.35	gold quality
hypothalamus	UBERON:0001898	87.33	gold quality
spinal cord	UBERON:0002240	87.29	gold quality
Ammon’s horn	UBERON:0001954	87.08	gold quality
postcentral gyrus	UBERON:0002581	87.06	gold quality
substantia nigra	UBERON:0002038	86.95	gold quality
stromal cell of endometrium	CL:0002255	86.86	gold quality
forebrain	UBERON:0001890	86.82	gold quality
central nervous system	UBERON:0001017	86.74	gold quality
brain	UBERON:0000955	86.73	gold quality
adrenal tissue	UBERON:0018303	86.50	gold quality
Brodmann (1909) area 46	UBERON:0006483	86.28	silver quality
left testis	UBERON:0004533	86.27	gold quality
tibial nerve	UBERON:0001323	86.24	gold quality
superior frontal gyrus	UBERON:0002661	85.94	gold quality
parotid gland	UBERON:0001831	85.85	gold quality
midbrain	UBERON:0001891	85.50	gold quality
right testis	UBERON:0004534	85.48	gold quality
temporal lobe	UBERON:0001871	85.44	gold quality
hindlimb stylopod muscle	UBERON:0004252	85.36	gold quality
sural nerve	UBERON:0015488	85.16	gold quality
parietal lobe	UBERON:0001872	84.65	silver quality
kidney epithelium	UBERON:0004819	84.65	gold quality
inferior olivary complex	UBERON:0002127	84.36	silver quality
kidney	UBERON:0002113	84.20	gold quality
metanephric glomerulus	UBERON:0004736	84.09	gold quality
testis	UBERON:0000473	83.90	gold quality
embryo	UBERON:0000922	83.57	gold quality
renal glomerulus	UBERON:0000074	83.43	gold quality
cortex of kidney	UBERON:0001225	83.41	gold quality
cortical plate	UBERON:0005343	83.25	gold quality
entorhinal cortex	UBERON:0002728	83.22	silver quality
gastrocnemius	UBERON:0001388	83.09	gold quality
primary visual cortex	UBERON:0002436	83.05	gold quality
metanephros	UBERON:0000081	82.84	gold quality
nephron tubule	UBERON:0001231	82.81	silver quality
adenohypophysis	UBERON:0002196	82.60	gold quality
ventricular zone	UBERON:0003053	82.38	gold quality
saliva-secreting gland	UBERON:0001044	82.29	gold quality
muscle of leg	UBERON:0001383	82.12	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	81.93	silver quality
left coronary artery	UBERON:0001626	81.54	gold quality
body of stomach	UBERON:0001161	81.43	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.33	gold quality
minor salivary gland	UBERON:0001830	81.11	gold quality
paraflocculus	UBERON:0005351	81.10	gold quality
metanephros cortex	UBERON:0010533	81.10	gold quality
esophagus mucosa	UBERON:0002469	80.72	gold quality
mucosa of transverse colon	UBERON:0004991	80.66	gold quality
coronary artery	UBERON:0001621	80.61	gold quality
middle frontal gyrus	UBERON:0002702	80.53	gold quality
lower esophagus mucosa	UBERON:0035834	80.34	gold quality
pituitary gland	UBERON:0000007	80.25	gold quality
Brodmann (1909) area 10	UBERON:0013541	79.91	gold quality
occipital lobe	UBERON:0002021	79.44	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	79.11	gold quality
stomach	UBERON:0000945	78.88	gold quality
mouth mucosa	UBERON:0003729	78.58	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	78.34	gold quality
mammary gland	UBERON:0001911	78.04	gold quality
thoracic mammary gland	UBERON:0005200	77.99	gold quality
small intestine Peyer’s patch	UBERON:0003454	77.95	gold quality
right ovary	UBERON:0002118	77.78	gold quality
muscle organ	UBERON:0001630	77.48	gold quality
right coronary artery	UBERON:0001625	77.31	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

