MTHFD1

Summary

MTHFD1 (methylenetetrahydrofolate dehydrogenase, cyclohydrolase and formyltetrahydrofolate synthetase 1, HGNC:7432) is a protein-coding gene on chromosome 14q23.3, encoding C-1-tetrahydrofolate synthase, cytoplasmic (P11586). Trifunctional enzyme that catalyzes the interconversion of three forms of one-carbon-substituted tetrahydrofolate: (6R)-5,10-methylene-5,6,7,8-tetrahydrofolate, 5,10-methenyltetrahydrofolate and (6S)-10-formyltetrahydrofolate. It is a selective cancer dependency (DepMap: 28.7% of cell lines).

This gene encodes a protein that possesses three distinct enzymatic activities, 5,10-methylenetetrahydrofolate dehydrogenase, 5,10-methenyltetrahydrofolate cyclohydrolase and 10-formyltetrahydrofolate synthetase. Each of these activities catalyzes one of three sequential reactions in the interconversion of 1-carbon derivatives of tetrahydrofolate, which are substrates for methionine, thymidylate, and de novo purine syntheses. The trifunctional enzymatic activities are conferred by two major domains, an aminoterminal portion containing the dehydrogenase and cyclohydrolase activities and a larger synthetase domain.

Source: NCBI Gene 4522 — RefSeq curated summary.

At a glance

• Gene–disease (curated): combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia (Definitive, ClinGen)
• GWAS associations: 5
• Clinical variants (ClinVar): 634 total — 13 pathogenic, 23 likely-pathogenic
• Phenotypes (HPO): 27
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 28.7% of screened cell lines
• MANE Select transcript: NM_005956

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7432
Approved symbol	MTHFD1
Name	methylenetetrahydrofolate dehydrogenase, cyclohydrolase and formyltetrahydrofolate synthetase 1
Location	14q23.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000100714
Ensembl biotype	protein_coding
OMIM	172460
Entrez	4522

Gene structure

Transcript identifiers

Ensembl transcripts: 58 — 34 protein_coding, 11 retained_intron, 8 nonsense_mediated_decay, 5 protein_coding_CDS_not_defined

ENST00000545908, ENST00000553391, ENST00000553405, ENST00000554057, ENST00000554353, ENST00000554677, ENST00000554739, ENST00000554768, ENST00000555252, ENST00000555709, ENST00000555858, ENST00000556284, ENST00000556771, ENST00000557370, ENST00000557539, ENST00000650853, ENST00000651537, ENST00000651891, ENST00000652179, ENST00000652337, ENST00000652503, ENST00000652509, ENST00000697166, ENST00000697167, ENST00000697168, ENST00000697169, ENST00000697170, ENST00000697171, ENST00000697172, ENST00000697173, ENST00000697174, ENST00000697175, ENST00000697176, ENST00000697177, ENST00000900021, ENST00000900022, ENST00000900023, ENST00000900024, ENST00000900025, ENST00000900026, ENST00000900027, ENST00000900028, ENST00000900029, ENST00000900030, ENST00000900031, ENST00000940485, ENST00000940486, ENST00000940487, ENST00000940488, ENST00000940489, ENST00000940490, ENST00000940491, ENST00000940492, ENST00000940493, ENST00000940494, ENST00000940495, ENST00000940496, ENST00000941180

RefSeq mRNA: 2 — MANE Select: NM_005956 NM_001364837, NM_005956

CCDS: CCDS91885, CCDS9763

Canonical transcript exons

ENST00000652337 — 28 exons

Exon	Start	End
ENSE00003488507	64454723	64454875
ENSE00003489347	64440126	64440266
ENSE00003496006	64442263	64442402
ENSE00003504328	64453754	64453861
ENSE00003584908	64442054	64442165
ENSE00003595047	64441385	64441453
ENSE00003597105	64411090	64411149
ENSE00003597432	64449445	64449622
ENSE00003664296	64444693	64444734
ENSE00003687807	64448217	64448317
ENSE00003702587	64426019	64426192
ENSE00003702681	64400793	64400877
ENSE00003703215	64415639	64415739
ENSE00003704544	64424804	64424931
ENSE00003704756	64425730	64425827
ENSE00003705361	64431532	64431639
ENSE00003705557	64431787	64431861
ENSE00003706402	64430184	64430230
ENSE00003706446	64427337	64427473
ENSE00003707395	64439096	64439172
ENSE00003708552	64419814	64419925
ENSE00003708688	64415358	64415494
ENSE00003708921	64435569	64435671
ENSE00003710947	64412472	64412525
ENSE00003785445	64417888	64418024
ENSE00003845797	64459759	64460025
ENSE00003849178	64388353	64388468
ENSE00003969821	64458214	64458307

Expression profiles

Bgee: expression breadth ubiquitous, 289 present calls, max score 98.85.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 38.6101 / max 753.4331, expressed in 1806 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
140094	36.9963	1805
140095	1.4156	713
140096	0.1982	63

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	98.85	gold quality
liver	UBERON:0002107	98.16	gold quality
ventricular zone	UBERON:0003053	96.23	gold quality
hindlimb stylopod muscle	UBERON:0004252	95.46	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	95.42	gold quality
muscle of leg	UBERON:0001383	95.32	gold quality
gastrocnemius	UBERON:0001388	95.31	gold quality
calcaneal tendon	UBERON:0003701	95.17	gold quality
colonic epithelium	UBERON:0000397	95.16	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	95.07	gold quality
adipose tissue	UBERON:0001013	94.96	gold quality
ganglionic eminence	UBERON:0004023	94.72	gold quality
apex of heart	UBERON:0002098	94.69	gold quality
subcutaneous adipose tissue	UBERON:0002190	94.65	gold quality
connective tissue	UBERON:0002384	94.61	gold quality
caudate nucleus	UBERON:0001873	94.34	gold quality
nucleus accumbens	UBERON:0001882	94.31	gold quality
muscle organ	UBERON:0001630	94.30	gold quality
biceps brachii	UBERON:0001507	94.20	gold quality
embryo	UBERON:0000922	94.13	gold quality
right coronary artery	UBERON:0001625	93.98	gold quality
adult mammalian kidney	UBERON:0000082	93.91	gold quality
endometrium epithelium	UBERON:0004811	93.90	gold quality
adipose tissue of abdominal region	UBERON:0007808	93.88	gold quality
left coronary artery	UBERON:0001626	93.86	gold quality
heart left ventricle	UBERON:0002084	93.78	gold quality
metanephros cortex	UBERON:0010533	93.76	gold quality
omental fat pad	UBERON:0010414	93.68	gold quality
cardiac ventricle	UBERON:0002082	93.67	gold quality
peritoneum	UBERON:0002358	93.66	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-CURD-88	yes	1633.47
E-MTAB-9435	yes	1423.67
E-MTAB-9067	yes	20.28
E-MTAB-8142	yes	16.41
E-ANND-3	yes	7.46
E-MTAB-7316	no	810.42

