TPI1

Summary

TPI1 (triosephosphate isomerase 1, HGNC:12009) is a protein-coding gene on chromosome 12p13.31, encoding Triosephosphate isomerase (P60174). Triosephosphate isomerase is an extremely efficient metabolic enzyme that catalyzes the interconversion between dihydroxyacetone phosphate (DHAP) and D-glyceraldehyde-3-phosphate (G3P) in glycolysis and gluconeogenesis. It is a selective cancer dependency (DepMap: 84.3% of cell lines).

This gene encodes an enzyme, consisting of two identical proteins, which catalyzes the isomerization of glyceraldehydes 3-phosphate (G3P) and dihydroxy-acetone phosphate (DHAP) in glycolysis and gluconeogenesis. Mutations in this gene are associated with triosephosphate isomerase deficiency. Pseudogenes have been identified on chromosomes 1, 4, 6 and 7. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 7167 — RefSeq curated summary.

At a glance

• Gene–disease (curated): triosephosphate isomerase deficiency (Strong, GenCC)
• GWAS associations: 2
• Clinical variants (ClinVar): 176 total — 7 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 42
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 84.3% of screened cell lines
• MANE Select transcript: NM_000365

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12009
Approved symbol	TPI1
Name	triosephosphate isomerase 1
Location	12p13.31
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000111669
Ensembl biotype	protein_coding
OMIM	190450
Entrez	7167

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 19 protein_coding, 2 retained_intron

ENST00000229270, ENST00000396705, ENST00000462761, ENST00000474253, ENST00000482209, ENST00000488464, ENST00000493987, ENST00000495834, ENST00000535434, ENST00000613953, ENST00000854164, ENST00000854165, ENST00000854166, ENST00000854167, ENST00000854168, ENST00000854169, ENST00000934760, ENST00000934761, ENST00000934762, ENST00000948630, ENST00000948631

RefSeq mRNA: 3 — MANE Select: NM_000365 NM_000365, NM_001159287, NM_001258026

CCDS: CCDS53740, CCDS58206, CCDS8566

Canonical transcript exons

ENST00000396705 — 7 exons

Exon	Start	End
ENSE00001385368	6870265	6870948
ENSE00001742890	6867531	6867681
ENSE00003507218	6869099	6869183
ENSE00003538452	6868864	6868987
ENSE00003697036	6869688	6869773
ENSE00003700131	6869258	6869390
ENSE00003700470	6870049	6870136

Expression profiles

Bgee: expression breadth ubiquitous, 308 present calls, max score 99.75.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 82.7648 / max 1805.8429, expressed in 1821 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
123779	78.4746	1819
123780	1.8016	707
123783	1.2844	556
123782	1.0375	634
123781	0.1668	78

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right frontal lobe	UBERON:0002810	99.75	gold quality
prefrontal cortex	UBERON:0000451	99.70	gold quality
right hemisphere of cerebellum	UBERON:0014890	99.69	gold quality
ventricular zone	UBERON:0003053	99.66	gold quality
mucosa of transverse colon	UBERON:0004991	99.65	gold quality
cerebellar hemisphere	UBERON:0002245	99.64	gold quality
hindlimb stylopod muscle	UBERON:0004252	99.64	gold quality
cerebellar cortex	UBERON:0002129	99.63	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	99.62	gold quality
right adrenal gland	UBERON:0001233	99.60	gold quality
left adrenal gland	UBERON:0001234	99.58	gold quality
metanephros cortex	UBERON:0010533	99.57	gold quality
right adrenal gland cortex	UBERON:0035827	99.57	gold quality
left adrenal gland cortex	UBERON:0035825	99.55	gold quality
vastus lateralis	UBERON:0001379	99.54	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	99.54	gold quality
lower esophagus mucosa	UBERON:0035834	99.54	gold quality
Brodmann (1909) area 9	UBERON:0013540	99.53	gold quality
right atrium auricular region	UBERON:0006631	99.52	gold quality
cerebellum	UBERON:0002037	99.51	gold quality
esophagus mucosa	UBERON:0002469	99.51	gold quality
gastrocnemius	UBERON:0001388	99.50	gold quality
frontal cortex	UBERON:0001870	99.50	gold quality
heart left ventricle	UBERON:0002084	99.50	gold quality
apex of heart	UBERON:0002098	99.50	gold quality
frontal lobe	UBERON:0016525	99.50	gold quality
muscle of leg	UBERON:0001383	99.49	gold quality
cardiac ventricle	UBERON:0002082	99.49	gold quality
adrenal cortex	UBERON:0001235	99.48	gold quality
muscle organ	UBERON:0001630	99.48	gold quality

Single-cell (SCXA)

Detected in 22 experiment(s), a significant marker in 13.