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Thalamus	tissue	93.7
Periaqueductal gray	tissue	88.9
Midbrain	tissue	82.2
Superior colliculi	tissue	79.5
Pons	tissue	79.0
Medulla oblongata	tissue	78.0
Substantia nigra	tissue	74.1
Hypothalamus	tissue	69.7
Spinal cord	tissue	68.1
Cerebral cortex	tissue	64.8	medium
Liver	tissue	64.8	high
Somatosensory cortex	tissue	64.8
Motor cortex	tissue	62.8
Putamen	tissue	61.1
Hippocampal formation	tissue	60.0
Adipose tissue	tissue	57.1	not detected
Basal ganglia	tissue	56.6	medium
Ventral forebrain	tissue	55.9
Nucleus accumbens	tissue	55.8
Prefrontal cortex	tissue	54.9
Hippocampus	tissue	53.7	medium
Temporal cortex	tissue	53.3
Occipital cortex	tissue	53.3
Entorhinal cortex	tissue	52.8
Insular cortex	tissue	52.6
Septum	tissue	52.4
Retrosplenial cortex	tissue	52.4
Amygdala	tissue	51.6
Retrosplenial and cingulate cortex	tissue	51.5
Cerebellum	tissue	51.0	high
Postcentral gyrus	tissue	50.2
Locus coeruleus	tissue	46.7
Corpus callosum	tissue	43.0
Caudate putamen	tissue	42.9
Frontal cortex	tissue	39.7
Olfactory bulb	tissue	38.1
Salivary gland	tissue	33.3	medium
Choroid plexus	tissue	22.8
Kidney	tissue	21.7	high
Parathyroid gland	tissue	17.1	high
Adrenal gland	tissue	12.4	high
Pituitary gland	tissue	10.1
Seminal vesicle	tissue	8.7	high
Skeletal muscle	tissue	7.5	not detected
Small intestine	tissue	7.2	high
Tongue	tissue	6.2
Duodenum	tissue	6.1	medium
Esophagus	tissue	5.4	medium
Testis	tissue	5.1	high
Prostate	tissue	4.9	high
Breast	tissue	4.7	low
Vagina	tissue	4.6	not detected
Pancreas	tissue	4.6	medium
Placenta	tissue	4.1	high
Thyroid gland	tissue	4.1	low
Heart muscle	tissue	4.0	medium
Colon	tissue	3.9	high
Stomach 1	tissue	3.3	high
Bone marrow	tissue	3.3	not detected
Ovary	tissue	3.2	not detected

Brain sub-regions (HPA Brain Atlas): detected in 290; highest nTPM — Posterior thalamic nucleus (91.1), Medial geniculate body (82.6), Medial dorsal thalamic nucleus (78.7), Inferior olive (77.7), Ventral posteromedial thalamic nucleus (77.0).

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets:

Target	Regulation
FASN	Repression

Upstream regulators (CollecTRI, top): AP1, AR, ESR1, EZH2, FOXA2, FOXD4, GLI3, HIF1A, HNF4A, MAFA, NKX6-1, PDX1, PPARG, RNF2, RXRA, SP1, SUZ12, TP53, USF1, YBX1, ZNF236

miRNA regulators (miRDB)

Targeting PC by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

17 miRNAs:

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

gnomAD constraint: pLI 0.0651, LOEUF 0.539, missense Z 3.78 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000393960 splits into 2 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
11:66,848,902–66,849,100	98 / 91.2	1.07	no
11:66,849,101–66,872,159	1143 / 1551.9	0.74	no
ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map
DepMap (CRISPR cell-line fitness): dependent in 19.4% of screened cell lines.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): SK-MEL-24 (-2.1), Panc 03.27 (-1.554), WM1799 (-1.477), HCA-1 (-1.365), HEC-1-B (-1.331), Ishikawa (Heraklio) 02 ER- (-1.249), CCK-81 (-1.238), T98G (-1.225), HSC-3 (-1.209), HEC-116 (-1.19), VMRC-RCW (-1.161), UPCI-SCC-040 (-1.107), HCS-2 (-1.069), TGW (-1.015), Ca9-22 (-0.999).

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)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:97520) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 25 distinct phenotype terms.

