FPGS

Summary

FPGS (folylpolyglutamate synthase, HGNC:3824) is a protein-coding gene on chromosome 9q34.11, encoding Folylpolyglutamate synthase, mitochondrial (Q05932). Catalyzes conversion of folates to polyglutamate derivatives allowing concentration of folate compounds in the cell and the intracellular retention of these cofactors, which are important substrates for most of the folate-dependent enzymes that are involved in one-carbon transfe…. It is a selective cancer dependency (DepMap: 44.3% of cell lines).

This gene encodes the folylpolyglutamate synthetase enzyme. This enzyme has a central role in establishing and maintaining both cytosolic and mitochondrial folylpolyglutamate concentrations and, therefore, is essential for folate homeostasis and the survival of proliferating cells. This enzyme catalyzes the ATP-dependent addition of glutamate moieties to folate and folate derivatives. Alternative splicing results in transcript variants encoding different isoforms.

Source: NCBI Gene 2356 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 96 total
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 44.3% of screened cell lines
• MANE Select transcript: NM_004957

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3824
Approved symbol	FPGS
Name	folylpolyglutamate synthase
Location	9q34.11
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000136877
Ensembl biotype	protein_coding
OMIM	136510
Entrez	2356

Gene structure

Transcript identifiers

Ensembl transcripts: 37 — 23 protein_coding, 14 protein_coding_CDS_not_defined

ENST00000373225, ENST00000373228, ENST00000373247, ENST00000393706, ENST00000423577, ENST00000431857, ENST00000460181, ENST00000467826, ENST00000469310, ENST00000473536, ENST00000475270, ENST00000475765, ENST00000479147, ENST00000479375, ENST00000481552, ENST00000488307, ENST00000488506, ENST00000489522, ENST00000496586, ENST00000497386, ENST00000630236, ENST00000910442, ENST00000910443, ENST00000910444, ENST00000910445, ENST00000910446, ENST00000910447, ENST00000910448, ENST00000910449, ENST00000931641, ENST00000931642, ENST00000931643, ENST00000943702, ENST00000943703, ENST00000943704, ENST00000943705, ENST00000943706

RefSeq mRNA: 3 — MANE Select: NM_004957 NM_001018078, NM_001288803, NM_004957

CCDS: CCDS35148, CCDS35149, CCDS75905

Canonical transcript exons

ENST00000373247 — 15 exons

Exon	Start	End
ENSE00001713626	127813195	127814081
ENSE00002252674	127802882	127803062
ENSE00003460947	127808800	127808889
ENSE00003476578	127804285	127804413
ENSE00003480779	127808558	127808705
ENSE00003512474	127807209	127807286
ENSE00003524619	127809684	127809834
ENSE00003529540	127806973	127807087
ENSE00003545146	127808234	127808311
ENSE00003574757	127804499	127804552
ENSE00003606929	127807586	127807688
ENSE00003641151	127810031	127810106
ENSE00003646625	127804636	127804700
ENSE00003686597	127810945	127811011
ENSE00003687279	127807421	127807482

Expression profiles

Bgee: expression breadth ubiquitous, 224 present calls, max score 98.21.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 32.5523 / max 220.2426, expressed in 1818 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
98667	23.8424	1807
98671	4.2810	1251
98670	2.4149	1407
98668	1.3229	748
98669	0.6192	395
98673	0.0718	33

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left ovary	UBERON:0002119	98.21	gold quality
right ovary	UBERON:0002118	97.96	gold quality
left uterine tube	UBERON:0001303	97.05	gold quality
mucosa of stomach	UBERON:0001199	96.71	gold quality
left adrenal gland cortex	UBERON:0035825	96.54	gold quality
right uterine tube	UBERON:0001302	96.50	gold quality
right lobe of liver	UBERON:0001114	96.49	gold quality
left adrenal gland	UBERON:0001234	96.44	gold quality
right adrenal gland	UBERON:0001233	96.29	gold quality
right adrenal gland cortex	UBERON:0035827	96.14	gold quality
endocervix	UBERON:0000458	96.10	gold quality
apex of heart	UBERON:0002098	95.93	gold quality
upper lobe of left lung	UBERON:0008952	95.74	gold quality
body of uterus	UBERON:0009853	95.67	gold quality
right lung	UBERON:0002167	95.16	gold quality
right lobe of thyroid gland	UBERON:0001119	95.01	gold quality
tibial nerve	UBERON:0001323	94.94	gold quality
ascending aorta	UBERON:0001496	94.92	gold quality
thoracic aorta	UBERON:0001515	94.90	gold quality
metanephros cortex	UBERON:0010533	94.78	gold quality
left coronary artery	UBERON:0001626	94.75	gold quality
omental fat pad	UBERON:0010414	94.70	gold quality
peritoneum	UBERON:0002358	94.62	gold quality
sural nerve	UBERON:0015488	94.59	gold quality
descending thoracic aorta	UBERON:0002345	94.54	gold quality
left lobe of thyroid gland	UBERON:0001120	94.52	gold quality
right coronary artery	UBERON:0001625	94.49	gold quality
adrenal cortex	UBERON:0001235	94.47	gold quality
aorta	UBERON:0000947	94.36	gold quality
upper lobe of lung	UBERON:0008948	94.34	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	10.72
E-MTAB-7606	no	2003.74