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F4, MYC

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 28.7% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Genetic variation in the MTHFD1 gene is associated with an increase in the risk that a woman will bear a child with NTD. (PMID:12384833)
• Results conclude that women who are ‘QQ’ homozygote for the MTHFD1 1258G –> A (R653Q) polymorphism are almost three times more likely to develop severe abruptio placentae during their pregnancy than women who are ‘RQ’ or ‘RR.’ (PMID:15633187)
• Women who are MTHFD1 1958AA homozygous are at increased maternal risk for unexplained second trimester pregnancy loss. (PMID:16123074)
• carriers of the MTHFD1-1958A gene allele were more likely to develop choline deficiency on the low-choline diet unless treated with folic acid; premenopausal women carriers showed 15 times increased susceptibility to organ dysfunction on low-choline diet (PMID:16236726)
• Heterozygosity and homozygosity for the MTHFD1 1958G > A polymorphism are genetic determinants of neural tube defect risk. (PMID:16315005)
• MTHFR C677T gene polymorphism associated with a predisposition to increased plasma homocysteine levels could constitute a useful predictive marker for macroangiopathy in Chinese Type 2 diabetic patients. (PMID:17114913)
• Since MTHFD genes are located in 14q24 loci, our findings support the significance of chromosome 1q in etiopathogenesis of schizophrenia. (PMID:17417062)
• The results indicate that of the enzymes studied the polymorphisms of folate-dependent enzyme MTHFD1 have pointed to significant differences in intensity of turnover of circulating thiols between AD and PD patients. (PMID:17691219)
• The methylenetetrahydrofolate dehydrogenase (MTHFD1) 1958G>A variant is not associated with spina bifida risk in the Dutch population. (PMID:17894836)
• The aim of this study was to evaluate the role of two polymorphisms of the methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) gene, the A1958G and the G401A variants, on the risk of cleft lip with or without cleft palate in the Italian population. (PMID:18261183)
• The Arg653Gln polymorphism decreases enzyme stability and increases risk for congenital heart defects. (PMID:18767138)
• Data did not show differences in the distribution of MTR 2756A>G and MTHFD1 1958G>A polymorphic variants postmenopausal women with and without depression. The MTR GG genotype exhibited a 5.750-fold increased risk of depression in postmenopausal women. (PMID:18801628)
• SNP rs1076991 C > T as a potential risk factor for neural tube defects in a large homogenous Irish population (PMID:19130090)
• These data suggest that polymorphisms in MTHFD1 genes relevant to choline metabolism modulate parameters of choline status when folate intake is restricted. (PMID:19167960)
• The polymorphism distribution of genes encoding MTR, 5,10-methylenetetrahydrofolate dehydrogenase, 5,10-methenyltetrahydrofolate cyclohydrolase and MTHFD1 and MTHFR in patients with larynx cancer, was examined. (PMID:19649727)
• Induction of MTHFD1 antigen is associated with relapsed chronic myeloid leukemia. (PMID:19706888)
• No significant difference of allele and genotype contributions of the MTHFD1 polymorphism between Alzheimer’s disease cases and controls was detected in total samples. (PMID:20217437)
• c.1958 G>A polymorphism unlikely to play a major role in recurrent spontaneous abortion (PMID:20334533)
• G1793A gene polymorphism, HHcy, folate deficiency and low vitamin B(12) concentration were associated with ulcerative colitis in central China. (PMID:20594233)
• Data show that a significant association with NHL was observed only for MTHFD1 G1958A. (PMID:21055808)
• Polymorphic variants of folate metabolizing genes (C677T and A1298C MTHFR, C1420T SHMT1 and G1958A MTHFD) are not associated with the risk of breast cancer in West Siberian Region of Russia (PMID:21090237)
• the frequencies of MTHFD1 alleles, as well as the frequencies of MTHFD11958 genotypes (GG, GA, AA, GA+AA) do not correlate with Down syndrome pregnancies (PMID:21254748)
• Mutation in Methylenetetrahydrofolate Dehydrogenase gene is associated with thrombosis. (PMID:21271780)
• The genotype and allele frequencies of the MTR Asp919Gly, MTHFR Ala222Val, MTHFD1 Arg653Gln and MTRR Ile22Met gene variants did not display statistical differences between patients with cervical cancer and controls. (PMID:21349258)
• This is the first implication of chr14q23.2-23.3 in the etiology of autism and points to MTHFD1, PLEKHG3, and CHURC1 as potential candidate genes contributing to autism risk. (PMID:21360829)
• MTHFD1 1958GA or AA genotypes were associated with smoking (p = 0.04) and alcoholism (p = 0.03) and were more often found in more advanced stage tumors (p = 0.04) and in patients with a shorter survival (p = 0.03). (PMID:21537707)
• An important role of polymorphisms and gene-gene interactions within the folate pathway in high dose methotrexate-related toxicity in childhood acute lymphoblastic leukemia. (PMID:22074251)
• Our results among the Brazilian population did not support an association between MTHFD1 G1958A polymorphism and risk for Down synrome. (PMID:22339736)
• Our findings demonstrated the susceptible role of the mutant-type MTHFR C677T, MTHFR A1298C, and MTHFD G1958A in recurrent miscarriage. (PMID:23685927)
• MTHFD1 G1958A polymorphism might be associated with a decreased risk of ALL and other cancers. Meanwhile, the MTHFD1 G401A might play a protective role in the development of colon cancer. (PMID:23894459)
• This meta-analysis suggests that MTHFD1 G1958A polymorphism might not be a risk factor for prostate cancer (PMID:24197977)
• suggested that G401A polymorphism of MTHFD1 was not associated with ovarian cancer risk when using additive (PMID:24287951)
• Prematurity and 1958G>A (MTHFD1)were not associated. Increases in the inflammatory marker CRP (logistic regression, p = 0.055) and BMI (chi-square, p = 0.0113) were associated with AA genotype in women with low folate. (PMID:24368157)
• neither MTHFD G1958A nor TC C776G polymorphisms are an independent risk factor for Down syndrome. However, the combined MTHFD/MTHFR, TC/MTHFR genotypes play a role in the risk of bearing a Down syndrome child in the Chinese population. (PMID:24668664)
• The MTHFD1 G1958A polymorphism might be associated with maternal risk for neural tube defects. (PMID:24977710)
• We find no evidence for association of the MTHFD1 R134K and R653Q polymorphisms with migraine in our Australian case-control population (PMID:25039261)
• methylenetetrahydrofolate dehydrogenase gene variants in the cognitive function of ADHD (PMID:25079255)
• ACAT1, ACACA, ALDH6A1 and MTHFD1 represent novel biomarkers in adipose tissue associated with type 2 diabetes in obese individuals. (PMID:25099943)
• Mutated 401A allele of MTHFD1 gene is essential risk factor of fetal hypotrophy in population of Polish women. (PMID:25118499)
• The results indicated the MTHFD1 1958G>A polymorphism to be one of the important genetic determinants of NSCLP risk in South Indian subjects (PMID:25129243)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	mthfd1a	ENSDARG00000018266
danio_rerio	mthfd1b	ENSDARG00000040492
mus_musculus	Mthfd1	ENSMUSG00000021048
rattus_norvegicus	Mthfd1	ENSRNOG00000005602
rattus_norvegicus		ENSRNOG00000078727