Mouse phenotype (MP)	Records
hypoglycemia	1
abnormal liver physiology	1
increased circulating triglyceride level	1
increased circulating free fatty acids level	1
increased circulating ketone body level	1
hepatic steatosis	1
abnormal insulin secretion	1
abnormal insulin clearance	1
increased kidney weight	1
decreased lean body mass	1
improved glucose tolerance	1
decreased circulating glucose level	1
abnormal mitochondrial physiology	1
increased liver triglyceride level	1
increased total body fat amount	1
increased grip strength	1
decreased bone mineral content	1
increased susceptibility to weight loss	1
decreased respiratory quotient	1
abnormal fatty acid oxidation	1
preweaning lethality, complete penetrance	1
abnormal amino acid metabolism	1
decreased fasting circulating glucose level	1
increased circulating lactate level	1
impaired gluconeogenesis	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Mycobacterium tuberculosis variant bovis AF2122/97	P0A509	100.0%	Diamond
Mycobacterium tuberculosis CDC1551	P9WPQ2	100.0%	Diamond
Mycobacterium tuberculosis H37Rv	P9WPQ3	100.0%	Diamond
Escherichia coli K-12	P24182	99.8%	Diamond
Escherichia coli O157:H7	Q8X9B6	99.8%	Diamond
Saccharomyces cerevisiae JAY291	C7GRE4	99.7%	Diamond
Saccharomyces cerevisiae EC1118	C8ZF72	99.7%	Diamond
Saccharomyces cerevisiae S288C	P32874	99.7%	Diamond
Saccharomyces cerevisiae YJM789	A6ZMR9	99.6%	Diamond
Saccharomyces cerevisiae RM11-1a	B3LM95	99.6%	Diamond
Aspergillus terreus	O93918	99.6%	Diamond
Aspergillus terreus NIH2624	Q0CLK1	99.6%	Diamond
Salmonella enterica subsp. enterica serovar Typhimurium str. LT2	Q03030	97.5%	Diamond
Salmonella enterica subsp. enterica serovar Typhi	Q8XGX8	97.5%	Diamond
Bos taurus	Q29RK2	97.4%	Diamond
Populus trichocarpa	B9HBA8	94.1%	Diamond
Aspergillus niger	Q9HES8	93.3%	Diamond
Caenorhabditis briggsae	Q612F5	91.3%	Diamond
Sus scrofa	P0DTA4	88.6%	Diamond
Arabidopsis thaliana	O04983	87.5%	Diamond
Klebsiella pneumoniae	P13187	87.4%	Diamond
Mycobacterium leprae TN	P46392	86.0%	Diamond
Haemophilus influenzae Rd KW20	P43873	82.1%	Diamond
Komagataella pastoris	P78992	81.9%	Diamond
Ogataea angusta	Q8X1T3	81.9%	Diamond
Myxococcus xanthus	P81185	77.8%	Diamond
Haloferax mediterranei ATCC 33500	I3R7G3	76.9%	Diamond
Methanothermobacter thermautotrophicus str. Delta H	O27939	76.9%	Diamond
Archaeoglobus fulgidus DSM 4304	O30019	76.9%	Diamond
Allochromatium vinosum DSM 180	O52058	75.3%	Diamond
Hydrogenobacter thermophilus TK-6	D3DJ42	75.0%	Diamond
Oryza sativa Japonica Group	Q2QMG2	75.0%	Diamond
Lachancea kluyveri	A5H0J2	74.2%	Diamond
Pseudomonas aeruginosa PAO1	P37798	71.9%	Diamond
Glycine max	Q42777	71.7%	Diamond
Methanocaldococcus jannaschii DSM 2661	Q58626	70.4%	Diamond
Solanum lycopersicum	P05115	70.0%	Diamond
Schizosaccharomyces pombe 972h-	Q9UUE1	69.4%	Diamond
Bacillus subtilis subsp. subtilis str. 168	O34544	69.2%	Diamond
Dictyostelium discoideum	Q54KE6	67.9%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
MIR3163	ncRNA	100423029
C11orf86	protein-coding	254439
LRFN4	protein-coding	78999
TOP6BL	protein-coding	79703
RCE1	protein-coding	9986
SPTBN2	protein-coding	6712
MIR6860	ncRNA	102465518
SYT12	protein-coding	91683
RHOD	protein-coding	29984
RBM4	protein-coding	5936
RBM4B	protein-coding	83759

Protein

Protein identifiers

Pyruvate carboxylase, mitochondrial — P11498 (reviewed: P11498)

Alternative names: Pyruvic carboxylase

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

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 (9): NP_000911, NP_001035806, NP_001426281, NP_001426282, NP_001426284, NP_001426286, NP_001426287, NP_001426288, 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)

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

UniProt features (174 total): helix 52, 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 by resolution:

PDB	Title	Method	Resolution (Å)
8XL9	Structure of human pyruvate carboxylase	ELECTRON MICROSCOPY	2.61
3BG3	Crystal Structure of Human Pyruvate Carboxylase (missing the biotin carboxylase domain at …	X-RAY DIFFRACTION	2.8
3BG9	Crystal Structure of Human Pyruvate Carboxylase (missing the biotin carboxylase domain at …	X-RAY DIFFRACTION	3
7WTE	Cryo-EM structure of human pyruvate carboxylase with acetyl-CoA in the intermediate state …	ELECTRON MICROSCOPY	3.3
7WTB	Cryo-EM structure of human pyruvate carboxylase with acetyl-CoA	ELECTRON MICROSCOPY	3.7
8J7O	Human pyruvate carboxylase in BCCP-CTS state without BC	ELECTRON MICROSCOPY	3.83
7WTA	Cryo-EM structure of human pyruvate carboxylase in apo state	ELECTRON MICROSCOPY	3.9
7WTD	Cryo-EM structure of human pyruvate carboxylase with acetyl-CoA in the intermediate state …	ELECTRON MICROSCOPY	3.9
7WTC	Cryo-EM structure of human pyruvate carboxylase with acetyl-CoA in the ground state	ELECTRON MICROSCOPY	4
8HWL	Human Pyruvate Carboxylase	ELECTRON MICROSCOPY	5.63

Predicted structure (AlphaFold)

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

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Ligase, Metabolic proteins, Predicted intracellular proteins, Plasma proteins, Citric acid cycle related proteins, Disease related genes, Potential drug targets, Human disease related genes, Congenital disorders of metabolism, Congenital disorders of carbohydrate metabolism, Congenital disorders of amino acid metabolism, Essential proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): mitochondria

Antibody reliability (HPA): IH enhanced · IF enhanced

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)

Position	Role
328

Ligand- & substrate-binding residues (10)

Position	Role
571–575	substrate
572	Mn(2+)
644	substrate
741	Mn(2+)
771	Mn(2+)
773	Mn(2+)
908	substrate
152	ATP
236	ATP
271	ATP

Post-translational modifications (24)

Type	Positions
N6-acetyllysine	35, 39, 79, 148, 152, 241, 297, 319, 434, 589, 661, 717, 748, 892, 969, 992, 1061, 1090, 1124
N6-succinyllysine	79, 442
N6-carboxylysine	741
Phosphothreonine	1003
N6-biotinyllysine	1144

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 curated (TAS) of 14; 5 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

14 pathways:

ID	Pathway	Evidence
R-HSA-3371599	Defective HLCS causes multiple carboxylase deficiency ⚕	curated
R-HSA-196780	Biotin transport and metabolism	curated
R-HSA-70263	Gluconeogenesis	curated
R-HSA-70268	Pyruvate metabolism	curated
R-HSA-3323169	Defects in biotin (Btn) metabolism ⚕	—
R-HSA-3296482	Defects in vitamin and cofactor metabolism ⚕	—
R-HSA-1643685	Disease ⚕	—
R-HSA-5668914	Diseases of metabolism ⚕	—
R-HSA-1428517	Aerobic respiration and respiratory electron transport	—
R-HSA-70326	Glucose metabolism	—
R-HSA-1430728	Metabolism	—
R-HSA-71387	Metabolism of carbohydrates and carbohydrate derivatives	—
R-HSA-196854	Metabolism of vitamins and cofactors	—
R-HSA-196849	Metabolism of water-soluble vitamins and cofactors	—

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 (10): 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), 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

10 top-level categories:

Category	Pathways
Metabolism	3
Metabolism of water-soluble vitamins and cofactors	1
Defects in biotin (Btn) metabolism	1
Glucose metabolism	1
Aerobic respiration and respiratory electron transport	1
Metabolism of vitamins and cofactors	1
Diseases of metabolism	1
Defects in vitamin and cofactor metabolism	1
Disease	1
Metabolism of carbohydrates and carbohydrate derivatives	1

GO top-level categories

36 GO namespaces:

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
anion 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

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 10 of 24 annotations. The rest are phylogenetic / computational / electronic (IEA).

10 experimentally-supported GO terms:

GO term	NS	Evidence
NAD+ metabolic process	BP	direct assay
NADP+ metabolic process	BP	direct assay
host-mediated activation of viral process	BP	mutant phenotype
negative regulation of gene expression	BP	mutant phenotype
viral RNA genome packaging	BP	mutant phenotype
viral release from host cell	BP	mutant phenotype
cytoplasm	CC	direct assay
mitochondrion	CC	direct assay
identical protein binding	MF	physical interaction
pyruvate carboxylase activity	MF	mutant phenotype