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ETV6, MYC, PBX1, RUNX1, SP1, TCF3

miRNA regulators (miRDB)

21 targeting FPGS, 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-4692	100.00	67.32	2066
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-3150A-3P	99.76	64.44	1640
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-3175	99.65	66.30	2031
HSA-MIR-940	99.37	66.14	2064
HSA-MIR-6808-5P	99.31	66.23	2150
HSA-MIR-6893-5P	99.31	66.25	2119
HSA-MIR-320E	97.49	65.96	865
HSA-MIR-3157-5P	97.41	67.61	998
HSA-MIR-939-5P	97.10	65.80	1579
HSA-MIR-2861	95.24	65.47	1056

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 44.3% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 38)

• low folylpolyglutamate synthase expression is associated with development of aggressive metastatic behavior of the colorectal cancer (PMID:14676127)
• Significantly higher expression levels of FPGS were found in mucosa expressing the splice variant DCC342. (PMID:16122883)
• human mitochondrial FPGS is at least in part strongly associated with the inner mitochondrial membrane (PMID:16169100)
• Investigation of the molecular regulatory mechanisms directing FPGS gene expression in B precursor-ALL and T-ALL cells. (PMID:16707018)
• study identified FPGS polymorphisms; results indicate that two of the cytosolic nonsynonymous coding SNPs affected protein expression, in vitro substrate kinetics & folate & antifolate efficacy in cells expressing the polymorphisms (PMID:17875718)
• Results indicate that hFPGS can catalyze the processive addition of approximately four glutamate residues to DDAH 4PteGlu 1. (PMID:18672898)
• Aberrant splicing of folylpolyglutamate synthetase is associated with antifolate resistance in leukemia. (PMID:19131550)
• Data revealed that high FPGS gene expression, low GGH gene expression and low ABCC1 gene expression in CRC tissues were predictive factors for a high reduced folate level after LV administration. (PMID:19636555)
• FPGS gene is proposed as a novel causative gene for cleft lip. (PMID:21093159)
• intratumor FPGS plays an important role in the efficacy of oral fluoropyrimidine plus LV therapy for colorectal cancer. (PMID:21380490)
• The expression of mFPGS was different in A549 cells exposed to different methotrexate enantiomers. (PMID:21418912)
• This is one of the first studies to assess FPGS and GGH genetic variants in relation to plasma homocysteine. (PMID:22018726)
• The mbr enhanced the expression of FPGS significantly and increased sensitivity of Jurkat cells to MTX efficiently. (PMID:22698741)
• A novel missense mutation 502/490 T>C (L151/101P) in exon 5 of FPGS gene is firstly found in Chinese Han children, and the cytosolic and mitochondrial variants display allelic frequencies of 0.70 % and 0.47 % respectively. (PMID:22809608)
• High Folylpoly-glutamate synthetase expression is associated with response to therapy in non-small-cell lung cancer. (PMID:22895141)
• An interaction term, between FPGS rs7033913 heterozygotes and GGH rs11988534 homozygotes for the minor allele, had a p-value <0.0001 and may contribute to methotrexate toxicity in rheumatoid arthritis. (PMID:24447348)
• Genome-wide association studies identify 10 novel genetic loci as risk factors for methotrexate response in rheumatoid arthritis patients additionally to polymorphism in DHFR, FPGS and TYMS. (PMID:24583629)
• Polymorphism of FPGS rs1544105 G>A is associated with response to therapy in acute lymphoblastic leukemia. (PMID:24908438)
• mitochondrial FPGS is required because folate polyglutamates are not substrates for transport across the mitochondrial membrane (PMID:25164808)
• antifolate resistant leukemia cells harbor a heterozygous point mutation in exon12 of FPGS which disrupts FPGS activity by abolishing ATP binding, and alters the binding pattern of transcription factors to the genomic region of exon12. (PMID:25229333)
• study found that genetic polymorphism of FPGS rs10760502A > G is associated with susceptibility to primary retroperitoneal liposasrcoma (PMID:25765001)
• Genetic polymorphisms in the FPGS coding region are significantly associated with increased Acute Lymphoblastic Leukemia risk. (PMID:26107232)
• FPGS and ABCB1 genetic variants can influence the outcome in RA patients receiving MTX monotherapy. (PMID:26652611)
• the highest expression of GGH and EGFR was noted in the left-sided colon; the highest expression of DHFR, FPGS, TOP1 and ERCC1 was noted in the rectosigmoid, whereas TYMP expression was approximately equivalent in the right-sided colon and rectum (PMID:26676887)
• 529 adults (n = 325 European-Americans, 204 Egyptians) on a stable warfarin dose were genotyped for GGCX rs12714145 and rs10654848, FPGS rs7856096, and STX1B rs4889606. (PMID:26751406)
• data suggest that FPGS modulation affects global and promoter CpG DNA methylation and expression of several genes involved in important biological pathways (PMID:26895662)
• The association of aberrant folylpolyglutamate synthetase splicing with ex vivo methotrexate resistance and clinical outcome in childhood acute lymphoblastic leukemia. (PMID:27036162)
• Low expression level of FPGS is associated with neuroendocrine lung tumors. (PMID:27064343)
• These results indicate that elevated expressions of the tumor-related genes FPGS/GGH and VEGF are correlated with malignancy of thymic carcinoma and B3 thymoma tumors. (PMID:27387303)
• Our results revealed a significant difference of overall survival between patients with AA genotype and GA + GG genotype (P<0.05). Our study demonstrated a correlation of the polymorphism of FPGS rs1544105 with MTX treatment efficacy, as well as with overall survival, suggesting it could be used as an effective approach in the prediction of MTX treatment efficacy (PMID:27987364)
• analysis of seven polymorphisms in genes of folate transport and (de)glutamation pathway on methotrexate polyglutamate levels and response in patients with rheumatoid arthritis: ABCB1, FPGS, GGH and RFC1 (PMID:30022368)
• our study has established the de novo MTX-resistant cell line SF-86 and identified SKA1 as a novel regulator of FPGS, playing a key role in the development of de novo MTX-resistance in osteosarcoma (OS). (PMID:30851225)
• Effects of germline DHFR and FPGS variants on methotrexate metabolism and relapse of leukemia. (PMID:32391884)
• Association of NUDT15*3 and FPGS 2572C>T Variants with the Risk of Early Hematologic Toxicity During 6-MP and Low-Dose Methotrexate-Based Maintenance Therapy in Indian Patients with Acute Lymphoblastic Leukemia. (PMID:32481505)
• FPGS relapse-specific mutations in relapsed childhood acute lymphoblastic leukemia. (PMID:32694622)
• Association of altered folylpolyglutamate synthetase pre-mRNA splicing with methotrexate unresponsiveness in early rheumatoid arthritis. (PMID:32940699)
• Influence of FPGS, ABCC4, SLC29A1, and MTHFR genes on the pharmacogenomics of fluoropyrimidines in patients with gastrointestinal cancer from the Brazilian Amazon. (PMID:34331561)
• Effects of single nucleotide polymorphisms of the folylpolyglutamate synthase gene on pemetrexed administration-induced nephropathy. (PMID:37452621)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	fpgs	ENSDARG00000044809
mus_musculus	Fpgs	ENSMUSG00000009566
rattus_norvegicus	Fpgs	ENSRNOG00000050780
drosophila_melanogaster	Fpgs1	FBGN0030407
drosophila_melanogaster	Fpgs2	FBGN0051773
caenorhabditis_elegans		WBGENE00017777