Paralogs (3): MTHFD2 (ENSG00000065911), MTHFD1L (ENSG00000120254), MTHFD2L (ENSG00000163738)

Protein

Protein identifiers

C-1-tetrahydrofolate synthase, cytoplasmic — P11586 (reviewed: P11586)

Alternative names: Epididymis secretory sperm binding protein

All UniProt accessions (14): P11586, A0A494C1T2, A0A8C8UXK2, A0A8V8TKR5, A0A8V8TKS0, A0A8V8TKT4, A0A8V8TL46, A0A8V8TL50, A0A8V8TMA4, A0A8V8TMA9, F5H2F4, V9GYY3, V9GZ32, V9GZ78

UniProt curated annotations — full annotation on UniProt →

Function. Trifunctional enzyme that catalyzes the interconversion of three forms of one-carbon-substituted tetrahydrofolate: (6R)-5,10-methylene-5,6,7,8-tetrahydrofolate, 5,10-methenyltetrahydrofolate and (6S)-10-formyltetrahydrofolate. These derivatives of tetrahydrofolate are differentially required in nucleotide and amino acid biosynthesis, (6S)-10-formyltetrahydrofolate being required for purine biosynthesis while (6R)-5,10-methylene-5,6,7,8-tetrahydrofolate is used for serine and methionine biosynthesis for instance.

Subunit / interactions. Homodimer.

Subcellular location. Cytoplasm.

Tissue specificity. Ubiquitous.

Disease relevance. Neural tube defects, folate-sensitive (NTDFS) [MIM:601634] The most common NTDs are open spina bifida (myelomeningocele) and anencephaly. Disease susceptibility is associated with variants affecting the gene represented in this entry. Colorectal cancer (CRC) [MIM:114500] A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history. Disease susceptibility may be associated with variants affecting the gene represented in this entry. Susceptibility to colorectal cancer may be associated with the missense variant p.Arg134Lys, which has been observed in about 16% of the human population. The sequence shown in this entry represents the minor allele, as it is reported in the reference genome. Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia (CIMAH) [MIM:617780] An autosomal recessive disorder due to an inborn error of folate metabolism. Variable clinical manifestations include hemolytic uremic syndrome, macrocytosis, epilepsy, hearing loss, retinopathy, mild intellectual disability, and lymphopenia. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The N-terminal methylenetetrahydrofolate dehydrogenase and methenyltetrahydrofolate cyclohydrolase (D/C) domain carries both the methylenetetrahydrofolate dehydrogenase and methenyltetrahydrofolate cyclohydrolase activities. The larger C-terminal formyltetrahydrofolate synthetase domain carries a third formyltetrahydrofolate synthetase activity.

Pathway. One-carbon metabolism; tetrahydrofolate interconversion.

Similarity. In the N-terminal section; belongs to the tetrahydrofolate dehydrogenase/cyclohydrolase family. In the C-terminal section; belongs to the formate–tetrahydrofolate ligase family.

RefSeq proteins (2): NP_001351766, NP_005947* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000559	Formate_THF_ligase	Family
IPR000672	THF_DH/CycHdrlase	Family
IPR020628	Formate_THF_ligase_CS	Conserved_site
IPR020630	THF_DH/CycHdrlase_cat_dom	Domain
IPR020631	THF_DH/CycHdrlase_NAD-bd_dom	Domain
IPR020867	THF_DH/CycHdrlase_CS	Conserved_site
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR036291	NAD(P)-bd_dom_sf	Homologous_superfamily
IPR046346	Aminoacid_DH-like_N_sf	Homologous_superfamily

Pfam: PF00763, PF01268, PF02882

Enzyme classification (BRENDA):

• EC 1.5.1.5 — methylenetetrahydrofolate dehydrogenase (NADP+) (BRENDA: 24 organisms, 41 substrates, 41 inhibitors, 70 Km, 28 kcat entries)
• EC 3.5.4.9 — methenyltetrahydrofolate cyclohydrolase (BRENDA: 53 organisms, 34 substrates, 29 inhibitors, 57 Km, 13 kcat entries)
• EC 6.3.3.2 — 5-formyltetrahydrofolate cyclo-ligase (BRENDA: 18 organisms, 55 substrates, 43 inhibitors, 81 Km, 28 kcat entries)
• EC 6.3.4.3 — formate-tetrahydrofolate ligase (BRENDA: 73 organisms, 52 substrates, 32 inhibitors, 87 Km, 14 kcat entries)

Substrate kinetics (BRENDA)

54 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
5,10-METHENYLTETRAHYDROFOLATE	0.0045–2.36	30
ATP	0.0003–5	29
5-FORMYLTETRAHYDROFOLATE	0.0005–130	26
ATP	0.012–0.59	25
NADP+	0.0004–0.69	23
FORMATE	0.035–38	23
5,10-METHYLENETETRAHYDROFOLATE	0.0011–4.76	20
10-FORMYLTETRAHYDROFOLATE	0.009–0.47	14
TETRAHYDROFOLATE	0.015–2.3	14
METHENYLTETRAHYDROFOLATE	0.019–0.23	7
5,10-METHENYLTETRAHYDROFOLATE	0.068–0.302	5
5,10-METHYLENETETRAHYDROPTEROYLPOLY-L-GLUTAMATE	0.04–0.153	4
5,6,7,8-TETRAHYDROPTEROYLTRIGLUTAMATE	0.0003–0.025	4
(6R,S)-5-FORMYLTETRAHYDROPTEROYL-GLU	0.0044–0.0047	3
CTP	0.0016–0.6	3

Catalyzed reactions (Rhea), 3 shown:

• (6S)-5,6,7,8-tetrahydrofolate + formate + ATP = (6R)-10-formyltetrahydrofolate + ADP + phosphate (RHEA:20221)
• (6R)-5,10-methylene-5,6,7,8-tetrahydrofolate + NADP(+) = (6R)-5,10-methenyltetrahydrofolate + NADPH (RHEA:22812)
• (6R)-5,10-methenyltetrahydrofolate + H2O = (6R)-10-formyltetrahydrofolate + H(+) (RHEA:23700)

UniProt features (59 total): helix 12, sequence variant 11, strand 9, mutagenesis site 8, binding site 6, modified residue 4, turn 3, chain 2, region of interest 2, initiator methionine 1, active site 1

Structure

Experimental structures (PDB)

12 structures.

