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): 98 total
• GTEx eGene: eQTL in 24 tissues, sQTL in 38 (q < 0.05)
• ChEMBL bioactivity: 1 clinical-phase molecule tested; no curated mechanism-of-action drug
• Cancer dependency (DepMap): dependent in 44.3% of screened cell lines
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.17 (unconstrained)
• MANE Select transcript: NM_004957
• Notable: 98 clinical variants but no curated precision-oncology (CIViC) evidence yet

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: 60 — 30 protein_coding, 16 nonsense_mediated_decay, 14 protein_coding_CDS_not_defined

MANE Select: ENST00000373247

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2, TSL 2: 6, TSL 3: 2, TSL 5: 11

ENST00000373247, ENST00000373225, ENST00000373228, 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, ENST00000987385, ENST00000987386, ENST00000987387, ENST00000987388, ENST00001020679, ENST00001020680, ENST00001020681, ENST00001020682, ENST00001020683, ENST00001020684, ENST00001020686, ENST00001020687, ENST00001020688, ENST00001020689, ENST00001086848, ENST00001086850, ENST00001100575, ENST00001117391, ENST00001117392, ENST00001117393, ENST00001126532, ENST00001126533, ENST00001136516

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.

Highest expression (Bgee): ovary, uterine tube, mucosa of stomach, adrenal gland cortex, lobe of liver.

Genetic regulation across tissues (GTEx eQTL / sQTL)

FPGS is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 24 tissues and its splicing (sQTL) in 38 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 62 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Thyroid	sqtl	2.1e-62	-1.03	9:127823816:G:C
Nerve Tibial	sqtl	3.9e-62	-1.00	9:127817531:C:G
Artery Tibial	sqtl	7.5e-44	-0.79	9:127817814:T:C
Lung	sqtl	2.2e-41	-0.92	9:127814497:A:G
Skin Sun Exposed Lower leg	sqtl	8.1e-38	-0.80	9:127814497:A:G
Muscle Skeletal	sqtl	1.0e-33	-0.72	9:127814497:A:G
Cells Cultured fibroblasts	sqtl	1.4e-31	+0.70	9:127809844:A:G
Artery Aorta	sqtl	6.8e-31	+1.89	9:127803090:G:A
Adipose Subcutaneous	sqtl	1.7e-30	+0.73	9:127823816:G:C
Adipose Visceral Omentum	sqtl	5.6e-30	+0.70	9:127813796:T:C
Cells Cultured fibroblasts	eqtl	9.7e-29	-0.33	9:127809844:A:G
Spleen	sqtl	2.0e-22	-1.09	9:127823816:G:C
Ovary	sqtl	6.4e-22	-1.16	9:127786310:G:GC
Esophagus Muscularis	sqtl	7.2e-22	-0.66	9:127817531:C:G
Breast Mammary Tissue	sqtl	6.6e-21	+0.71	9:127813796:T:C
Adrenal Gland	sqtl	6.8e-21	+1.95	9:127803090:G:A
Prostate	sqtl	4.3e-19	-1.02	9:127786310:G:GC
Nerve Tibial	eqtl	4.4e-16	-0.14	9:127793618:T:C
Artery Coronary	sqtl	6.7e-16	-1.12	9:127823816:G:C
Testis	sqtl	5.9e-15	+1.63	9:127803090:G:A