Protein

Protein identifiers

Folylpolyglutamate synthase, mitochondrial — Q05932 (reviewed: Q05932)

Alternative names: Folylpoly-gamma-glutamate synthetase, Tetrahydrofolylpolyglutamate synthase

All UniProt accessions (4): Q05932, Q5JU20, Q5JU21, Q5JU23

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes conversion of folates to polyglutamate derivatives allowing concentration of folate compounds in the cell and the intracellular retention of these cofactors, which are important substrates for most of the folate-dependent enzymes that are involved in one-carbon transfer reactions involved in purine, pyrimidine and amino acid synthesis. Unsubstituted reduced folates are the preferred substrates. Metabolizes methotrexate (MTX) to polyglutamates.

Subunit / interactions. Monomer.

Subcellular location. Mitochondrion inner membrane. Mitochondrion matrix Cytoplasm.

Activity regulation. Activated by 10 mM sodium bicarbonate.

Cofactor. A monovalent cation. K(+) is most effective, followed by NH4(+) and Rb(+). Na(+), Li(+) and Cs(+) are ineffective.

Pathway. Cofactor biosynthesis; tetrahydrofolylpolyglutamate biosynthesis.

Miscellaneous. Produced by alternative initiation at Met-43 of isoform 1. Produced by alternative splicing of isoform 1. Produced by alternative splicing of isoform 1.

Similarity. Belongs to the folylpolyglutamate synthase family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q05932-1	1, Mitochondrial	yes
Q05932-2	2, Cytoplasmic
Q05932-3	3
Q05932-4	4

RefSeq proteins (3): NP_001018088, NP_001275732, NP_004948* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001645	Folylpolyglutamate_synth	Family
IPR018109	Folylpolyglutamate_synth_CS	Conserved_site
IPR023600	Folylpolyglutamate_synth_euk	Family
IPR036565	Mur-like_cat_sf	Homologous_superfamily
IPR036615	Mur_ligase_C_dom_sf	Homologous_superfamily

Enzyme classification (BRENDA):