PDB	Method	Resolution (Å)
1A4I	X-RAY DIFFRACTION	1.5
9ISE	X-RAY DIFFRACTION	1.99
9ISL	X-RAY DIFFRACTION	2.06
9IUO	X-RAY DIFFRACTION	2.09
1DIA	X-RAY DIFFRACTION	2.2
1DIG	X-RAY DIFFRACTION	2.2
6ECP	X-RAY DIFFRACTION	2.2
6ECR	X-RAY DIFFRACTION	2.2
9ITD	X-RAY DIFFRACTION	2.28
9ISR	X-RAY DIFFRACTION	2.5
1DIB	X-RAY DIFFRACTION	2.7
6ECQ	X-RAY DIFFRACTION	2.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P11586-F1	94.63	0.90

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): 56

Ligand- & substrate-binding residues (6): 272–276; 380–387; 52–56; 99–101; 172–174; 197

Post-translational modifications (4): 1, 318, 413, 490

Mutagenesis-validated functional residues (8):

Position	Phenotype
49	no effect on methylenetetrahydrofolate dehydrogenase (nadp+) activity. no effect on methenyltetrahydrofolate cyclohydrol
49	reduced methylenetetrahydrofolate dehydrogenase (nadp+) activity by 75%. reduced methenyltetrahydrofolate cyclohydrolase
52	reduced methylenetetrahydrofolate dehydrogenase (nadp+) activity by 99%. reduced methenyltetrahydrofolate cyclohydrolase
52	slightly reduced methylenetetrahydrofolate dehydrogenase (nadp+) activity. slightly reduced methenyltetrahydrofolate cyc
56	decreased methylenetetrahydrofolate dehydrogenase (nadp+) activity over 90%. loss of methenyltetrahydrofolate cyclohydro
56	moderate decrease of methylenetetrahydrofolate dehydrogenase (nadp+) activity. loss of methenyltetrahydrofolate cyclohyd
56	reduced methylenetetrahydrofolate dehydrogenase (nadp+) activity. reduced methenyltetrahydrofolate cyclohydrolase activi
147	reduced methylenetetrahydrofolate dehydrogenase (nadp+) activity by 50%. reduced methenyltetrahydrofolate cyclohydrolase

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-196757	Metabolism of folate and pterines
R-HSA-1430728	Metabolism
R-HSA-196849	Metabolism of water-soluble vitamins and cofactors
R-HSA-196854	Metabolism of vitamins and cofactors

MSigDB gene sets: 430 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_DN, GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_DN, GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_DN, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, MODULE_93, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_MYELOID_CELL_HOMEOSTASIS, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_EMBRYONIC_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, GOBP_EMBRYONIC_SKELETAL_SYSTEM_MORPHOGENESIS, FRASOR_RESPONSE_TO_SERM_OR_FULVESTRANT_DN, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_AMINO_ACID_BIOSYNTHETIC_PROCESS

GO Biological Process (19): neutrophil homeostasis (GO:0001780), neural tube closure (GO:0001843), purine nucleotide biosynthetic process (GO:0006164), L-methionine metabolic process (GO:0006555), heart development (GO:0007507), obsolete methionine biosynthetic process (GO:0009086), purine ribonucleotide biosynthetic process (GO:0009152), 10-formyltetrahydrofolate biosynthetic process (GO:0009257), transsulfuration (GO:0019346), tetrahydrofolate interconversion (GO:0035999), folic acid metabolic process (GO:0046655), embryonic neurocranium morphogenesis (GO:0048702), embryonic viscerocranium morphogenesis (GO:0048703), somite development (GO:0061053), one-carbon metabolic process (GO:0006730), folic acid-containing compound metabolic process (GO:0006760), obsolete serine family amino acid metabolic process (GO:0009069), small molecule metabolic process (GO:0044281), tetrahydrofolate metabolic process (GO:0046653)

GO Molecular Function (10): formate-tetrahydrofolate ligase activity (GO:0004329), methenyltetrahydrofolate cyclohydrolase activity (GO:0004477), methylenetetrahydrofolate dehydrogenase (NADP+) activity (GO:0004488), ATP binding (GO:0005524), nucleotide binding (GO:0000166), catalytic activity (GO:0003824), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), hydrolase activity (GO:0016787), ligase activity (GO:0016874)

GO Cellular Component (5): mitochondrion (GO:0005739), cytosol (GO:0005829), membrane (GO:0016020), extracellular exosome (GO:0070062), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Metabolism of water-soluble vitamins and cofactors	1
Metabolism of vitamins and cofactors	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
catalytic activity	3
cellular anatomical structure	3
L-amino acid metabolic process	2
proteinogenic amino acid metabolic process	2
folic acid-containing compound metabolic process	2
embryonic morphogenesis	2
embryonic cranial skeleton morphogenesis	2
cytoplasm	2
leukocyte homeostasis	1
myeloid cell homeostasis	1
primary neural tube formation	1
tube closure	1
purine nucleotide metabolic process	1
nucleotide biosynthetic process	1
purine-containing compound biosynthetic process	1
sulfur amino acid metabolic process	1
animal organ development	1
circulatory system development	1
purine nucleotide biosynthetic process	1
purine ribonucleotide metabolic process	1
ribonucleotide biosynthetic process	1
10-formyltetrahydrofolate metabolic process	1
dicarboxylic acid biosynthetic process	1
tetrahydrofolate biosynthetic process	1
homocysteine metabolic process	1
one-carbon metabolic process	1
tetrahydrofolate metabolic process	1
dicarboxylic acid metabolic process	1
embryo development	1
epithelium development	1
small molecule metabolic process	1
modified amino acid metabolic process	1
pteridine-containing compound metabolic process	1
metabolic process	1
ligase activity, forming carbon-nitrogen bonds	1
cyclohydrolase activity	1
oxidoreductase activity, acting on the CH-NH group of donors, NAD or NADP as acceptor	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
nucleoside phosphate binding	1

Protein interactions and networks

STRING

2682 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MTHFD1	SHMT1	P34896	974
MTHFD1	GART	P22102	953
MTHFD1	MTR	Q99707	944
MTHFD1	ATIC	P31939	943
MTHFD1	MTRR	Q9UBK8	941
MTHFD1	MTHFR	P42898	932
MTHFD1	H7C2H4	H7C2H4	869
MTHFD1	DHFR	P00374	862
MTHFD1	BRD4	O60885	859
MTHFD1	P0DN79	P0DN79	857
MTHFD1	SHMT2	P34897	836
MTHFD1	DHFR2	Q86XF0	809
MTHFD1	TYMS	P04818	807
MTHFD1	GLDC	P23378	785
MTHFD1	FPGS	Q05932	771

IntAct

158 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CA10	WDHD1	psi-mi:“MI:0914”(association)	0.640
rep	MTHFD1	psi-mi:“MI:0914”(association)	0.640
UNC119	UNC119B	psi-mi:“MI:0914”(association)	0.640
FHL2	CNOT1	psi-mi:“MI:0914”(association)	0.530
Tax	TAX1BP3	psi-mi:“MI:0914”(association)	0.520
CFTR	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
DDX21	MED19	psi-mi:“MI:2364”(proximity)	0.480
	MTHFD1	psi-mi:“MI:0915”(physical association)	0.400
DNAJC17	MTHFD1	psi-mi:“MI:0915”(physical association)	0.400
IQCH	MTHFD1	psi-mi:“MI:0915”(physical association)	0.400
MTHFD1	AHNAK	psi-mi:“MI:0915”(physical association)	0.400
	TK2	psi-mi:“MI:0915”(physical association)	0.400
STK4	EIF3CL	psi-mi:“MI:0914”(association)	0.350