Experiment	Marker?	Max mean expression
E-MTAB-7249	yes	11431.68
E-HCAD-8	yes	2097.47
E-MTAB-9067	yes	1436.35
E-HCAD-6	yes	771.75
E-HCAD-4	yes	78.04
E-HCAD-5	yes	53.07
E-CURD-46	yes	25.93
E-CURD-122	yes	23.77
E-MTAB-10042	yes	17.36
E-MTAB-10553	yes	7.89
E-MTAB-7316	yes	7.66
E-CURD-88	yes	5.63
E-ENAD-20	no	3470.52
E-GEOD-75140	no	3082.76
E-CURD-6	no	2663.94

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): JUN, MYC, SP1, TBP

miRNA regulators (miRDB)

41 targeting TPI1, 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-7152-3P	99.97	67.47	849
HSA-MIR-22-3P	99.93	68.13	917
HSA-MIR-378G	99.71	64.90	1106
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-7150	99.62	66.80	1322
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-885-5P	99.59	68.59	879
HSA-MIR-5584-5P	99.49	68.22	2814
HSA-MIR-7515	99.31	68.22	1795
HSA-MIR-6731-5P	99.28	67.42	2375
HSA-MIR-8085	99.28	67.56	2362
HSA-MIR-6878-3P	99.24	64.23	920
HSA-MIR-4434	99.10	67.01	1984
HSA-MIR-5703	99.10	67.09	2053
HSA-MIR-4699-5P	98.99	67.50	1210
HSA-MIR-3154	98.94	66.55	1455
HSA-MIR-6829-5P	98.86	65.12	1480
HSA-MIR-6512-5P	98.76	69.29	1195
HSA-MIR-9500	98.62	66.54	1845
HSA-MIR-3187-5P	98.36	65.74	1776
HSA-MIR-4436B-3P	98.25	65.26	1494
HSA-MIR-6735-5P	98.24	65.36	1488
HSA-MIR-6882-3P	98.23	67.01	1119
HSA-MIR-7843-5P	98.12	65.26	1421
HSA-MIR-4483	98.09	64.12	1642
HSA-MIR-4632-5P	97.82	65.38	1470
HSA-MIR-6879-5P	97.77	65.52	1521
HSA-MIR-1285-3P	97.72	67.02	1932
HSA-MIR-5189-5P	97.72	66.96	1814