• EC 6.3.2.17 — tetrahydrofolate synthase (BRENDA: 22 organisms, 210 substrates, 92 inhibitors, 247 Km, 25 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
ATP	0.0046–35.7	39
AMINOPTERIN	0.004–0.18	18
L-GLU	0.053–150	15
METHOTREXATE	0.019–0.138	15
5,10-METHYLENE-5,6,7,8-TETRAHYDROFOLIC ACID	0.03–3.8	14
5,6,7,8-TETRAHYDROFOLIC ACID	0.01–0.655	11
5,6,7,8-TETRAHYDROPTEROYL-GLU	0.0021–6.8	10
GLU	0.332–5.984	9
L-GLUTAMATE	0.24–26.69	8
7,8-DIHYDROPTEROATE	0.0063–0.98	7
L-GLUTAMIC ACID	0.43–350	7
PTEROYL-GLU	0.059–0.137	5
10-FORMYL-5,6,7,8-TETRAHYDROPTEROYL-GLU	0.0022–0.014	4
5,6,7,8-TETRAHYDROPTEROYL-GLU4	0.0016–0.002	4
7,8-DIHYDROPTEROYL-GLU	0.0008–0.0086	4

Catalyzed reactions (Rhea), 1 shown:

• (6S)-5,6,7,8-tetrahydrofolyl-(gamma-L-Glu)(n) + L-glutamate + ATP = (6S)-5,6,7,8-tetrahydrofolyl-(gamma-L-Glu)(n+1) + ADP + phosphate + H(+) (RHEA:10580)

UniProt features (21 total): sequence variant 7, binding site 6, splice variant 3, modified residue 2, transit peptide 1, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q05932-F1	83.05	0.63

Functional residue map

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

Ligand- & substrate-binding residues (6): 106–109; 130; 200; 228; 363; 377

Post-translational modifications (2): 43, 539

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-196757	Metabolism of folate and pterines

MSigDB gene sets: 137 (showing top): RNGTGGGC_UNKNOWN, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, GOBP_GLUTAMATE_METABOLIC_PROCESS, GOBP_GLUTAMINE_FAMILY_AMINO_ACID_METABOLIC_PROCESS, GOBP_DICARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_PTERIDINE_CONTAINING_COMPOUND_BIOSYNTHETIC_PROCESS, GOBP_FOLIC_ACID_CONTAINING_COMPOUND_BIOSYNTHETIC_PROCESS, GOBP_PTERIDINE_CONTAINING_COMPOUND_METABOLIC_PROCESS, GOBP_AMIDE_METABOLIC_PROCESS, ZHAN_V2_LATE_DIFFERENTIATION_GENES, GOBP_ONE_CARBON_METABOLIC_PROCESS, GOCC_MITOCHONDRIAL_ENVELOPE, GOBP_ORGANIC_ACID_METABOLIC_PROCESS, GOMF_LIGASE_ACTIVITY_FORMING_CARBON_NITROGEN_BONDS, GOMF_ACID_AMINO_ACID_LIGASE_ACTIVITY

GO Biological Process (9): nucleobase-containing compound metabolic process (GO:0006139), glutamate metabolic process (GO:0006536), one-carbon metabolic process (GO:0006730), folic acid-containing compound metabolic process (GO:0006760), cell population proliferation (GO:0008283), folic acid metabolic process (GO:0046655), tetrahydrofolylpolyglutamate biosynthetic process (GO:0046901), biosynthetic process (GO:0009058), folic acid-containing compound biosynthetic process (GO:0009396)

GO Molecular Function (6): tetrahydrofolylpolyglutamate synthase activity (GO:0004326), ATP binding (GO:0005524), metal ion binding (GO:0046872), nucleotide binding (GO:0000166), ligase activity (GO:0016874), acid-amino acid ligase activity (GO:0016881)

GO Cellular Component (6): cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), mitochondrial matrix (GO:0005759), cytosol (GO:0005829), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Metabolism of water-soluble vitamins and cofactors	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
dicarboxylic acid metabolic process	2
folic acid-containing compound metabolic process	2
cytoplasm	2
primary metabolic process	1
amino acid metabolic process	1
small molecule metabolic process	1
modified amino acid metabolic process	1
pteridine-containing compound metabolic process	1
cellular process	1
folic acid-containing compound biosynthetic process	1
tetrahydrofolylpolyglutamate metabolic process	1
metabolic process	1
modified amino acid biosynthetic process	1
pteridine-containing compound biosynthetic process	1
acid-amino acid ligase activity	1
tetrahydrofolylpolyglutamate biosynthetic process	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
cation binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
catalytic activity	1
ligase activity, forming carbon-nitrogen bonds	1
intracellular anatomical structure	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
mitochondrion	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

2014 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FPGS	DHFR	P00374	810
FPGS	TYMS	P04818	808
FPGS	DHFR2	Q86XF0	790
FPGS	GGH	Q92820	776
FPGS	MTHFD1	P11586	771
FPGS	ATIC	P31939	767
FPGS	GART	P22102	746
FPGS	MTHFR	P42898	729
FPGS	SLC19A1	P41440	723
FPGS	SHMT1	P34896	716
FPGS	MTHFD1L	Q6UB35	689
FPGS	SHMT2	P34897	643
FPGS	MTHFS	P49914	625
FPGS	MTHFD2	P13995	625
FPGS	SLC46A1	Q96NT5	596