BioGRID (351): MTHFD1 (Affinity Capture-MS), MTHFD1 (Affinity Capture-MS), MTHFD1 (Affinity Capture-MS), MTHFD1 (Affinity Capture-MS), MTHFD1 (Reconstituted Complex), MTHFD1 (Affinity Capture-MS), MTHFD1 (Co-fractionation), MTHFD1 (Co-fractionation), MTHFD1 (Co-fractionation), MTHFD1 (Co-fractionation), MTHFD1 (Co-fractionation), MTHFD1 (Co-fractionation), MTHFD1 (Co-fractionation), PAPOLA (Co-fractionation), PFKL (Co-fractionation)

ESM2 similar proteins: A0A061AE05, A0A1Q3EPD6, A0A2R2JFI5, A0A4S8L4Q5, A0A4Y7TJF3, A0A5C3KU62, A0LSL4, A1A3C7, A2C620, A8NV38, A9BEG7, A9KDE5, A9NBT9, B3EU98, B3PVW2, B5ZV80, B6J3V5, B6J6M2, B9JG53, O93937, P05373, P05990, P09831, P11586, P27653, P43703, P52647, P52965, P77966, P78937, P94281, P9WEM8, P9WEM9, P9WEN0, P9WEN1, P9WEN2, P9WEN3, Q06879, Q12T12, Q1MNC6

Diamond homologs: A0KIN9, A0KSN0, A1B1M8, A1JMA3, A1RFN3, A1SAE2, A2RGS2, A3CL27, A3CZY6, A3DI22, A3PM52, A3QA17, A4FL80, A4J0S6, A4SPE5, A4WQ11, A4YAP3, A5G276, A5UPV2, A6WSY9, A7N5E9, A7NGQ9, A8F7D5, A8FQV1, A8H8Z4, A8MIN1, A9B4H8, A9IM41, A9KNJ5, A9L3Z6, A9WIW3, B0K5A5, B0KC36, B0TBP1, B0TVP3, B0UQF5, B1KJC0, B1ZJ88, B2IC30, B4ET09

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
MTHFD1	“up-regulates quantity”	(6R)-5,10-methenyltetrahydrofolate	“chemical modification”
MTHFD1	“up-regulates quantity”	10-formyltetrahydrofolate(2-)	“chemical modification”
MTHFD1	“up-regulates quantity”	formate	“chemical modification”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	13
Likely pathogenic	23
Uncertain significance	223
Likely benign	312
Benign	23

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1359353	NM_005956.4(MTHFD1):c.2548G>T (p.Glu850Ter)	Pathogenic
1454401	NM_005956.4(MTHFD1):c.970C>T (p.Arg324Ter)	Pathogenic
2000402	NM_005956.4(MTHFD1):c.1231C>T (p.Gln411Ter)	Pathogenic
2036806	NM_005956.4(MTHFD1):c.924del (p.Asn308fs)	Pathogenic
208193	NM_005956.4(MTHFD1):c.826G>C (p.Gly276Arg)	Pathogenic
2103110	NM_005956.4(MTHFD1):c.677G>A (p.Trp226Ter)	Pathogenic
2769546	NM_005956.4(MTHFD1):c.316G>T (p.Glu106Ter)	Pathogenic
3353536	NM_005956.4(MTHFD1):c.886G>T (p.Glu296Ter)	Pathogenic
3708491	NM_005956.4(MTHFD1):c.2479_2480insTTGCACA (p.Arg827fs)	Pathogenic
446305	NM_005956.4(MTHFD1):c.1674G>A (p.Thr558=)	Pathogenic
446307	NM_005956.4(MTHFD1):c.673G>T (p.Glu225Ter)	Pathogenic
446308	NG_012450.1:g.(45534_?)_(?_47555)del	Pathogenic
4718029	NM_005956.4(MTHFD1):c.2375del (p.Gly792fs)	Pathogenic
1347752	NM_005956.4(MTHFD1):c.953+1G>A	Likely pathogenic
1696278	NM_005956.4(MTHFD1):c.1006C>T (p.Arg336Ter)	Likely pathogenic
1696279	NM_005956.4(MTHFD1):c.2529del (p.Glu844fs)	Likely pathogenic
1878421	NM_005956.4(MTHFD1):c.2629C>T (p.Gln877Ter)	Likely pathogenic
2119897	NM_005956.4(MTHFD1):c.1494+1G>A	Likely pathogenic
2125486	NM_005956.4(MTHFD1):c.1090_1127+63del	Likely pathogenic
2431552	NM_005956.4(MTHFD1):c.479-2A>G	Likely pathogenic
2501176	NM_005956.4(MTHFD1):c.1807G>T (p.Glu603Ter)	Likely pathogenic
2762608	NM_005956.4(MTHFD1):c.1494+1G>C	Likely pathogenic
2908283	NM_005956.4(MTHFD1):c.1996+1G>A	Likely pathogenic
3576654	NM_005956.4(MTHFD1):c.253dup (p.Ile85fs)	Likely pathogenic
3576655	NM_005956.4(MTHFD1):c.428_429del (p.Cys143fs)	Likely pathogenic
3576656	NM_005956.4(MTHFD1):c.731dup (p.Asp244fs)	Likely pathogenic
3576657	NM_005956.4(MTHFD1):c.1755_1756del (p.Arg585fs)	Likely pathogenic
3612559	NM_005956.4(MTHFD1):c.615+1G>A	Likely pathogenic
3648561	NM_005956.4(MTHFD1):c.1264+1G>A	Likely pathogenic
3722181	NM_005956.4(MTHFD1):c.241-4_250del	Likely pathogenic

SpliceAI

3817 predictions. Top by Δscore:

Variant	Effect	Δscore
14:64388454:G:GT	donor_gain	1.0000
14:64388454:G:T	donor_gain	1.0000
14:64388467:GC:G	donor_gain	1.0000
14:64388469:G:GG	donor_gain	1.0000
14:64400789:CTAG:C	acceptor_loss	1.0000
14:64400790:TAG:T	acceptor_loss	1.0000
14:64400791:A:AG	acceptor_gain	1.0000
14:64400791:A:C	acceptor_loss	1.0000
14:64400791:AG:A	acceptor_gain	1.0000
14:64400792:G:GG	acceptor_gain	1.0000
14:64400792:GG:G	acceptor_gain	1.0000
14:64400792:GGC:G	acceptor_gain	1.0000
14:64400792:GGCA:G	acceptor_gain	1.0000
14:64400792:GGCAA:G	acceptor_gain	1.0000
14:64400873:TACAG:T	donor_loss	1.0000
14:64400874:ACAG:A	donor_loss	1.0000
14:64400875:CAG:C	donor_loss	1.0000
14:64400876:AGGTA:A	donor_loss	1.0000
14:64400877:GGTA:G	donor_loss	1.0000
14:64400878:GT:G	donor_loss	1.0000
14:64400879:T:A	donor_loss	1.0000
14:64412466:TTGCA:T	acceptor_loss	1.0000
14:64412467:TGCAG:T	acceptor_loss	1.0000
14:64412468:GCAGA:G	acceptor_loss	1.0000
14:64412469:CAGAT:C	acceptor_loss	1.0000
14:64412470:A:AG	acceptor_gain	1.0000
14:64412470:AGA:A	acceptor_loss	1.0000
14:64412470:AGATT:A	acceptor_gain	1.0000
14:64412471:G:GG	acceptor_gain	1.0000
14:64412471:GATT:G	acceptor_gain	1.0000