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 84.3% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• kinetic, thermodynamic, structural and ultrastructural data for characterization of mutant isomerase structures and for the TPI-related metabolic processes in normal and deficient cells (PMID:12023819)
• Minor structural changes in a mutated human melanoma antigen (TPI) correspond to dramatically enhanced stimulation of a CD4+ tumor-infiltrating lymphocyte line. (PMID:12051920)
• A patient with triosephosphate isomerase (TPI) deficiency exhibited worsening of abnormal involuntary movements of the dystonic type and developed psychiatric symptoms while on selegiline. (PMID:14743370)
• IgG-type anti-TPI autoantibodies were detected in 24.7% of the serum samples and 24.1% of the synovial fluid samples from the patients with osteoarthritis (PMID:15146421)
• anti-TPI antibodies are closely associated with neuropsychiatric lupus (PMID:15358119)
• We found that a low TPI activity in the mutant cells (lower than predicted from the protein level and specific activity of the purified recombinant enzyme) is coupled with an increase in the activities of glycolytic kinases (PMID:16086671)
• Mutations causing TPI deficiency in humans are characterized by progressive neurological dysfunction, neurodegeneration, and early death. (PMID:17008404)
• TPI and GAPDH may be candidate Ags for an autoimmune response to neurons and axons in multiple sclerosis. (PMID:17015754)
• anti-TPI form immune complexes in CSF and contribute to the pathogenesis of neuropsychiatric lupus by activating the complement system (PMID:17064784)
• the dimerization behavior of TPI is influenced by the particular mutations investigated, and by the use of a potential alternative translation initiation site in the TPI gene (PMID:17183658)
• Triosephosphate isomerase (TPI), a glycolytic pathway enzyme, was identified as a downregulated protein in SGC7901/VCR cells (PMID:18309519)
• TPI variants occur less frequent than expected and inactive alleles are not enriched in German centenarians (PMID:18510744)
• human triosephosphate isomerase mutation E104D is related to alterations of a conserved water network at the dimer interface (PMID:18562316)
• Population samples from Angola, Mozambique and S. Tome e Principe has 3 haplotypes of the TPI gene promoter variants -5A-8G-24T,-5G-8G-24T and -5G-8A-24T in malaria-infected individuals. (PMID:18792062)
• This protein has been found differentially expressed in the Wernicke’s Area from patients with schizophrenia. (PMID:19405953)
• TPI1 were up-regulated with the malignancy of prostate cancer cell lines and have their potential as serum biomarkers for indicating the developmental stage of prostate cancer. (PMID:20233700)
• of two previously undescribed mutations: c.722 T>C (Phe240Ser) and c.28 insG; each of the two unrelated patients showed the new mutation in compound heterozygosity with the most common variant Glu104Asp, resulting in a very severe clinical pattern. (PMID:20374271)
• This protein has been found differentially expressed in thalami from patients with schizophrenia. (PMID:20471030)
• structural changes rather than abnormal catalysis may play an important role in the clinical manifestations of TPI deficiency; the postulated high aggregation ability of the unstable Glu104Asp mutant would lead to more serious symptoms (PMID:20546019)
• A patient with triosephosphate isomerase-deficiency was found to be homozygous for a Val231Met mutation. (PMID:21215915)
• [Review] The activity of glycolytic enzyme TPI reveals a mechanistic link between energy metabolism and age-related proteostatic dysfunction which can suppress generation of altered proteins that characterize the aged phenotype in cells and tissues. (PMID:21651995)
• A proteomic approach for identification and localization of the pericellular components of chondrocytes. (PMID:21698479)
• study found promoter SNPs of CKB and TPI1 were weakly associated with schizophrenia;in addition, IFNG polymorphisms were associated with schizophrenia; results suggest that IFNG and proteins affected by IFNG may play a role in the pathogenesis of schizophrenia (PMID:22623148)
• we review the relationship between modified TPI and Alzheimer disease (AD), highlighting the relevance of this protein in AD pathology (PMID:23233058)
• Data suggest that exchange reactions during gluconeogenesis catalyzed by triose-phosphate isomerase and transaldolase do not differ between subjects with type 2 diabetes and control subjects under fasting or hyperglycemic conditions. (PMID:23736541)
• E104D mutant is highly susceptible to proteolysis, which in all likelihood contributes to the pathogenesis of enzymopathy. In addition, the proteolysis data on wild type HsTIM illustrate an asymmetric conduct of the two monomers. (PMID:24056040)
• TPI-PEP co-crystal structure, demonstrating that PEP directly binds into the catalytic pocket of TPI. (PMID:24598263)
• results suggest amyloid-beta oligomers induce neuronal death by triggering methylglyoxal(MG) production; increased release of MG is a direct consequence of triosephosphate isomerase nitrotyrosination due to amyloid-beta peptide action at the 2 tyrosines associated with the catalytic center (PMID:24614897)
• Polyvinylpyrrolidone stabilised silver nanoparticles (60 nM; 2-6 nm diameter) selectively inhibited PfTIM with a 7-fold decrease in enzyme catalytic efficiency (K(cat)/K(m)) over hTIM. (PMID:26353595)
• our findings are the first to identify, to our knowledge, a functional synaptic defect in TPI deficiency derived from molecular changes in the TPI dimer interface. (PMID:27031109)
• TPI1 functions as a tumor suppressor in hepatocellular carcinoma and might serve as a potential therapeutic target for the treatment of HCC (PMID:27908734)
• Disease-associated variants change well-conserved residues in the protein’s sequence and affect protein stability. (PMID:28341520)
• A guide to the effects of a large portion of the residues of triosephosphate isomerase on catalysis, stability, druggability, and human disease has been presented. (Review) (PMID:28378917)
• Results revealed that TPI expression might be considered as a novel prognostic factor to evaluate gastric cancer patients’ survival (PMID:28489783)
• first study describing features of human triosephosphate isomerase S-nitrosylation (PMID:29678765)
• we identified two novel microRNAs, miR-22 and miR-28, that target the TPI messenger RNA (mRNA) and regulate its expression. miR-22 and the miR-28 showed significant inverse expression status viz-a-viz the expression of the TPI (PMID:29856481)
• Triosephosphate isomerase deficiency: Effect of F240L mutation on enzyme structure. (PMID:32585311)
• Proteomics analysis identified TPI1 as a novel biomarker for predicting recurrence of intrahepatic cholangiocarcinoma. (PMID:33089343)
• Glycolysis- and immune-related novel prognostic biomarkers of Ewing’s sarcoma: glucuronic acid epimerase and triosephosphate isomerase 1. (PMID:34233293)
• TPI1-reduced extracellular vesicles mediated by Rab20 downregulation promotes aerobic glycolysis to drive hepatocarcinogenesis. (PMID:34401050)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	tpi1a	ENSDARG00000025012
danio_rerio	tpi1b	ENSDARG00000040988
mus_musculus	Tpi1	ENSMUSG00000023456
rattus_norvegicus	Tpi1l1	ENSRNOG00000015290
rattus_norvegicus	Tpi1l2	ENSRNOG00000031706
rattus_norvegicus	Tpi1l1	ENSRNOG00000055222
drosophila_melanogaster	Tpi	FBGN0086355
caenorhabditis_elegans		WBGENE00006601