IntAct

27 interactions, top by confidence:

A	B	Type	Score
TOR1AIP2	TMEM223	psi-mi:“MI:0914”(association)	0.530
HMGCL	DBT	psi-mi:“MI:0914”(association)	0.530
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
	DENND11	psi-mi:“MI:0914”(association)	0.350
	NUDT19	psi-mi:“MI:0914”(association)	0.350
AVPR2	GXYLT2	psi-mi:“MI:0914”(association)	0.350
GPR17	TMEM120B	psi-mi:“MI:0914”(association)	0.350
PTCD1	VWA8	psi-mi:“MI:0914”(association)	0.350
GPR182	METTL15	psi-mi:“MI:0914”(association)	0.350
PTH2R	METTL15	psi-mi:“MI:0914”(association)	0.350
NIT1	NUDT19	psi-mi:“MI:0914”(association)	0.350
THEM4	PRORP	psi-mi:“MI:0914”(association)	0.350
LIPH	B4GALT5	psi-mi:“MI:0914”(association)	0.350
LAMP2	HSPA12A	psi-mi:“MI:0914”(association)	0.350
CGA	TRIO	psi-mi:“MI:0914”(association)	0.350
HMGCL	GLS	psi-mi:“MI:0914”(association)	0.350
PALM2AKAP2	ANK2	psi-mi:“MI:0914”(association)	0.350
GPR182	SLC12A8	psi-mi:“MI:0914”(association)	0.350
QRSL1	VWA8	psi-mi:“MI:0914”(association)	0.350
AMACR	VWA8	psi-mi:“MI:0914”(association)	0.350
FAHD1	VWA8	psi-mi:“MI:0914”(association)	0.350
DNAI2	APAF1	psi-mi:“MI:0914”(association)	0.350
ACAA2	GLS	psi-mi:“MI:0914”(association)	0.350
CIB2	RIPK2	psi-mi:“MI:0914”(association)	0.350
KLK2	VWA8	psi-mi:“MI:0914”(association)	0.350
SLC1A2	UBXN8	psi-mi:“MI:0914”(association)	0.350

BioGRID (45): FPGS (Affinity Capture-MS), FPGS (Affinity Capture-MS), FPGS (Affinity Capture-MS), FPGS (Affinity Capture-MS), FPGS (Affinity Capture-MS), FPGS (Affinity Capture-MS), FPGS (Affinity Capture-MS), FPGS (Affinity Capture-MS), FPGS (Affinity Capture-MS), FPGS (Affinity Capture-RNA), FPGS (Affinity Capture-MS), FPGS (Proximity Label-MS), FPGS (Affinity Capture-MS), FPGS (Affinity Capture-MS), FPGS (Affinity Capture-MS)

ESM2 similar proteins: A0A061IR73, A0A7N9VSG0, A7YSY2, D3KCC4, D3ZU57, D4A2B7, O08644, O15197, O19179, O43542, O75064, O95382, P0C0K6, P0C0K7, P51840, P52785, P52824, P54777, Q02846, Q05932, Q13470, Q13608, Q1HG60, Q3ZBE0, Q4KM32, Q5JZY3, Q643R3, Q6MG64, Q6NVG1, Q6ZPS2, Q76MJ5, Q7TNJ2, Q80SX8, Q8BYG9, Q8IZY2, Q8NFF5, Q8R5G7, Q8TDZ2, Q8WWN8, Q91V24

Diamond homologs: A6H751, A6ZP80, B3LJR0, B5VSC3, C8ZGZ3, E7KIA3, E7KUJ4, E7NMM0, E7Q9C7, E7QKX4, F4J2K2, F4JYE9, F4K2A1, O13492, O74742, P08192, P43775, P48760, P57265, Q05865, Q05932, Q08645, Q09509, Q12676, Q54CY5, Q89AT2, Q8K9X3, Q8W035, Q924L9, Q9HS44, Q9Y893, I6Y0R5, Q9UTD0, P36001, D4GW05, P15925, C0HMD9, O04862, O05701, P05382

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	67
Likely benign	7
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

1959 predictions. Top by Δscore:

Variant	Effect	Δscore
9:127803053:G:GT	donor_gain	1.0000
9:127804266:T:TA	acceptor_gain	1.0000
9:127804271:ACTGT:A	acceptor_gain	1.0000
9:127804275:T:TA	acceptor_gain	1.0000
9:127804412:AGGTA:A	donor_loss	1.0000
9:127804413:GG:G	donor_loss	1.0000
9:127804414:G:GG	donor_gain	1.0000
9:127804414:GT:G	donor_loss	1.0000
9:127804415:T:G	donor_loss	1.0000
9:127804494:CCCAG:C	acceptor_loss	1.0000
9:127804495:CCAG:C	acceptor_loss	1.0000
9:127804549:G:GT	donor_gain	1.0000
9:127804549:G:T	donor_gain	1.0000
9:127804550:A:T	donor_gain	1.0000
9:127804550:AAGG:A	donor_loss	1.0000
9:127804552:GGTGA:G	donor_loss	1.0000
9:127804553:G:A	donor_loss	1.0000
9:127804554:T:G	donor_loss	1.0000
9:127804634:A:G	acceptor_gain	1.0000
9:127806972:GCT:G	acceptor_gain	1.0000
9:127807083:CCAAG:C	donor_loss	1.0000
9:127807084:CAAGG:C	donor_loss	1.0000
9:127807085:AAG:A	donor_loss	1.0000
9:127807086:AGG:A	donor_loss	1.0000
9:127807087:GGTG:G	donor_loss	1.0000
9:127807088:GT:G	donor_loss	1.0000
9:127807089:T:A	donor_loss	1.0000
9:127807101:G:GT	donor_gain	1.0000
9:127807483:G:GC	donor_loss	1.0000
9:127807484:T:A	donor_loss	1.0000

AlphaMissense

3779 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:127804699:A:C	S129R	0.996
9:127806973:C:A	S129R	0.996
9:127806973:C:G	S129R	0.996
9:127806999:A:T	E138V	0.996
9:127807002:G:C	R139P	0.996
9:127807008:G:C	R141P	0.996
9:127813548:A:C	S570R	0.996
9:127813550:C:A	S570R	0.996
9:127813550:C:G	S570R	0.996
9:127807440:A:T	E200V	0.994
9:127807672:A:T	K243I	0.994
9:127804529:C:G	H100D	0.993
9:127806978:C:A	P131H	0.993
9:127807628:C:A	H228Q	0.993
9:127807628:C:G	H228Q	0.993
9:127809701:T:A	W360R	0.993
9:127809701:T:C	W360R	0.993
9:127813546:G:A	G569D	0.993
9:127806981:A:G	H132R	0.992
9:127806982:C:A	H132Q	0.992
9:127806982:C:G	H132Q	0.992
9:127809708:G:A	G362D	0.992
9:127809711:G:C	R363P	0.992
9:127809743:T:A	W374R	0.992
9:127809743:T:C	W374R	0.992
9:127813545:G:C	G569R	0.992
9:127813549:G:T	S570I	0.992
9:127804538:G:T	G103W	0.991
9:127804547:G:T	G106W	0.991
9:127804636:G:C	G108R	0.991

dbSNP variants (sampled 300 via entrez): RS1000259164 (9:127803896 G>A,C), RS1000280267 (9:127812725 C>G), RS1000900482 (9:127813821 C>G,T), RS1001014419 (9:127802630 G>C), RS1001045385 (9:127802903 C>A,G,T), RS1001276226 (9:127808557 G>A,T), RS1001332767 (9:127801814 C>A), RS1001400806 (9:127808470 G>A), RS1002136923 (9:127801667 G>A), RS1002170832 (9:127813513 G>A), RS1003024791 (9:127805176 A>G), RS1003109457 (9:127811571 T>C), RS1003291160 (9:127805965 C>T), RS1003353642 (9:127806459 T>C), RS1003530845 (9:127800881 G>A,T)

Disease associations

OMIM: gene MIM:136510 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST005951_65	Body mass index	5.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3171 (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: 398,396 (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
CHEMBL34259	METHOTREXATE	4	398,396

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

PharmGKB clinical annotations

4 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs1544105	Efficacy	3	methotrexate	Rheumatoid arthritis
rs1544105	Efficacy	3	methotrexate	Acute lymphoblastic leukemia
rs1544105	Metabolism/PK	3	methotrexate	Acute lymphoblastic leukemia
rs7856096	Dosage	3	warfarin

PharmGKB variants

6 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs10106	FPGS		0.00	0
rs1054774	CDK9, FPGS		0.00	0
rs1544105	FPGS	3	3.25	3	methotrexate
rs4451422	ENG, FPGS		0.00	0
rs7856096	FPGS	3	5.75	1	warfarin
rs10760502	FPGS		0.00	0