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

showing 100 of 273 tissues 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
granulocyte	CL:0000094	94.28	gold quality
popliteal artery	UBERON:0002250	94.24	gold quality
tibial artery	UBERON:0007610	94.24	gold quality
body of stomach	UBERON:0001161	94.17	gold quality
adrenal gland	UBERON:0002369	93.99	gold quality
ectocervix	UBERON:0012249	93.99	gold quality
gastrocnemius	UBERON:0001388	93.97	gold quality
body of pancreas	UBERON:0001150	93.67	gold quality
adipose tissue of abdominal region	UBERON:0007808	93.57	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	93.48	gold quality
stromal cell of endometrium	CL:0002255	93.46	gold quality
lower esophagus muscularis layer	UBERON:0035833	93.45	gold quality
lower esophagus	UBERON:0013473	93.44	gold quality
muscle of leg	UBERON:0001383	93.41	gold quality
right atrium auricular region	UBERON:0006631	93.40	gold quality
adenohypophysis	UBERON:0002196	93.38	gold quality
coronary artery	UBERON:0001621	93.35	gold quality
small intestine Peyer’s patch	UBERON:0003454	93.25	gold quality
ovary	UBERON:0000992	92.91	gold quality
minor salivary gland	UBERON:0001830	92.91	gold quality
thyroid gland	UBERON:0002046	92.78	gold quality
hindlimb stylopod muscle	UBERON:0004252	92.53	gold quality
spleen	UBERON:0002106	92.47	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	92.35	gold quality
muscle layer of sigmoid colon	UBERON:0035805	92.05	gold quality
esophagus	UBERON:0001043	91.98	gold quality
right hemisphere of cerebellum	UBERON:0014890	91.98	gold quality
stomach	UBERON:0000945	91.75	gold quality
heart left ventricle	UBERON:0002084	91.60	gold quality
cerebellar hemisphere	UBERON:0002245	91.58	gold quality
transverse colon	UBERON:0001157	91.50	gold quality
cerebellar cortex	UBERON:0002129	91.44	gold quality
pancreas	UBERON:0001264	91.38	gold quality
lower esophagus mucosa	UBERON:0035834	91.29	gold quality
cardiac atrium	UBERON:0002081	91.28	gold quality
mucosa of transverse colon	UBERON:0004991	91.25	gold quality
esophagus mucosa	UBERON:0002469	91.14	gold quality
pituitary gland	UBERON:0000007	91.10	gold quality
gall bladder	UBERON:0002110	90.96	gold quality
subcutaneous adipose tissue	UBERON:0002190	90.88	gold quality
cardiac ventricle	UBERON:0002082	90.84	gold quality
islet of Langerhans	UBERON:0000006	90.67	gold quality
small intestine	UBERON:0002108	90.64	gold quality
heart	UBERON:0000948	90.48	gold quality
saliva-secreting gland	UBERON:0001044	90.24	gold quality
mouth mucosa	UBERON:0003729	90.18	gold quality
skin of leg	UBERON:0001511	89.97	gold quality
vermiform appendix	UBERON:0001154	89.92	gold quality
lymph node	UBERON:0000029	89.89	gold quality
smooth muscle tissue	UBERON:0001135	89.86	gold quality
muscle organ	UBERON:0001630	89.12	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	89.08	gold quality
skin of abdomen	UBERON:0001416	88.97	gold quality
ganglionic eminence	UBERON:0004023	88.93	gold quality
cerebellum	UBERON:0002037	88.87	gold quality
monocyte	CL:0000576	88.74	gold quality
colonic epithelium	UBERON:0000397	88.73	gold quality
right frontal lobe	UBERON:0002810	88.67	gold quality
leukocyte	CL:0000738	88.66	gold quality
liver	UBERON:0002107	88.64	gold quality
mononuclear cell	CL:0000842	88.52	gold quality
adipose tissue	UBERON:0001013	88.38	gold quality
cortical plate	UBERON:0005343	88.29	gold quality
vagina	UBERON:0000996	88.09	gold quality
rectum	UBERON:0001052	88.01	gold quality
ventricular zone	UBERON:0003053	87.80	gold quality
prostate gland	UBERON:0002367	87.61	gold quality
connective tissue	UBERON:0002384	87.55	gold quality
left testis	UBERON:0004533	87.36	gold quality
cingulate cortex	UBERON:0003027	87.26	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