AlphaMissense

6126 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:64427452:G:C	G415R	1.000
14:64427473:G:C	G422R	1.000
14:64442084:T:C	F639L	1.000
14:64442085:T:G	F639C	1.000
14:64442086:T:A	F639L	1.000
14:64442086:T:G	F639L	1.000
14:64442092:C:A	N641K	1.000
14:64442092:C:G	N641K	1.000
14:64442277:T:C	F671L	1.000
14:64442279:T:A	F671L	1.000
14:64442279:T:G	F671L	1.000
14:64427362:G:T	G385W	0.999
14:64427365:A:C	K386Q	0.999
14:64427366:A:T	K386I	0.999
14:64427368:A:C	S387R	0.999
14:64427370:C:A	S387R	0.999
14:64427370:C:G	S387R	0.999
14:64427447:C:A	S413Y	0.999
14:64427447:C:T	S413F	0.999
14:64427453:G:A	G415D	0.999
14:64427461:T:C	F418L	0.999
14:64427463:T:A	F418L	0.999
14:64427463:T:G	F418L	0.999
14:64427465:G:A	G419E	0.999
14:64427472:A:C	K421N	0.999
14:64427472:A:T	K421N	0.999
14:64427473:G:T	G422C	0.999
14:64430184:G:A	G422D	0.999
14:64430190:C:A	A424D	0.999
14:64431537:T:A	N439K	0.999

dbSNP variants (sampled 300 via entrez): RS1000002948 (14:64386824 GA>G), RS1000102651 (14:64400288 T>C), RS1000130782 (14:64391143 C>G,T), RS1000153749 (14:64401308 G>A), RS1000209894 (14:64401658 G>A), RS1000216080 (14:64389565 C>G,T), RS1000221470 (14:64426720 C>T), RS1000242915 (14:64442373 G>T), RS1000339816 (14:64458107 T>A), RS1000373363 (14:64436796 C>G), RS1000382194 (14:64396025 A>T), RS1000447083 (14:64437045 T>A,G), RS1000461965 (14:64387804 G>A), RS1000543647 (14:64434949 C>T), RS1000544402 (14:64407888 T>C,G)

Disease associations

OMIM: gene MIM:172460 | disease phenotypes: MIM:601634, MIM:617780

GenCC curated gene-disease

Disease	Classification	Inheritance
combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia	Definitive	AR

Mondo (3): neural tube defects, folate-sensitive (MONDO:0011120), combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia (MONDO:0060611), severe combined immunodeficiency (MONDO:0015974)

Orphanet (3): Combined immunodeficiency-megaloblastic anemia due to methylenetetrahydrofolate dehydrogenase 1 deficiency (Orphanet:658813), Spina bifida and other spinal dysraphisms (Orphanet:823), Severe combined immunodeficiency (Orphanet:183660)

HPO phenotypes

27 total (27 of 27 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000365	Hearing impairment
HP:0000964	Eczematoid dermatitis
HP:0001250	Seizure
HP:0001256	Mild intellectual disability
HP:0001876	Pancytopenia
HP:0001888	Decreased total lymphocyte count
HP:0001889	Megaloblastic anemia
HP:0001894	Thrombocytosis
HP:0001939	Abnormality of metabolism/homeostasis
HP:0001972	Macrocytic anemia
HP:0002013	Vomiting
HP:0002160	Hyperhomocystinemia
HP:0002719	Recurrent infections
HP:0002960	Autoimmunity
HP:0003095	Septic arthritis
HP:0003223	Decreased circulating methylcobalamin concentration
HP:0003593	Infantile onset
HP:0004313	Decreased circulating immunoglobulin concentration
HP:0004430	Severe combined immunodeficiency
HP:0004821	Hypersegmentation of neutrophil nuclei
HP:0006532	Recurrent pneumonia
HP:0010301	Spinal dysraphism
HP:0010972	Anemia of inadequate production
HP:0025406	Asthenia
HP:0025435	Increased circulating lactate dehydrogenase concentration
HP:0025517	Hypoplastic hippocampus

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST000477_33	Cognitive performance	8.000000e-07
GCST004627_154	Lymphocyte count	2.000000e-12
GCST006414_22	Atrial fibrillation	3.000000e-31
GCST006658_1	Longevity	1.000000e-07
GCST007576_163	Chronotype	6.000000e-09

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0003926	neuropsychological test
EFO:0004587	lymphocyte count
EFO:0008328	chronotype measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D016511	Severe Combined Immunodeficiency	C16.320.798.750; C16.614.815; C18.452.284.800; C20.673.795.750
C536409	Neural tube defect, folate-sensitive (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2541 (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: 158 (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
CHEMBL12213	KETOTREXATE	2	158

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

PharmGKB clinical annotations

3 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs2236225	Efficacy	3	cisplatin;doxorubicin;methotrexate	Osteosarcoma
rs2236225	Efficacy	3	methotrexate	Acute lymphoblastic leukemia;Mesothelioma
rs2236225	Toxicity	3	methotrexate	Acute lymphoblastic leukemia;Anemia;Leukopenia;Mucositis;Non-Hodgkin Lymphoma;Osteosarcoma;Thrombocytopenia;Toxic liver disease

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2236225	MTHFD1	3	3.00	3	methotrexate;cisplatin;doxorubicin;methotrexate

ChEMBL bioactivities

27 potent at pChembl≥5 of 34 total, top 25 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.80	IC50	16	nM	CHEMBL5879031
7.06	Kd	87.14	nM	CHEMBL5653589
7.06	ED50	87.14	nM	CHEMBL5653589
7.02	IC50	96	nM	CHEMBL1233930
6.92	IC50	120	nM	CHEMBL6133989
6.64	IC50	230	nM	CHEMBL6103492
6.42	IC50	380	nM	CHEMBL6102567
6.24	IC50	570	nM	CHEMBL4463968
6.23	IC50	590	nM	CHEMBL6102973
6.20	IC50	630	nM	CHEMBL3622702
6.10	IC50	790	nM	CHEMBL6134698
5.96	IC50	1100	nM	CHEMBL4470947
5.75	IC50	1790	nM	CHEMBL6159806
5.66	IC50	2200	nM	CHEMBL6102503
5.54	IC50	2900	nM	CHEMBL4483030
5.38	IC50	4200	nM	CHEMBL4542665
5.38	IC50	4140	nM	CHEMBL6152791
5.31	IC50	4900	nM	CHEMBL4584730
5.30	IC50	5000	nM	CHEMBL4441993
5.29	IC50	5160	nM	CHEMBL6149895
5.28	IC50	5200	nM	CHEMBL4534641
5.27	IC50	5400	nM	CHEMBL4441792
5.19	IC50	6400	nM	CHEMBL4546647
5.10	IC50	8000	nM	CHEMBL4538356
5.08	IC50	8400	nM	CHEMBL4460077