ChEMBL bioactivities

29 potent at pChembl≥5 of 33 total, top 26 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.77	Ki	1.7	nM	CHEMBL38937
8.08	Ki	8.3	nM	CHEMBL288142
8.06	Ki	8.8	nM	CHEMBL130518
7.96	Ki	11	nM	CHEMBL133637
7.70	IC50	20	nM	CHEMBL306014
7.19	Ki	64	nM	CHEMBL289923
6.92	IC50	120	nM	CHEMBL431954
6.82	Ki	150	nM	CHEMBL339240
6.70	Ki	200	nM	CHEMBL331279
6.70	Ki	200	nM	CHEMBL83868
6.68	IC50	210	nM	CHEMBL289923
6.52	Ki	300	nM	CHEMBL281656
6.38	Ki	420	nM	CHEMBL43288
6.30	Ki	500	nM	CHEMBL335629
6.05	Ki	900	nM	CHEMBL340993
5.92	Ki	1200	nM	CHEMBL39107
5.72	Ki	1900	nM	CHEMBL281024
5.55	Ki	2800	nM	CHEMBL41161
5.50	IC50	3200	nM	METHOTREXATE
5.40	Ki	4000	nM	CHEMBL28049
5.24	IC50	5700	nM	CHEMBL304352
5.23	Ki	5900	nM	CHEMBL41743
5.23	Ki	5900	nM	CHEMBL289372
5.22	Ki	6000	nM	CHEMBL431290
5.07	IC50	8600	nM	CHEMBL307085
5.00	Ki	1e+04	nM	CHEMBL25870