Protein

Protein identifiers

Triosephosphate isomerase — P60174 (reviewed: P60174)

Alternative names: Methylglyoxal synthase, Triose-phosphate isomerase

All UniProt accessions (5): P60174, U3KPS5, U3KPZ0, U3KQF3, V9HWK1

UniProt curated annotations — full annotation on UniProt →

Function. Triosephosphate isomerase is an extremely efficient metabolic enzyme that catalyzes the interconversion between dihydroxyacetone phosphate (DHAP) and D-glyceraldehyde-3-phosphate (G3P) in glycolysis and gluconeogenesis. It is also responsible for the non-negligible production of methylglyoxal a reactive cytotoxic side-product that modifies and can alter proteins, DNA and lipids.

Subunit / interactions. Homodimer.

Subcellular location. Cytoplasm.

Disease relevance. Triosephosphate isomerase deficiency (TPID) [MIM:615512] An autosomal recessive multisystem disorder characterized by congenital hemolytic anemia, progressive neuromuscular dysfunction, susceptibility to bacterial infection, and cardiomyopathy. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Carbohydrate degradation; glycolysis; D-glyceraldehyde 3-phosphate from glycerone phosphate: step 1/1. Carbohydrate biosynthesis; gluconeogenesis.

Miscellaneous. Produced by alternative splicing.

Similarity. Belongs to the triosephosphate isomerase family.

Isoforms (3)

UniProt ID	Names	Canonical?
P60174-1	1	yes
P60174-3	2
P60174-4	3

RefSeq proteins (3): NP_000356, NP_001152759, NP_001244955 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000652	Triosephosphate_isomerase	Family
IPR013785	Aldolase_TIM	Homologous_superfamily
IPR020861	Triosephosphate_isomerase_AS	Active_site
IPR022896	TrioseP_Isoase_bac/euk	Family
IPR035990	TIM_sf	Homologous_superfamily

Pfam: PF00121

Enzyme classification (BRENDA):

• EC 5.3.1.1 — triose-phosphate isomerase (BRENDA: 65 organisms, 44 substrates, 155 inhibitors, 233 Km, 204 kcat entries)

Substrate kinetics (BRENDA)

4 substrates with measured Km, best-characterized 4. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
D-GLYCERALDEHYDE 3-PHOSPHATE	—	181
DIHYDROXYACETONE PHOSPHATE	0.0025–18	21
GLYCERONE PHOSPHATE	0.26–2.5	21
DIHYDROXYACETONE 3-PHOSPHATE	0.59–25	9

Catalyzed reactions (Rhea), 2 shown:

• dihydroxyacetone phosphate = methylglyoxal + phosphate (RHEA:17937)
• D-glyceraldehyde 3-phosphate = dihydroxyacetone phosphate (RHEA:18585)

UniProt features (72 total): modified residue 19, helix 15, strand 10, sequence variant 8, sequence conflict 8, turn 3, active site 2, splice variant 2, binding site 2, initiator methionine 1, chain 1, cross-link 1

Structure

Experimental structures (PDB)

29 structures.

PDB	Method	Resolution (Å)
9F69	X-RAY DIFFRACTION	1.17
9FFC	X-RAY DIFFRACTION	1.25
7RDE	X-RAY DIFFRACTION	1.31
4UNL	X-RAY DIFFRACTION	1.5
4POC	X-RAY DIFFRACTION	1.6
6UPF	X-RAY DIFFRACTION	1.65
4ZVJ	X-RAY DIFFRACTION	1.7
2JK2	X-RAY DIFFRACTION	1.7
6UP1	X-RAY DIFFRACTION	1.83
2VOM	X-RAY DIFFRACTION	1.85
4BR1	X-RAY DIFFRACTION	1.9
6UP5	X-RAY DIFFRACTION	1.92
1KLU	X-RAY DIFFRACTION	1.93
4POD	X-RAY DIFFRACTION	1.99
4UNK	X-RAY DIFFRACTION	2
6UP8	X-RAY DIFFRACTION	2
7T0Q	X-RAY DIFFRACTION	2
7UXB	X-RAY DIFFRACTION	2
6D43	X-RAY DIFFRACTION	2.04
7UXV	X-RAY DIFFRACTION	2.15
6NLH	X-RAY DIFFRACTION	2.2
1WYI	X-RAY DIFFRACTION	2.2
7SX1	X-RAY DIFFRACTION	2.23
6C2G	X-RAY DIFFRACTION	2.3
1KLG	X-RAY DIFFRACTION	2.4
4E41	X-RAY DIFFRACTION	2.6
1HTI	X-RAY DIFFRACTION	2.8
2IAM	X-RAY DIFFRACTION	2.8
2IAN	X-RAY DIFFRACTION	2.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P60174-F1	96.87	0.96