Protein interactions and networks

STRING

showing 15 of 2,164 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PC	HLCS	P50747	959
PC	PKM	P14618	923
PC	PCK1	P35558	921
PC	FBP1	P09467	912
PC	BTD	P43251	882
PC	PFKM	P08237	878
PC	PCK2	Q16822	836
PC	PFKFB3	Q16875	822
PC	CS	O75390	787
PC	PYDC1	Q8WXC3	774
PC	G6PC1	P35575	764
PC	G6PC3	Q9BUM1	752
PC	MCM2	P49736	738
PC	GPD2	P43304	738
PC	G6PC2	Q9NQR9	733

IntAct

Human interaction partners of PC in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

9 partners by confidence:

Partner	Interaction type	MIscore	Records
ME1	colocalization	0.670	10
ASS1	association	0.530	3
MDH1	association	0.460	6
CER1	association	0.350	1
DNAJB9	association	0.350	1
PTPN9	association	0.350	1
TMEM87A	association	0.350	1
UXT	association	0.350	1
LCOR	physical association	0.000	1

BioGRID (249 interactions; top human partners by supporting records): CBWD1 (Affinity Capture-MS; 3 records), ANTXR1 (Affinity Capture-MS; 2 records), ASS1 (Affinity Capture-MS; 2 records), BPNT1 (Affinity Capture-MS; 2 records), CCNF (Proximity Label-MS; 2 records), DEFA5 (Affinity Capture-MS; 2 records), EGFR (Affinity Capture-MS; 2 records), FASN (Co-fractionation; 2 records), HSD3B2 (Affinity Capture-MS; 2 records), HSPA1A (Affinity Capture-MS; 2 records), HSPA4 (Affinity Capture-Western; 2 records), PARK2 (Affinity Capture-MS; 2 records), PFAS (Co-fractionation; 2 records), STRAP (Affinity Capture-MS; 2 records), TOPBP1 (Proximity Label-MS; 2 records)

SIGNOR signaling

4 signaling 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

Genetic variants

Variant evidence for PC: 1,522 ClinVar records (166 pathogenic / likely pathogenic); 16 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

1,522 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	66
Likely pathogenic	100
Uncertain significance	306
Likely benign	887
Benign	19

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 166 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
556347	NM_001040716.2(PC):c.2493_2494del (p.Val831_Phe832insTer)	Pathogenic	criteria provided, multiple submitters, no conflicts	4
2094	NM_001040716.2(PC):c.1828G>A (p.Ala610Thr)	Pathogenic	criteria provided, multiple submitters, no conflicts	3
3902729	NM_001040716.2(PC):c.787C>T (p.Arg263Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
551488	NM_001040716.2(PC):c.633+2T>C	Likely pathogenic	criteria provided, multiple submitters, no conflicts	4
2097	NM_001040716.2(PC):c.1351C>T (p.Arg451Cys)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	3
448903	NM_001040716.2(PC):c.1368+1G>A	Likely pathogenic	criteria provided, multiple submitters, no conflicts	3
2677480	NM_001040716.2(PC):c.1826-1G>C	Likely pathogenic	criteria provided, multiple submitters, no conflicts	3
1315508	NM_001040716.2(PC):c.1983-116C>T	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2
1315511	NM_001040716.2(PC):c.2435C>A (p.Ala812Asp)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2
1724661	NM_001040716.2(PC):c.280C>T (p.Gln94Ter)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2
1726517	NM_001040716.2(PC):c.2971G>T (p.Glu991Ter)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2
555085	NM_001040716.2(PC):c.3359_3362dup (p.Ile1123fs)	Pathogenic	criteria provided, single submitter	2
203922	NM_001040716.2(PC):c.797C>A (p.Ser266Tyr)	Pathogenic	criteria provided, single submitter	1
487339	NM_001040716.2(PC):c.2668G>T (p.Val890Phe)	Pathogenic	criteria provided, single submitter	1
575715	NM_001040716.2(PC):c.372_375del (p.Ala125fs)	Pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore PC’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 32 predictions of 2,525):

Position(s)	Effect	Δscore	Sites
11:66849228–66849229	donor_loss	1.0000	5
11:66849232	donor_gain	1.0000
11:66849371	acceptor_loss	1.0000
11:66849610	donor_loss	1.0000
11:66849726	donor_gain	1.0000
11:66849860–66849861	acceptor_loss	1.0000	6
11:66849935–66849936	donor_loss	1.0000	4
11:66850117–66850118	acceptor_loss	1.0000	3
11:66850218–66850219	donor_loss	1.0000	5
11:66850924–66850925	acceptor_loss	1.0000	5