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 78 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Skeletal muscle	tissue	26.6	medium
Adipose tissue	tissue	19.2	not detected
Liver	tissue	19.2	medium
Ovary	tissue	19.1	not detected
Bone marrow	tissue	18.6	not detected
Heart muscle	tissue	18.4	not detected
Tongue	tissue	17.7
Pituitary gland	tissue	17.6
Vagina	tissue	17.1	not detected
Spinal cord	tissue	17.1
Lymph node	tissue	16.6	not detected
Cerebellum	tissue	15.7	not detected
Fallopian tube	tissue	15.5	medium
Urinary bladder	tissue	15.4	medium
Medulla oblongata	tissue	14.9
Appendix	tissue	14.7	not detected
Substantia nigra	tissue	14.5
Corpus callosum	tissue	14.5
Superior colliculi	tissue	14.3
Midbrain	tissue	14.0
Thalamus	tissue	14.0
Pons	tissue	13.7
Periaqueductal gray	tissue	13.5
Hypothalamus	tissue	13.2
Hippocampal formation	tissue	12.8
Stomach 1	tissue	12.7	low
Thymus	tissue	12.5
Putamen	tissue	12.4
Choroid plexus	tissue	12.4
Spleen	tissue	12.4	not detected
Tonsil	tissue	12.4	medium
Salivary gland	tissue	12.2	medium
Lung	tissue	12.2	not detected
Endometrium 1	tissue	12.1	medium
Ventral forebrain	tissue	12.1
Basal ganglia	tissue	12.0	not detected
Septum	tissue	12.0
Adrenal gland	tissue	11.9	not detected
Cerebral cortex	tissue	11.4	low
Motor cortex	tissue	11.4
Pancreas	tissue	11.2	low
Seminal vesicle	tissue	11.0	medium
Insular cortex	tissue	11.0
Amygdala	tissue	10.9
Prefrontal cortex	tissue	10.6
Olfactory bulb	tissue	10.4
Hippocampus	tissue	10.3	not detected
Temporal cortex	tissue	10.2
Small intestine	tissue	10.1	medium
Retrosplenial cortex	tissue	10.1
Prostate	tissue	10.0	medium
Entorhinal cortex	tissue	10.0
Thyroid gland	tissue	9.9	not detected
Duodenum	tissue	9.9	low
Locus coeruleus	tissue	9.9
Somatosensory cortex	tissue	9.8
Occipital cortex	tissue	9.7
Parathyroid gland	tissue	9.6	not detected
Retrosplenial and cingulate cortex	tissue	9.5
Colon	tissue	9.2	medium

Brain sub-regions (HPA Brain Atlas): detected in 189; highest nTPM — Blood vessel (28.3), Ventral spinal cord (17.1), Dorsal spinal cord (16.5), Area postrema (15.1), Cervical spinal cord, ventral horn (14.7).

Regulation

Is transcription factor: no

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

miRNA regulators (miRDB)

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

21 miRNAs:

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

gnomAD constraint: pLI 2.27e-17, LOEUF 1.17, missense Z 0.683 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000373247 splits into 3 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
9:127,802,925–127,804,308	111 / 95.4	1.16	no
9:127,804,309–127,808,693	240 / 348.6	0.69	no
9:127,808,694–127,813,601	351 / 363.7	0.97	no
DepMap (CRISPR cell-line fitness): dependent in 44.3% of screened cell lines.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): SNU-1 (-2.77), SU-DHL-10 (-2.185), SU-DHL-8 (-2.122), NCI-H209 (-1.987), OVCAR-5 (-1.893), HT (-1.87), OCI-AML3 (-1.844), NCI-H2171 (-1.815), OCI-LY-19 (-1.799), RPMI 8226 (-1.79), HCT-15 (-1.744), Lu-135 (-1.715), Evsa-T (-1.681), ESO51 (-1.666), KE-39 (-1.635).

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

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:95576) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 1 distinct phenotype terms.

Mouse phenotype (MP)	Records
decreased body weight	1

Additional cross-species homologs

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

Organism	UniProt	Identity	Method
Saccharomyces cerevisiae YJM789	A6ZP80	100.0%	Diamond
Saccharomyces cerevisiae RM11-1a	B3LJR0	100.0%	Diamond
Saccharomyces cerevisiae EC1118	C8ZGZ3	100.0%	Diamond
Saccharomyces cerevisiae Lalvin QA23	E7KUJ4	100.0%	Diamond
Saccharomyces cerevisiae VL3	E7QKX4	100.0%	Diamond
Saccharomyces cerevisiae S288C	Q08645	100.0%	Diamond
Saccharomyces cerevisiae AWRI1631	B5VSC3	99.8%	Diamond
Saccharomyces cerevisiae AWRI796	E7KIA3	99.8%	Diamond
Saccharomyces cerevisiae FostersO	E7NMM0	99.8%	Diamond
Saccharomyces cerevisiae FostersB	E7Q9C7	99.8%	Diamond
Cricetulus griseus	Q924L9	87.2%	Diamond
Bos taurus	A6H751	84.7%	Diamond
Buchnera aphidicola str. APS (Acyrthosiphon pisum)	P57265	60.3%	Diamond
Buchnera aphidicola str. Sg (Schizaphis graminum)	Q8K9X3	60.3%	Diamond
Arabidopsis thaliana	F4K2A1	59.7%	Diamond
Halobacterium salinarum NRC-1	Q9HS44	59.0%	Diamond
Candida albicans	Q9Y893	51.7%	Diamond
Buchnera aphidicola str. Bp (Baizongia pistaciae)	Q89AT2	50.7%	Diamond
Escherichia coli K-12	P08192	49.5%	Diamond
Haemophilus influenzae Rd KW20	P43775	49.5%	Diamond
Schizosaccharomyces pombe 972h-	O74742	44.4%	Diamond
Neurospora crassa OR74A	O13492	42.9%	Diamond
Dictyostelium discoideum	Q54CY5	38.5%	Diamond
Lacticaseibacillus casei	P15925	36.5%	Diamond
Bacillus subtilis subsp. subtilis str. 168	Q05865	36.0%	Diamond