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 (2): 96 (electrophile); 166 (proton acceptor)

Ligand- & substrate-binding residues (2): 12; 14

Post-translational modifications (20): 106, 149, 156, 156, 159, 173, 194, 194, 194, 198, 209, 212, 214, 223, 238, 142, 14, 21, 68, 80

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-70171	Glycolysis
R-HSA-70263	Gluconeogenesis

MSigDB gene sets: 435 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, GGGACCA_MIR133A_MIR133B, GOBP_NUCLEOSIDE_DIPHOSPHATE_METABOLIC_PROCESS, MODY_HIPPOCAMPUS_POSTNATAL, MODULE_151, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, GOBP_POLYOL_METABOLIC_PROCESS, DITTMER_PTHLH_TARGETS_UP, GOBP_POLYOL_CATABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, GOBP_MONOSACCHARIDE_CATABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, TGACCTY_ERR1_Q2, KEGG_GLYCOLYSIS_GLUCONEOGENESIS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS

GO Biological Process (8): gluconeogenesis (GO:0006094), glycolytic process (GO:0006096), methylglyoxal biosynthetic process (GO:0019242), glycerol catabolic process (GO:0019563), glyceraldehyde-3-phosphate biosynthetic process (GO:0046166), canonical glycolysis (GO:0061621), glucose metabolic process (GO:0006006), glyceraldehyde-3-phosphate metabolic process (GO:0019682)

GO Molecular Function (7): triose-phosphate isomerase activity (GO:0004807), methylglyoxal synthase activity (GO:0008929), ubiquitin protein ligase binding (GO:0031625), protein homodimerization activity (GO:0042803), protein binding (GO:0005515), lyase activity (GO:0016829), isomerase activity (GO:0016853)

GO Cellular Component (5): obsolete extracellular space (GO:0005615), nucleus (GO:0005634), cytosol (GO:0005829), extracellular exosome (GO:0070062), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Glucose metabolism	2

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
aldehyde biosynthetic process	2
catalytic activity	2
cellular anatomical structure	2
glucose metabolic process	1
hexose biosynthetic process	1
phosphoglycerate kinase activity	1
phosphoglycerate mutase activity	1
phosphopyruvate hydratase activity	1
pyruvate kinase activity	1
pyruvate metabolic process	1
generation of precursor metabolites and energy	1
aerobic respiration	1
carbohydrate catabolic process	1
pyridine nucleotide catabolic process	1
glyceraldehyde-3-phosphate dehydrogenase [NAD(P)+] (phosphorylating) activity	1
ADP catabolic process	1
ATP metabolic process	1
nicotinamide nucleotide metabolic process	1
methylglyoxal metabolic process	1
ketone biosynthetic process	1
glycerol metabolic process	1
alditol catabolic process	1
glyceraldehyde-3-phosphate metabolic process	1
organophosphate biosynthetic process	1
carbohydrate derivative biosynthetic process	1
glucokinase activity	1
glyceraldehyde-3-phosphate dehydrogenase (NAD+) (phosphorylating) activity	1
glucose catabolic process	1
glycolytic process through glucose-6-phosphate	1
hexose metabolic process	1
aldehyde metabolic process	1
organophosphate metabolic process	1
carbohydrate derivative metabolic process	1
intramolecular oxidoreductase activity, interconverting aldoses and ketoses	1
carbon-oxygen lyase activity, acting on phosphates	1
ubiquitin-like protein ligase binding	1
identical protein binding	1
protein dimerization activity	1
binding	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

114 interactions, top by confidence:

A	B	Type	Score
MED20	MED19	psi-mi:“MI:0914”(association)	0.840
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
PYGO2	BCL9	psi-mi:“MI:0914”(association)	0.690
HTT	TPI1	psi-mi:“MI:0915”(physical association)	0.560
EGFR	TPI1	psi-mi:“MI:0915”(physical association)	0.550
TPI1	PCNA	psi-mi:“MI:0407”(direct interaction)	0.540
TPI1	PCNA	psi-mi:“MI:0915”(physical association)	0.540
TPI1	TERF1	psi-mi:“MI:0915”(physical association)	0.510
CFTR	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
	GNAT3	psi-mi:“MI:0915”(physical association)	0.400
	TK2	psi-mi:“MI:0915”(physical association)	0.400
TPI1	YWHAZ	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (396): TPI1 (Affinity Capture-MS), TPI1 (Affinity Capture-MS), TPI1 (Affinity Capture-MS), TPI1 (Affinity Capture-MS), TPI1 (Affinity Capture-MS), TPI1 (Affinity Capture-MS), AKR1B1 (Co-fractionation), ANP32E (Co-fractionation), ASS1 (Co-fractionation), CRIP1 (Co-fractionation), ESD (Co-fractionation), HNRNPR (Co-fractionation), NDUFV1 (Co-fractionation), PGM2 (Co-fractionation), PGM2L1 (Co-fractionation)

ESM2 similar proteins: A0A1L5YRA2, B0BM40, F5A6E9, O02611, O77458, P00939, P00941, P00942, P04828, P07669, P15426, P17751, P29613, P36186, P36187, P48499, P48500, P48501, P54714, P55275, P60174, P60175, P82204, P86216, P91919, P92119, Q10657, Q12574, Q1MTI4, Q27775, Q29371, Q2QD07, Q589R5, Q5E956, Q5R928, Q60HC9, Q6BMB8, Q6C2T9, Q6CJG5, Q6FRI3

Diamond homologs: A0A1L5YRA2, A1APN8, A1AXX3, A1BHJ1, A1TLL4, A1U604, A1WXW9, A3DBQ1, A4G646, A4VPP4, A6KXL2, A6LFF0, A6SY03, A8MFY0, A9BNB6, B0BM40, B1GZW3, B3EPH5, B3QPT6, B3QV54, F5A6E9, O02611, O77458, P00939, P00940, P00941, P00942, P04789, P04828, P07669, P12863, P15426, P17751, P21820, P29613, P30741, P34937, P36186, P36187, P46225

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
TPI1	“down-regulates quantity”	“glycerone phosphate(2-)”	“chemical modification”
TPI1	“up-regulates quantity”	“D-glyceraldehyde 3-phosphate(2-)”	“chemical modification”
SRC	“up-regulates quantity by stabilization”	TPI1	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	7
Likely pathogenic	4
Uncertain significance	78
Likely benign	56
Benign	10

Top pathogenic / likely-pathogenic (11)

Variant ID	HGVS	Classification
12471	NM_000365.6(TPI1):c.125G>A (p.Cys42Tyr)	Pathogenic
12472	NM_000365.6(TPI1):c.511A>G (p.Ile171Val)	Pathogenic
12473	NM_000365.6(TPI1):c.436G>T (p.Glu146Ter)	Pathogenic
136172	NM_000365.6(TPI1):c.722T>C (p.Phe241Ser)	Pathogenic
136173	NM_000365.6(TPI1):c.32dup (p.Asn12fs)	Pathogenic
2063765	NM_000365.6(TPI1):c.366dup (p.Gly123fs)	Pathogenic
4538464	TPI1, IVS3, +1, C-G	Pathogenic
1698892	NM_000365.6(TPI1):c.544-1G>C	Likely pathogenic
3009611	NM_000365.6(TPI1):c.324+1G>C	Likely pathogenic
3065734	NM_000365.6(TPI1):c.32del (p.Gly11fs)	Likely pathogenic
3392566	NM_000365.6(TPI1):c.218G>C (p.Gly73Ala)	Likely pathogenic

SpliceAI

867 predictions. Top by Δscore:

Variant	Effect	Δscore
12:6867680:CGGT:C	donor_loss	1.0000
12:6867682:G:C	donor_loss	1.0000
12:6867682:G:GG	donor_gain	1.0000
12:6867683:T:A	donor_loss	1.0000
12:6868844:T:TA	acceptor_gain	1.0000
12:6868862:A:AG	acceptor_gain	1.0000
12:6868863:G:GG	acceptor_gain	1.0000
12:6869256:A:AG	acceptor_gain	1.0000
12:6869257:G:GG	acceptor_gain	1.0000
12:6869257:GCT:G	acceptor_gain	1.0000
12:6869339:G:T	donor_gain	1.0000
12:6869678:T:TA	acceptor_gain	1.0000
12:6869684:GCAG:G	acceptor_loss	1.0000
12:6869685:CA:C	acceptor_loss	1.0000
12:6869686:A:AC	acceptor_loss	1.0000
12:6869686:A:AG	acceptor_gain	1.0000
12:6869687:G:GT	acceptor_gain	1.0000
12:6869687:GAT:G	acceptor_gain	1.0000
12:6869769:AACAG:A	donor_loss	1.0000
12:6869771:CAGG:C	donor_loss	1.0000
12:6869772:AGGT:A	donor_loss	1.0000
12:6869773:GG:G	donor_loss	1.0000
12:6869775:T:G	donor_loss	1.0000
12:6870047:A:AG	acceptor_gain	1.0000
12:6870047:AG:A	acceptor_gain	1.0000
12:6870048:G:GC	acceptor_gain	1.0000
12:6870048:GG:G	acceptor_gain	1.0000
12:6870048:GGCCC:G	acceptor_gain	1.0000
12:6870132:TGGAG:T	donor_gain	1.0000
12:6870133:GGAG:G	donor_gain	1.0000

AlphaMissense

1620 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:6867608:G:C	K14N	1.000
12:6867608:G:T	K14N	1.000
12:6869147:C:A	H96Q	1.000
12:6869147:C:G	H96Q	1.000
12:6869158:G:T	R100M	1.000
12:6869314:C:G	C127W	1.000
12:6869735:T:A	W169R	1.000
12:6869735:T:C	W169R	1.000
12:6869737:G:C	W169C	1.000
12:6869737:G:T	W169C	1.000
12:6869745:G:A	G172D	1.000
12:6870134:G:A	G210E	1.000
12:6867602:C:A	N12K	0.999
12:6867602:C:G	N12K	0.999
12:6867603:T:A	W13R	0.999
12:6867603:T:C	W13R	0.999
12:6867606:A:G	K14E	0.999
12:6867607:A:C	K14T	0.999
12:6868966:G:A	G73E	0.999
12:6868971:T:C	F75L	0.999
12:6868973:T:A	F75L	0.999
12:6868973:T:G	F75L	0.999
12:6868978:G:A	G77E	0.999
12:6869142:G:A	G95R	0.999
12:6869142:G:C	G95R	0.999
12:6869142:G:T	G95W	0.999
12:6869143:G:A	G95E	0.999
12:6869143:G:T	G95V	0.999
12:6869145:C:A	H96N	0.999
12:6869145:C:G	H96D	0.999

dbSNP variants (sampled 300 via entrez): RS1000165675 (12:6865564 G>C), RS1000300966 (12:6865861 G>A,C), RS1000452414 (12:6871110 G>A), RS1000885016 (12:6870999 G>A,T), RS1001711110 (12:6871422 G>A), RS1001731071 (12:6866639 C>T), RS1002698256 (12:6870534 A>G), RS1003736385 (12:6871238 G>A,C), RS1004327815 (12:6867912 G>C), RS1004629014 (12:6867025 C>A), RS1006937482 (12:6869929 T>G), RS1008870100 (12:6870979 T>C), RS1008976023 (12:6865532 G>C), RS1010202719 (12:6866347 G>A), RS1010333975 (12:6871175 C>T)

Disease associations

OMIM: gene MIM:190450 | disease phenotypes: MIM:615512

GenCC curated gene-disease

Disease	Classification	Inheritance
triosephosphate isomerase deficiency	Strong	Autosomal recessive

Mondo (1): triosephosphate isomerase deficiency (MONDO:0014221)

Orphanet (1): Triose phosphate-isomerase deficiency (Orphanet:868)

HPO phenotypes

42 total (30 of 42 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000543	Optic disc pallor
HP:0000762	Decreased nerve conduction velocity
HP:0000952	Jaundice
HP:0001081	Cholelithiasis
HP:0001082	Cholecystitis
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001265	Hyporeflexia
HP:0001290	Generalized hypotonia
HP:0001324	Muscle weakness
HP:0001332	Dystonia
HP:0001337	Tremor
HP:0001508	Failure to thrive
HP:0001522	Death in infancy
HP:0001562	Oligohydramnios
HP:0001635	Congestive heart failure
HP:0001639	Hypertrophic cardiomyopathy
HP:0001744	Splenomegaly
HP:0001878	Hemolytic anemia
HP:0001895	Normochromic anemia
HP:0001897	Normocytic anemia
HP:0001972	Macrocytic anemia
HP:0002059	Cerebral atrophy
HP:0002093	Respiratory insufficiency
HP:0002098	Respiratory distress
HP:0002317	Unsteady gait
HP:0002747	Respiratory insufficiency due to muscle weakness
HP:0002808	Kyphosis