PubChem BioAssay actives

13 with measured affinity, of 78 total; 13 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	2148794: Binding affinity to human MTHFD1 incubated for 45 mins by Kinobead based pull down assay	kd	0.0871	uM
(2S)-2-[[4-[(6aR)-3-amino-1,9-dioxo-5,6,6a,7-tetrahydro-2H-imidazo[1,5-f]pteridin-8-yl]benzoyl]amino]pentanedioic acid	1634024: Inhibition of His-tagged human MTHFD1 ( 1 to 306 residues) expressed in Escherichia coli BL21 (DE3) pre-incubated for 10 mins before folitixorin and NADP+ addition measured after 15 mins by NAD(P)H-Glo detection reagent based luminescence assay	ic50	0.0960	uM
N-[4-[8-[(3S)-3,4-dimethylpiperazin-1-yl]-7-methyl-5-oxo-2,4-dihydro-1H-chromeno[3,4-c]pyridine-3-carbonyl]-2-(trifluoromethoxy)phenyl]methanesulfonamide	1541134: Inhibition of recombinant MTHFD1 (unknown origin) using THF as substrate incubated for 30 mins in presence of NAD	ic50	0.5700	uM
N-[2-chloro-4-[8-[(3S)-3,4-dimethylpiperazin-1-yl]-7-methyl-5-oxo-2,4-dihydro-1H-chromeno[3,4-c]pyridine-3-carbonyl]phenyl]methanesulfonamide	1541134: Inhibition of recombinant MTHFD1 (unknown origin) using THF as substrate incubated for 30 mins in presence of NAD	ic50	1.1000	uM
N-[4-[7-methyl-8-(4-methylpiperazin-1-yl)-5-oxo-2,4-dihydro-1H-chromeno[3,4-c]pyridine-3-carbonyl]-2-(trifluoromethoxy)phenyl]methanesulfonamide	1541134: Inhibition of recombinant MTHFD1 (unknown origin) using THF as substrate incubated for 30 mins in presence of NAD	ic50	2.9000	uM
N-[2-bromo-4-[7-methyl-8-(4-methylpiperazin-1-yl)-5-oxo-2,4-dihydro-1H-chromeno[3,4-c]pyridine-3-carbonyl]phenyl]methanesulfonamide	1541134: Inhibition of recombinant MTHFD1 (unknown origin) using THF as substrate incubated for 30 mins in presence of NAD	ic50	4.2000	uM
N-[2-chloro-4-[7-methyl-5-oxo-8-[(3S,5R)-3,4,5-trimethylpiperazin-1-yl]-2,4-dihydro-1H-chromeno[3,4-c]pyridine-3-carbonyl]phenyl]methanesulfonamide	1541134: Inhibition of recombinant MTHFD1 (unknown origin) using THF as substrate incubated for 30 mins in presence of NAD	ic50	4.9000	uM
4-[8-[2-(dimethylamino)ethoxy]-7-methyl-5-oxo-2,4-dihydro-1H-chromeno[3,4-c]pyridine-3-carbonyl]benzoic acid;hydrochloride	1541134: Inhibition of recombinant MTHFD1 (unknown origin) using THF as substrate incubated for 30 mins in presence of NAD	ic50	5.0000	uM
3-(2,2-dioxo-1,3-dihydro-2,1-benzothiazole-5-carbonyl)-7-methyl-8-(4-methylpiperazin-1-yl)-2,4-dihydro-1H-chromeno[3,4-c]pyridin-5-one;2,2,2-trifluoroacetic acid	1541134: Inhibition of recombinant MTHFD1 (unknown origin) using THF as substrate incubated for 30 mins in presence of NAD	ic50	5.2000	uM
4-[8-[4-(dimethylamino)phenyl]-5-oxo-2,4-dihydro-1H-chromeno[3,4-c]pyridine-3-carbonyl]benzoic acid	1541134: Inhibition of recombinant MTHFD1 (unknown origin) using THF as substrate incubated for 30 mins in presence of NAD	ic50	5.4000	uM
N-[2-chloro-4-[7-methyl-8-(4-methylpiperazin-1-yl)-5-oxo-2,4-dihydro-1H-chromeno[3,4-c]pyridine-3-carbonyl]phenyl]methanesulfonamide	1541134: Inhibition of recombinant MTHFD1 (unknown origin) using THF as substrate incubated for 30 mins in presence of NAD	ic50	6.4000	uM
N-[2-fluoro-4-[7-methyl-8-(4-methylpiperazin-1-yl)-5-oxo-2,4-dihydro-1H-chromeno[3,4-c]pyridine-3-carbonyl]phenyl]methanesulfonamide	1541134: Inhibition of recombinant MTHFD1 (unknown origin) using THF as substrate incubated for 30 mins in presence of NAD	ic50	8.0000	uM
8-[2-(dimethylamino)ethoxy]-3-(2,2-dioxo-1,3-dihydro-2,1-benzothiazole-5-carbonyl)-7-methyl-2,4-dihydro-1H-chromeno[3,4-c]pyridin-5-one;2,2,2-trifluoroacetic acid	1541134: Inhibition of recombinant MTHFD1 (unknown origin) using THF as substrate incubated for 30 mins in presence of NAD	ic50	8.4000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, affects cotreatment, increases expression	6
bisphenol A	increases expression, decreases expression, decreases methylation	4
trichostatin A	affects cotreatment, increases expression	3
sodium arsenite	affects expression, decreases expression	2
cobaltous chloride	decreases expression	2
entinostat	increases expression, affects cotreatment	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, increases expression	2
Resveratrol	affects cotreatment, increases expression	2
Arsenic Trioxide	increases degradation, increases sumoylation, decreases reaction, decreases expression	2
Acetaminophen	affects expression, decreases expression	2
Doxorubicin	affects expression, decreases expression	2
Estradiol	decreases expression, increases expression	2
Rotenone	decreases expression, increases expression	2
Cyclosporine	decreases expression	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
aristolochic acid I	increases expression	1
GSK-J4	decreases expression	1
bisphenol F	increases expression	1
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
sodium arsenate	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, decreases expression, affects localization	1
decabromobiphenyl ether	decreases expression	1
beta-lapachone	decreases expression	1
tetrabromobisphenol A	decreases expression	1
zinc chromate	increases abundance, decreases expression	1
ochratoxin A	increases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
hydroquinone	decreases expression	1
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	decreases reaction, increases degradation	1