Genomic neighbors (locus context)

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

Symbol	Type	Entrez
SH2D3C	protein-coding	10044
MIR3960	ncRNA	100616250
CDK9	protein-coding	1025
TTC16	protein-coding	158248
TOR2A	protein-coding	27433
MIR2861	ncRNA	100422910
ENG	protein-coding	2022
MIR4672	ncRNA	100616429
ST6GALNAC4-ST6GALNAC6-AK1	ncRNA	123987602
AK1	protein-coding	203
ST6GALNAC6	protein-coding	30815

Protein

Protein identifiers

Folylpolyglutamate synthase, mitochondrial — Q05932 (reviewed: Q05932)

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

All UniProt accessions (5): Q05932, Q5JU20, Q5JU21, Q5JU23, Q96G81

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)

• (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

Predicted structure (AlphaFold)

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

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Ligase, Metabolic proteins, Predicted intracellular proteins, FDA approved drug targets, Small molecule drugs

Protein evidence: Evidence at protein level

Antibody reliability (HPA): IH approved

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)

Position	Role
106–109	ATP
130	Mg(2+)
200	Mg(2+)
228	Mg(2+)
363	ATP
377	ATP

Post-translational modifications (2)

Type	Positions
N-acetylmethionine	43
Phosphoserine	539

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 1; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

1 pathways:

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

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 (5): cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), mitochondrial matrix (GO:0005759), cytosol (GO:0005829)

Reactome top-level categories

1 top-level categories:

Category	Pathways
Metabolism of water-soluble vitamins and cofactors	1

GO top-level categories

31 GO namespaces:

Category	Terms
dicarboxylic acid metabolic process	2
folic acid-containing compound metabolic process	2
cellular anatomical structure	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
anion 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

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 8 of 20 annotations. The rest are phylogenetic / computational / electronic (IEA).

8 experimentally-supported GO terms:

GO term	NS	Evidence
cell population proliferation	BP	mutant phenotype
folic acid-containing compound metabolic process	BP	direct assay
glutamate metabolic process	BP	direct assay
tetrahydrofolylpolyglutamate biosynthetic process	BP	direct assay
cytosol	CC	direct assay
mitochondrial matrix	CC	direct assay
mitochondrion	CC	high-throughput
tetrahydrofolylpolyglutamate synthase activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 1,264 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FPGS	TYMS	P04818	800
FPGS	DHFR	P00374	792
FPGS	GGH	Q92820	786
FPGS	DHFR2	Q86XF0	760
FPGS	MTHFD1	P11586	746
FPGS	MTHFR	P42898	728
FPGS	SLC19A1	P41440	706
FPGS	ATIC	P31939	698
FPGS	GART	P22102	670
FPGS	MTHFD1L	Q6UB35	657
FPGS	SHMT1	P34896	656
FPGS	MTHFS	P49914	584
FPGS	SHMT2	P34897	574
FPGS	SLC46A1	Q96NT5	569
FPGS	MTR	Q99707	552