HPA cancer prognostics

RNA cancer specificity: Cancer enhanced (Liver Hepatocellular Carcinoma)

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

7 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	2.81e-13
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	6.67e-07
Kidney Renal Clear Cell Carcinoma (validation)	favorable	0.000116
Pancreatic Adenocarcinoma (TCGA)	unfavorable	0.000277
Skin Cutaneous Melanoma (TCGA)	unfavorable	0.000509
Ovary Serous Cystadenocarcinoma (TCGA)	unfavorable	0.000597
Colon Adenocarcinoma (TCGA)	favorable	0.000868

Disease associations

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

GenCC curated gene-disease

4 curated gene-disease records:

Disease	Classification	Inheritance	Records
pyruvate carboxylase deficiency disease	Definitive	Autosomal recessive	4
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

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (13 panels, 13 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

13 panels:

Panel	Rating
DDG2P	green
Fetal anomalies	green
Hyperammonaemia	green
Hypotonic infant	green
Intellectual disability	green
Ketotic hypoglycaemia	green
Leukodystrophy, childhood onset	green
Likely inborn error of metabolism	green
Mitochondrial disorders	green
Paediatric disorders	green
Possible mitochondrial disorder, nuclear genes	green
Undiagnosed metabolic disorders	green
Unexplained death in infancy and sudden unexplained death in childhood	green

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

19 phenotypes (HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001943	Hypoglycemia
HP:0002049	Proximal renal tubular acidosis
HP:0002151	Increased circulating lactate concentration
HP:0002169	Clonus
HP:0002240	Hepatomegaly
HP:0002305	Athetosis
HP:0002415	Leukodystrophy
HP:0003128	Lactic acidosis
HP:0003348	Hyperalaninemia
HP:0003542	Increased circulating pyruvate concentration
HP:0003577	Congenital onset
HP:0003593	Infantile onset
HP:0006970	Periventricular leukomalacia
HP:0007190	Neuronal loss in the cerebral cortex

GWAS associations

16 associations:

Study	Trait	p-value
GCST90020029_1575	Waist circumference adjusted for body mass index	1e-30
GCST012227_237	Hip circumference adjusted for BMI	1e-25
GCST012226_788	Waist circumference adjusted for body mass index	5e-16
GCST90020028_1515	Hip circumference adjusted for BMI	4e-13
GCST90020024_651	A body shape index	8e-13
GCST012227_240	Hip circumference adjusted for BMI	2e-10
GCST90020029_1576	Waist circumference adjusted for body mass index	3e-9
GCST012465_46	Bipolar disorder	5e-9
GCST90020028_1514	Hip circumference adjusted for BMI	7e-9
GCST012226_789	Waist circumference adjusted for body mass index	2e-8
GCST008103_6	Bipolar disorder	4e-8
GCST008972_198	Urate levels	5e-8
GCST90020027_715	Waist-hip index	5e-8
GCST001241_12	Bipolar disorder	2e-7
GCST006088_11	Familial squamous cell lung carcinoma	1e-6
GCST001353_7	HIV-1 susceptibility	8e-6

EFO canonical traits (from GWAS)

6 canonical traits:

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 disease descriptors:

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 (CPIC guideline: no)

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

Binding affinities (BindingDB)

7 measured of 29 human assays (29 total across all organisms); most potent 7 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL5569150	IC50	54 nM
CHEMBL5566098	IC50	58 nM
CHEMBL450226	IC50	69 nM
CHEMBL5574397	IC50	73 nM
CHEMBL5570469	IC50	175 nM
CHEMBL5571609	IC50	793 nM
CHEMBL5570175	IC50	894 nM

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	affects methylation, decreases methylation, increases expression, increases methylation	5
sodium arsenite	decreases expression, increases expression	4
Tetrachlorodibenzodioxin	affects expression, increases expression	4
bisphenol A	affects cotreatment, decreases methylation, increases expression	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	increases expression, increases abundance, affects cotreatment	1
glycidyl methacrylate	decreases expression	1
lead acetate	decreases expression	1
nobiletin	decreases reaction, decreases expression	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	affects binding, increases reaction	1
sulforaphane	decreases expression	1
benzo(e)pyrene	affects methylation	1
aflatoxin B2	decreases methylation	1
cupric chloride	decreases expression	1
methacrylaldehyde	increases abundance, affects cotreatment, increases expression	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)

Via MONDO — disease-level, not drug-specific.

1 trials:

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

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for PC across ~30M SureChEMBL compounds — explore on Sugi Predict.