ChEMBL screening assays

30 unique, capped per target: 30 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4022807	Binding	Inhibition of MTHFD1 (unknown origin) using NADP/5,10-methylene THF as substrate after 30 mins by HPLC method	Discovery of N-(6-Fluoro-1-oxo-1,2-dihydroisoquinolin-7-yl)-5-[(3R)-3-hydroxypyrrolidin-1-yl]thiophene-2-sulfonamide (LSN 3213128), a Potent and Selective Nonclassical Antifolate Aminoimidazole-4-carboxamide Ribonucleotide Formyltransferase (AICARFT) Inhibitor Effective at Tumor Suppression in a Cancer Xenograft Model. — J Med Chem

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D9KQ	Ubigene HEK293 MTHFD1 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00220766	PHASE3	COMPLETED	Rapid Infusion of Immune Globulin Intravenous (Human) In Primary Immunodeficiency Patients
NCT01420627	PHASE3	COMPLETED	EZN-2279 in Patients With ADA-SCID
NCT06940570	PHASE3	SUSPENDED	Methadone as an Alternative Treatment for Children Underdoing HSCT
NCT00000603	PHASE2	COMPLETED	Cord Blood Stem Cell Transplantation Study (COBLT)
NCT00794508	PHASE2	COMPLETED	MND-ADA Transduction of CD34+ Cells From Children With ADA-SCID
NCT01182675	PHASE2	TERMINATED	Hematopoietic Stem Cell Transplantation (HSCT) for Children With SCID Utilizing Alemtuzumab, Plerixafor & Filgrastim
NCT01529827	PHASE2	COMPLETED	Fludarabine Phosphate, Melphalan, and Low-Dose Total-Body Irradiation Followed by Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Hematologic Malignancies
NCT01821781	PHASE2	ACTIVE_NOT_RECRUITING	Immune Disorder HSCT Protocol
NCT02177760	PHASE2	WITHDRAWN	Sirolimus Prophylaxis for aGVHD in TME SCID
NCT03619551	PHASE2	ACTIVE_NOT_RECRUITING	Conditioning SCID Infants Diagnosed Early
NCT00008450	PHASE1	COMPLETED	Total-Body Irradiation Followed By Cyclosporine and Mycophenolate Mofetil in Treating Patients With Severe Combined Immunodeficiency Undergoing Donor Bone Marrow Transplant
NCT00028236	PHASE1	COMPLETED	Stem Cell Gene Therapy to Treat X-Linked Severe Combined Immunodeficiency (XSCID)
NCT00152100	PHASE1	COMPLETED	Transplantation of Hematopoietic Cells in Children With Severe Combined Immunodeficiency Syndrome
NCT02860559	PHASE1	UNKNOWN	Safety and Early Efficacy Study of TBX-1400 in Patients With Severe Combined Immunodeficiency
NCT01019876	PHASE2/PHASE3	COMPLETED	Risk-Adapted Allogeneic Stem Cell Transplantation For Mixed Donor Chimerism In Patients With Non-Malignant Diseases
NCT00228852	PHASE1/PHASE2	COMPLETED	IMM 0212: Busulfan With Fludarabine and Antithymocyte Globulin as Preparative Therapy for Hematopoietic Stem Cell Transplant for the Treatment of Severe Congenital T-Cell Immunodeficiency
NCT00579137	PHASE1/PHASE2	TERMINATED	Allogeneic SCT Of Pts With SCID And Other Primary Immunodeficiency Disorders
NCT01129544	PHASE1/PHASE2	COMPLETED	Gene Transfer for Severe Combined Immunodeficiency, X-linked (SCID-X1) Using a Self-inactivating (SIN) Gammaretroviral Vector
NCT01852370	PHASE1/PHASE2	ENROLLING_BY_INVITATION	Sequential Cadaveric Lung and Bone Marrow Transplant for Immune Deficiency Diseases
NCT02127892	PHASE1/PHASE2	TERMINATED	SCID Bu/Flu/ATG Study With T Cell Depletion
NCT02963064	PHASE1/PHASE2	TERMINATED	JSP191 Antibody Targeting Conditioning in SCID Patients
NCT03513328	PHASE1/PHASE2	COMPLETED	Conditioning Regimen for Allogeneic Hematopoietic Stem-Cell Transplantation
NCT03538899	PHASE1/PHASE2	RECRUITING	Autologous Gene Therapy for Artemis-Deficient SCID
NCT03597594	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Haplocompatible Transplant Using TCRα/β Depletion Followed by CD45RA-Depleted Donor Lymphocyte Infusions for Severe Combined Immunodeficiency (SCID)
NCT00001255	Not specified	COMPLETED	Gene Transfer Therapy for Severe Combined Immunodeficieny Disease (SCID) Due to Adenosine Deaminase (ADA) Deficiency: A Natural History Study
NCT00006054	Not specified	TERMINATED	Allogeneic Bone Marrow Transplantation in Patients With Primary Immunodeficiencies
NCT00006335	Not specified	COMPLETED	Influences on Female Adolescents’ Decisions Regarding Testing for Carrier Status of XSCID
NCT00055172	Not specified	RECRUITING	Genetic Basis of Immunodeficiency
NCT00695279	Not specified	COMPLETED	Long Term Follow Up Of Patients Who Have Received Gene Therapy Or Gene Marked Products
NCT00845416	Not specified	COMPLETED	Newborn Screening for Severe Combined Immunodeficiency (SCID) in a High-Risk Population
NCT01186913	Not specified	ENROLLING_BY_INVITATION	Natural History Study of SCID Disorders
NCT01346150	Not specified	UNKNOWN	Patients Treated for SCID (1968-Present)
NCT01652092	Not specified	ACTIVE_NOT_RECRUITING	Allogeneic Hematopoietic Stem Cell Transplant for Patients With Primary Immune Deficiencies
NCT01953016	Not specified	COMPLETED	Participation in a Research Registry for Immune Disorders
NCT02231983	Not specified	UNKNOWN	Clinical Characteristics and Genetic Profiles of Severe Combined Immunodeficiency in China
NCT02590328	Not specified	COMPLETED	Neonatal Screening of Severe Combined Immunodeficiencies
NCT04049084	Not specified	ENROLLING_BY_INVITATION	An Observational LTFU Study for Patients Previously Treated With Autologous ex Vivo Gene Therapy for ADA-SCID
NCT04172181	Not specified	UNKNOWN	Multi-center Clinical Study of Cord Blood Stem Cell Transplantation for SCID
NCT04246840	Not specified	COMPLETED	Study Through Imaging of Visceral Lymphoid Organs in Patients With SCID Who Have Recieved Bone Marrow Allograft
NCT04331483	Not specified	WITHDRAWN	A Study to Assess a Physical Activity Program in Children, Adolescents and Young Adults Requiring Hematopoietic Stem Cell Allografts