IntAct

BioGRID (46 interactions; top human partners by supporting records): HMGCL (Affinity Capture-MS; 3 records), PALM2 (Affinity Capture-MS; 3 records), LAMP2 (Affinity Capture-MS; 2 records), LIPH (Affinity Capture-MS; 2 records), NIT1 (Affinity Capture-MS; 2 records), THEM4 (Affinity Capture-MS; 2 records), TOR1AIP2 (Affinity Capture-MS; 2 records), ACAA2 (Affinity Capture-MS), ACACA (Negative Genetic), AMACR (Affinity Capture-MS), ATG3 (Phenotypic Suppression), AVPR2 (Affinity Capture-MS), BAD (Proximity Label-MS), BICD2 (Proximity Label-MS), CGA (Affinity Capture-MS)

Disease & clinical

Genetic variants

Variant evidence for FPGS: 98 ClinVar records (0 pathogenic / likely pathogenic); 4 PharmGKB clinical annotations; 1 GWAS association.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	67
Likely benign	9
Benign	2

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 37 predictions of 1,057):

Position(s)	Effect	Δscore	Sites
9:127804414–127804415	donor_loss	1.0000	5
9:127804549–127804550	donor_gain	1.0000	2
9:127804553–127804554	donor_loss	1.0000	5
9:127804634	acceptor_gain	1.0000
9:127807088–127807089	donor_loss	1.0000	5
9:127807483–127807484	donor_loss	1.0000	5
9:127807585	acceptor_loss	1.0000	2
9:127808231	acceptor_gain	1.0000
9:127808232–127808233	acceptor_loss	1.0000	5
9:127808556–127808557	acceptor_loss	1.0000	6

AlphaMissense

969 missense substitutions predicted likely pathogenic (of 3,779 scored), across 261 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
H228	8	0.980	0.993
D208	8	0.974	0.986
D377	8	0.971	0.986
H132	8	0.955	0.992
H380	8	0.955	0.982
F438	8	0.943	0.988
H100	8	0.933	0.993
F189	8	0.928	0.984
D227	8	0.927	0.972
S570	8	0.921	0.996
F152	8	0.905	0.979
F433	8	0.887	0.975
F178	8	0.886	0.982
F517	8	0.875	0.979
D452	8	0.760	0.890
D532	8	0.715	0.841
E200	7	0.985	0.994
K243	7	0.959	0.994
K107	7	0.951	0.990
E138	7	0.942	0.996

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

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

1 prognostic cancer types:

Cancer	Prognostic	p-value
Lung Squamous Cell Carcinoma (TCGA)	unfavorable	0.000357

Disease associations

OMIM: gene MIM:136510 | disease phenotypes:

GWAS associations

1 associations:

Study	Trait	p-value
GCST005951_75	Body mass index	5e-9

EFO canonical traits (from GWAS)

1 canonical traits:

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

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 402,177 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

1 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL34259	METHOTREXATE	4	402,177

PharmGKB: 1 entry (CPIC guideline: no)

PharmGKB clinical annotations

4 annotations by evidence level (1 strongest → 4):

Variant	Association	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

2 variants:

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1544105	FPGS	3	3.25	3	methotrexate
rs7856096	FPGS	3	5.75	1	warfarin

PharmGKB variant annotations

Per-publication pharmacogenomic findings for this gene (significant associations).

showing 15 of 16 published findings:

Variant	Drug(s)	Category	Finding	PMID
rs7856096	warfarin	Dosage	Allele G is associated with decreased dose of warfarin as compared to allele A.	PMID:25079360
rs10106	methotrexate	Efficacy, Toxicity, Other	Genotype TT is associated with decreased likelihood of discontinuation when treated with methotrexate in people with Arthritis, Rheumatoid as compared to genotypes CC + CT.	PMID:26652611
rs10760502	methotrexate	Efficacy, Toxicity, Other	Genotype AA is associated with decreased likelihood of discontinuation when treated with methotrexate in people with Arthritis, Rheumatoid as compared to genotypes AG + GG.	PMID:26652611
rs10106	methotrexate	Toxicity	Genotype TT is associated with increased likelihood of Drug Toxicity when treated with methotrexate in people with Arthritis, Rheumatoid as compared to genotypes CC + CT.	PMID:26652611
rs10106	methotrexate	Toxicity	Genotypes CC + CT is associated with decreased likelihood of Drug Toxicity when treated with methotrexate in people with Arthritis, Rheumatoid as compared to genotype TT.	PMID:27992285
rs1544105	methotrexate	Metabolism/PK	Genotype TT is associated with increased concentrations of methotrexate in children with Precursor Cell Lymphoblastic Leukemia-Lymphoma as compared to genotypes CC + CT.	PMID:27987364
rs1544105	methotrexate	Efficacy	Genotype TT is associated with increased response to methotrexate in children with Precursor Cell Lymphoblastic Leukemia-Lymphoma as compared to genotypes CC + CT.	PMID:27987364
rs1544105	antineoplastic agents	Toxicity	Genotype TT is associated with decreased likelihood of gastrointestinal toxicity when treated with antineoplastic agents in children with Precursor Cell Lymphoblastic Leukemia-Lymphoma as compared to genotypes CC + CT.	PMID:36952646
rs1544105	methotrexate	Efficacy	Genotypes CT + TT is associated with increased likelihood of Disease Progression when treated with methotrexate in people with Acute lymphoblastic leukemia as compared to genotype CC.	PMID:41269429
rs1544105		Other	Genotype CC is associated with increased expression of FPGS in 293T cells as compared to genotype TT.	PMID:41269429
rs10106	methotrexate	Efficacy	Genotypes CC + CT is associated with increased clinical benefit to methotrexate in people with Rheumatoid arthritis as compared to genotype TT.	PMID:41932892
rs10106	methotrexate	Toxicity	Genotypes CC + CT is associated with increased likelihood of Drug Toxicity when treated with methotrexate in people with Rheumatoid arthritis as compared to genotype TT.	PMID:41932892
rs1544105	methotrexate	Efficacy	Genotypes CT + TT is associated with increased clinical benefit to methotrexate in people with Rheumatoid arthritis as compared to genotype CC.	PMID:41932892
rs1544105	methotrexate	Toxicity	Genotypes CT + TT is associated with increased likelihood of Drug Toxicity when treated with methotrexate in people with Rheumatoid arthritis as compared to genotype CC.	PMID:41932892
rs1544105	methotrexate	Efficacy	Genotypes CT + TT are associated with decreased response to methotrexate in people with Arthritis, Rheumatoid as compared to genotype CC.	PMID:19902562

Binding affinities (BindingDB)