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST006585_2765	Blood protein levels	3.000000e-08
GCST010002_206	Refractive error	3.000000e-62

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C566029	Triosephosphate Isomerase Deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4880 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 40,951 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1023	BEXAROTENE	4	40,951

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs12302749	TPI1, USP5	3	0.00	1	methylphenidate

ChEMBL bioactivities

16 potent at pChembl≥5 of 18 total, top 16 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.20	Kd	62.46	nM	CHEMBL5653589
7.20	ED50	62.46	nM	CHEMBL5653589
6.74	Kd	182.7	nM	CHEMBL3752910
6.74	ED50	182.7	nM	CHEMBL3752910
6.21	IC50	610	nM	CHEMBL6165785
6.00	IC50	990	nM	CHEMBL5222013
5.96	IC50	1100	nM	CHEMBL6151211
5.85	IC50	1400	nM	CHEMBL5592631
5.77	IC50	1700	nM	CHEMBL6165112
5.72	IC50	1900	nM	CHEMBL5592379
5.72	IC50	1890	nM	BEXAROTENE
5.66	IC50	2200	nM	CHEMBL6149960
5.52	Ki	3000	nM	PHOSPHOGLYCOLOHYDROXAMATE
5.40	Ki	4000	nM	PHOSPHOGLYCOLOHYDROXAMATE
5.35	Ki	4500	nM	CHEMBL195976
5.10	IC50	7990	nM	CHEMBL5592551

PubChem BioAssay actives

9 with measured affinity, of 33 total; 8 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
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149642: Binding affinity to human TPI1 incubated for 45 mins by Kinobead based pull down assay	kd	0.0625	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149642: Binding affinity to human TPI1 incubated for 45 mins by Kinobead based pull down assay	kd	0.1827	uM
ethyl N-[6-[2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]phenyl]-1H-benzimidazol-2-yl]carbamate	2115908: Inhibition of TPI (unknown origin)	ic50	0.9900	uM
2-(4-fluorophenyl)-7-(furan-3-yl)chromen-4-one	2115908: Inhibition of TPI (unknown origin)	ic50	1.4000	uM
6-amino-5-[[4-(dimethylamino)phenyl]methylideneamino]-1-methylpyrimidine-2,4-dione	2115908: Inhibition of TPI (unknown origin)	ic50	1.9000	uM
[2-(hydroxyamino)-2-oxoethyl] dihydrogen phosphate	292822: Inhibition of triosephosphate isomerase	ki	3.0000	uM
[(2E)-2-amino-2-hydroxyiminoethyl] dihydrogen phosphate	292822: Inhibition of triosephosphate isomerase	ki	4.5000	uM
(3Z)-3-[[4-[2-(4-bromophenyl)-2-oxoethoxy]phenyl]methylidene]-1H-indol-2-one	2115908: Inhibition of TPI (unknown origin)	ic50	7.9900	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, affects cotreatment, increases expression	6
sodium arsenite	decreases expression, increases expression	5
bisphenol A	increases expression, affects expression, decreases expression	3
Cisplatin	increases expression, affects response to substance	3
Cyclosporine	decreases expression	3
Cadmium Chloride	decreases expression, increases abundance, increases expression	3
Particulate Matter	decreases expression, increases expression, affects expression, increases abundance	3
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	2
chloropicrin	affects expression, decreases expression	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	2
Acrolein	increases oxidation, increases abundance, affects cotreatment	2
Ethanol	decreases expression, increases expression	2
Doxorubicin	decreases expression, affects response to substance	2
Fluorouracil	decreases expression, affects response to substance	2
Ozone	increases abundance, affects cotreatment, increases oxidation	2
Quercetin	increases expression	2
Silicon Dioxide	increases secretion, increases expression	2
Tobacco Smoke Pollution	increases expression, affects expression	2
Tretinoin	decreases expression, increases expression	2
aristolochic acid I	increases expression	1
FR900359	affects phosphorylation	1
PF-06840003	decreases expression, decreases reaction	1
aminomethylphosphonic acid (AMPA)	increases expression	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
sodium arsenate	decreases expression	1
pyrogallol 1,3-dimethyl ether	decreases expression, affects cotreatment, affects localization, increases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
alpha-naphthoflavone	decreases reaction, increases expression, 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
CHEMBL1049666	Binding	Inhibition of human recombinant triosephosphate isomerase after 2 hrs	Selective inactivation of triosephosphate isomerase from Trypanosoma cruzi by brevifolin carboxylate derivatives isolated from Geranium bellum Rose. — Bioorg Med Chem Lett

Clinical trials (associated diseases)

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