PubChem BioAssay actives

30 with measured affinity, of 231 total; 25 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
5-amino-2-[[4-[(2,4-diamino-5-chloroquinazolin-6-yl)methylamino]benzoyl]amino]pentanoic acid	71216: The apparent Km of compound as a substrate for partially purified mouse liver Folyl-polyglutamate synthase	ki	0.0017	uM
5-amino-2-[[4-[(2-amino-5-chloro-4-oxo-3H-quinazolin-6-yl)methylamino]benzoyl]amino]pentanoic acid	71216: The apparent Km of compound as a substrate for partially purified mouse liver Folyl-polyglutamate synthase	ki	0.0083	uM
5-amino-2-[[4-[[2-amino-4-oxo-5-(trifluoromethyl)-3H-quinazolin-6-yl]methylamino]benzoyl]amino]pentanoic acid	71523: Inhibitory activity against hog liver Folyl polyglutamate synthetase (FPGS)	ki	0.0088	uM
5-amino-2-[[4-[[[2-amino-4-oxo-5-(trifluoromethyl)-3H-quinazolin-6-yl]amino]methyl]benzoyl]amino]pentanoic acid	71523: Inhibitory activity against hog liver Folyl polyglutamate synthetase (FPGS)	ki	0.0110	uM
2-[[3-carboxy-3-[[4-[(2,4-diaminopteridin-6-yl)methyl-methylamino]benzoyl]amino]propyl]-hydroxyphosphoryl]oxypentanedioic acid	71522: Compound was evaluated for its ability to inhibit Folyl-poly-gamma-glutamyl synthetase	ic50	0.0200	uM
5-amino-2-[[4-[(2-amino-4-oxo-5,6,7,8-tetrahydro-3H-pyrido[2,3-d]pyrimidin-6-yl)methylamino]benzoyl]amino]pentanoic acid	71508: Potent inhibitor of Folyl-polyglutamate synthase obtained from porcine	ki	0.0640	uM
(2S)-2-[[(3S)-3-carboxy-3-[[4-[(2,4-diaminopteridin-6-yl)methyl-methylamino]benzoyl]amino]propyl]-hydroxyphosphoryl]oxypentanedioic acid	71522: Compound was evaluated for its ability to inhibit Folyl-poly-gamma-glutamyl synthetase	ic50	0.1200	uM
5-amino-2-[[4-[[(5-fluoro-2-methyl-4-oxo-3H-quinazolin-6-yl)amino]methyl]benzoyl]amino]pentanoic acid	71523: Inhibitory activity against hog liver Folyl polyglutamate synthetase (FPGS)	ki	0.1500	uM
(2S)-5-amino-2-[6-[(2-amino-4-oxo-5,6,7,8-tetrahydro-3H-pyrido[2,3-d]pyrimidin-6-yl)methylamino]-3-oxo-1H-isoindol-2-yl]pentanoic acid	71353: Binding affinity as Competitive substrate in the presence of 50 gmM aminopterin towards recombinant Human Folyl-polyglutamate synthase (FPGS)	ki	0.2000	uM
5-amino-2-[[4-[(2-amino-4-oxo-5,6,7,8-tetrahydro-3H-pteridin-6-yl)methylamino]benzoyl]amino]pentanoic acid	71354: Inhibitory activity against mammalian Folyl-polyglutamate synthase	ki	0.2000	uM
(2S)-5-amino-2-[[4-[(2,4-diaminopteridin-6-yl)methylamino]benzoyl]amino]pentanoic acid	71355: Inhibitory constant against purified Folyl-polyglutamate synthase obtained from human	ki	0.3000	uM
5-amino-2-[[4-[(4-oxo-3H-quinazolin-6-yl)methylsulfanyl]benzoyl]amino]pentanoic acid	71216: The apparent Km of compound as a substrate for partially purified mouse liver Folyl-polyglutamate synthase	ki	0.4200	uM
5-amino-2-[[4-[[(2-amino-5-chloro-4-oxo-3H-quinazolin-6-yl)amino]methyl]benzoyl]amino]pentanoic acid	71523: Inhibitory activity against hog liver Folyl polyglutamate synthetase (FPGS)	ki	0.5000	uM
5-amino-2-[[4-[[(2-amino-5-fluoro-4-oxo-3H-quinazolin-6-yl)amino]methyl]benzoyl]amino]pentanoic acid	71523: Inhibitory activity against hog liver Folyl polyglutamate synthetase (FPGS)	ki	0.9000	uM
5-amino-2-[[4-[(4-oxo-3H-quinazolin-6-yl)methoxy]benzoyl]amino]pentanoic acid	71216: The apparent Km of compound as a substrate for partially purified mouse liver Folyl-polyglutamate synthase	ki	1.2000	uM
2-[[4-[(2,4-diaminopteridin-6-yl)methylamino]benzoyl]amino]-4-phosphonooxybutanoic acid	71355: Inhibitory constant against purified Folyl-polyglutamate synthase obtained from human	ki	1.9000	uM
5-amino-2-[[4-[(2-amino-4-oxo-3H-quinazolin-6-yl)methylsulfanyl]benzoyl]amino]pentanoic acid	71216: The apparent Km of compound as a substrate for partially purified mouse liver Folyl-polyglutamate synthase	ki	2.8000	uM
Methotrexate	71351: Compound was evaluated for the inhibitory activity against Folyl-polyglutamate synthase from CCRF-CEM human leukemia cells.	ic50	3.2000	uM
(2S)-5-amino-2-[[4-[(2,4-diaminopteridin-6-yl)methyl-methylamino]benzoyl]amino]pentanoic acid	71355: Inhibitory constant against purified Folyl-polyglutamate synthase obtained from human	ki	4.0000	uM
(2S)-2-[[(3S)-3-carboxy-3-[[4-(methylamino)benzoyl]amino]propyl]-hydroxyphosphoryl]oxypentanedioic acid	71522: Compound was evaluated for its ability to inhibit Folyl-poly-gamma-glutamyl synthetase	ic50	5.7000	uM
5-amino-2-[[4-[(2-amino-4-oxo-3H-pteridin-6-yl)methylamino]benzoyl]amino]pentanoic acid	71213: Binding affinity for hog liver Folyl-polyglutamate synthase was evaluated	ki	5.9000	uM
5-amino-2-[[4-[(2-amino-4-oxo-3H-quinazolin-6-yl)methoxy]benzoyl]amino]pentanoic acid	71216: The apparent Km of compound as a substrate for partially purified mouse liver Folyl-polyglutamate synthase	ki	5.9000	uM
(2S)-5-amino-2-[[4-[(2-amino-4-oxo-3H-pteridin-6-yl)methylamino]benzoyl]amino]pentanoic acid	71215: Inhibitory constant against purified Folyl-polyglutamate synthase obtained from hog	ki	6.0000	uM
(2S)-2-[[(3S)-3-[(4-aminobenzoyl)amino]-3-carboxypropyl]-hydroxyphosphoryl]oxypentanedioic acid	71522: Compound was evaluated for its ability to inhibit Folyl-poly-gamma-glutamyl synthetase	ic50	8.6000	uM
(2S)-5-amino-2-[[4-[(2-amino-4-oxo-5,6,7,8-tetrahydro-3H-pteridin-6-yl)methylamino]benzoyl]amino]-5-oxopentanoic acid	71215: Inhibitory constant against purified Folyl-polyglutamate synthase obtained from hog	ki	10.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases abundance, increases expression, decreases expression, affects cotreatment	3
Air Pollutants	increases abundance, increases oxidation, decreases expression, affects cotreatment	2
Folic Acid	affects expression, increases expression	2
GSK-J4	decreases expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
7-hydroxymethotrexate	decreases activity	1
beta-lapachone	increases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
cobalt oxide	increases expression	1
picoxystrobin	decreases expression	1
MT19c compound	decreases expression	1
Pemetrexed	increases response to substance	1
Decitabine	increases expression	1
Vorinostat	increases expression	1
Acetaminophen	decreases expression	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Antimycin A	decreases expression	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Benzo(a)pyrene	decreases methylation	1
Butyrates	increases expression	1
Chelating Agents	affects binding, decreases expression	1
Copper	decreases expression, affects binding	1
Doxorubicin	decreases expression	1
Fluorouracil	increases response to substance	1
Ivermectin	decreases expression	1
Methotrexate	increases metabolic processing	1
Ozone	affects cotreatment, increases oxidation, increases abundance	1
Plant Extracts	decreases expression	1
Smoke	decreases expression	1
Testosterone	increases expression	1

ChEMBL screening assays

71 unique, capped per target: 71 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL676936	Binding	Vmax of Hog Folyl-polyglutamate synthase relative to aminopterin	Thienyl and thiazolyl acyclic analogues of 5-deazatetrahydrofolic acid. — J Med Chem

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1ML	Abcam K-562 FPGS KO	Cancer cell line	Female
CVCL_D2J6	Abcam Raji FPGS KO	Cancer cell line	Male
CVCL_UQ53	Abcam Jurkat FPGS KO	Cancer cell line	Male

Clinical trials (associated diseases)

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