38 measured of 38 human assays (41 total across all organisms); most potent 38 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
5-Amino-2-{4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-pentanoic acid	IC50	1 nM
5-Amino-2-{4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-4,4-difluoro-pentanoic acid	IC50	1.3 nM
5-Amino-2-{4-[(2,4-diamino-5-chloro-quinazolin-6-ylmethyl)-amino]-benzoylamino}-pentanoic acid	KI	1.7 nM
2-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-3-hydroxy-pentanedioic acid	IC50	5.3 nM
2-{4-[1-(2,4-Diamino-pteridin-6-ylmethyl)-propyl]-benzoylamino}-4-methylene-pentanedioic acid	IC50	5.8 nM
2-{4-[2-(2,4-Diamino-pteridin-6-yl)-ethyl]-benzoylamino}-3-hydroxy-pentanedioic acid	IC50	5.9 nM
5-Amino-2-{4-[(2-amino-5-chloro-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl)-amino]-benzoylamino}-pentanoic acid	KI	8.3 nM
5-Amino-2-{4-[(2-amino-4-oxo-5-trifluoromethyl-3,4-dihydro-quinazolin-6-ylmethyl)-amino]-benzoylamino}-pentanoic acid	KI	8.8 nM
2-{4-[2-(2,4-Diamino-pteridin-6-yl)-ethyl]-benzoylamino}-4-methylene-pentanedioic acid	IC50	8.8 nM
5-Amino-2-{4-[(2-amino-4-oxo-5-trifluoromethyl-3,4-dihydro-quinazolin-6-ylamino)-methyl]-benzoylamino}-pentanoic acid	KI	11 nM
2-[(3-Carboxy-3-{4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-propyl)-hydroxy-phosphinoyloxy]-pentanedioic acid	IC50	20 nM
2-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-4-methylene-pentanedioic acid	IC50	44 nM
5-Amino-2-{4-[(2-amino-4-oxo-2,3,4,4a,5,6,7,8-octahydro-pyrido[2,3-d]pyrimidin-6-ylmethyl)-amino]-benzoylamino}-pentanoic acid	KI	64 nM
2-[(3-Carboxy-3-{4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-propyl)-hydroxy-phosphinoyloxy]-pentanedioic acid	IC50	120 nM
5-Amino-2-{4-[(5-fluoro-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylamino)-methyl]-benzoylamino}-pentanoic acid	KI	150 nM
5-Amino-2-{4-[(2-amino-4-hydroxy-5,6,7,8-tetrahydro-pteridin-6-ylmethyl)-amino]-benzoylamino}-pentanoic acid	KI	200 nM
(S)-5-Amino-2-{5-[(2-amino-4-oxo-3,4,5,6,7,8-hexahydro-pyrido[2,3-d]pyrimidin-6-ylmethyl)-amino]-1-oxo-1,3-dihydro-isoindol-2-yl}-pentanoic acid	KI	200 nM
5-Amino-2-{4-[(2,4-diamino-pteridin-6-ylmethyl)-amino]-benzoylamino}-pentanoic acid	KI	300 nM
5-Amino-2-[4-(4-oxo-3,4-dihydro-quinazolin-6-ylmethylsulfanyl)-benzoylamino]-pentanoic acid	KI	420 nM
5-Amino-2-{4-[(2-amino-5-chloro-4-oxo-3,4-dihydro-quinazolin-6-ylamino)-methyl]-benzoylamino}-pentanoic acid	KI	500 nM
5-Amino-2-{4-[(2-amino-5-fluoro-4-oxo-3,4-dihydro-quinazolin-6-ylamino)-methyl]-benzoylamino}-pentanoic acid	KI	900 nM
5-Amino-2-[4-(4-oxo-3,4-dihydro-quinazolin-6-ylmethoxy)-benzoylamino]-pentanoic acid	KI	1200 nM
2-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-amino]-benzoylamino}-4-phosphonooxy-butyric acid	KI	1900 nM
5-Amino-2-[4-(2-amino-4-oxo-3,4-dihydro-quinazolin-6-ylmethylsulfanyl)-benzoylamino]-pentanoic acid	KI	2800 nM
5-Amino-2-{4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-pentanoic acid	KI	4000 nM
2-{[3-Carboxy-3-(4-methylamino-benzoylamino)-propyl]-hydroxy-phosphinoyloxy}-pentanedioic acid	IC50	5700 nM
5-Amino-2-{4-[(2-amino-4-oxo-3,4-dihydro-pteridin-6-ylmethyl)-amino]-benzoylamino}-pentanoic acid	KI	5900 nM
5-Amino-2-[4-(2-amino-4-oxo-3,4-dihydro-quinazolin-6-ylmethoxy)-benzoylamino]-pentanoic acid	KI	5900 nM
5-Amino-2-{4-[(2-amino-4-hydroxy-pteridin-6-ylmethyl)-amino]-benzoylamino}-pentanoic acid	KI	6000 nM
2-{[3-(4-Amino-benzoylamino)-3-carboxy-propyl]-hydroxy-phosphinoyloxy}-pentanedioic acid	IC50	8600 nM
2-{4-[(2-Amino-4-oxo-1,4,5,6,7,8-hexahydro-pteridin-6-ylmethyl)-amino]-benzoylamino}-4-carbamoyl-butyric acid	KI	10000 nM
2-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-amino]-benzoylamino}-3-sulfo-propionic acid	KI	43000 nM
2-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-amino]-benzoylamino}-4-sulfo-butyric acid	KI	45000 nM
(S)-5-Amino-2-{5-[(2-amino-4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-6-ylmethyl)-amino]-1-oxo-1,3-dihydro-isoindol-2-yl}-pentanoic acid	KI	110000 nM
2-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-3-sulfo-propionic acid	KI	136000 nM
MTX	KI	137000 nM
2-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-4-phosphono-butyric acid	KI	185000 nM
2-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-4-sulfo-butyric acid	KI	188000 nM

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	affects cotreatment, increases abundance, increases oxidation, decreases expression	2
Folic Acid	increases expression, affects 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	increases oxidation, increases abundance, affects cotreatment	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	decreases expression, increases abundance, affects cotreatment	1
Benzo(a)pyrene	decreases methylation	1
Butyrates	increases expression	1
Chelating Agents	decreases expression, affects binding	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)

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

Predicted chemistry — Sugi Predict

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