Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTW3F1ZE)

• DOT Name: Folylpolyglutamate synthase, mitochondrial (FPGS)
• Synonyms: EC 6.3.2.17; Folylpoly-gamma-glutamate synthetase; FPGS; Tetrahydrofolylpolyglutamate synthase; Tetrahydrofolate synthase
• Gene Name: FPGS
• UniProt ID: FOLC_HUMAN
• EC Number: 6.3.2.17
• Sequence:
  MSRARSHLRAALFLAAASARGITTQVAARRGLSAWPVPQEPSMEYQDAVRMLNTLQTNAG
  YLEQVKRQRGDPQTQLEAMELYLARSGLQVEDLDRLNIIHVTGTKGKGSTCAFTECILRS
  YGLKTGFFSSPHLVQVRERIRINGQPISPELFTKYFWRLYHRLEETKDGSCVSMPPYFRF
  LTLMAFHVFLQEKVDLAVVEVGIGGAYDCTNIIRKPVVCGVSSLGIDHTSLLGDTVEKIA
  WQKGGIFKQGVPAFTVLQPEGPLAVLRDRAQQISCPLYLCPMLEALEEGGPPLTLGLEGE
  HQRSNAALALQLAHCWLQRQDRHGAGEPKASRPGLLWQLPLAPVFQPTSHMRLGLRNTEW
  PGRTQVLRRGPLTWYLDGAHTASSAQACVRWFRQALQGRERPSGGPEVRVLLFNATGDRD
  PAALLKLLQPCQFDYAVFCPNLTEVSSTGNADQQNFTVTLDQVLLRCLEHQQHWNHLDEE
  QASPDLWSAPSPEPGGSASLLLAPHPPHTCSASSLVFSCISHALQWISQGRDPIFQPPSP
  PKGLLTHPVAHSGASILREAAAIHVLVTGSLHLVGGVLKLLEPALSQ
• 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.
• KEGG Pathway:
  Folate biosynthesis (hsa00790)
  Metabolic pathways (hsa01100)
  Biosynthesis of cofactors (hsa01240)
  Antifolate resistance (hsa01523)
• Reactome Pathway: Metabolism of folate and pterines (R-HSA-196757)
• BioCyc Pathway: MetaCyc:HS06237-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	Folylpolyglutamate synthase, mitochondrial (FPGS) increases the response to substance of Fluorouracil.	[10]
Warfarin	DMJYCVW	Approved	Folylpolyglutamate synthase, mitochondrial (FPGS) affects the response to substance of Warfarin.	[11]
Pemetrexed	DMMX2E6	Approved	Folylpolyglutamate synthase, mitochondrial (FPGS) increases the response to substance of Pemetrexed.	[12]

8 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Folylpolyglutamate synthase, mitochondrial (FPGS).	[1]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Folylpolyglutamate synthase, mitochondrial (FPGS).	[2]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Folylpolyglutamate synthase, mitochondrial (FPGS).	[3]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Folylpolyglutamate synthase, mitochondrial (FPGS).	[4]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Folylpolyglutamate synthase, mitochondrial (FPGS).	[5]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Folylpolyglutamate synthase, mitochondrial (FPGS).	[6]
Folic acid	DMEMBJC	Approved	Folic acid increases the expression of Folylpolyglutamate synthase, mitochondrial (FPGS).	[7]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Folylpolyglutamate synthase, mitochondrial (FPGS).	[8]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Folylpolyglutamate synthase, mitochondrial (FPGS).	[9]

References

• [1] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [2] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [3] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [4] Histone deacetylase inhibitors induce FPGS mRNA expression and intracellular accumulation of long-chain methotrexate polyglutamates in childhood acute lymphoblastic leukemia: implications for combination therapy. Leukemia. 2010 Mar;24(3):552-62.
• [5] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [6] Methylation-dependent silencing of the reduced folate carrier gene in inherently methotrexate-resistant human breast cancer cells. J Biol Chem. 2001 Oct 26;276(43):39990-40000.
• [7] Folate deprivation induces BCRP (ABCG2) expression and mitoxantrone resistance in Caco-2 cells. Int J Cancer. 2008 Oct 1;123(7):1712-20.
• [8] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [9] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [10] Effects of folylpolyglutamate synthetase modulation on chemosensitivity of colon cancer cells to 5-fluorouracil and methotrexate. Gut. 2004 Dec;53(12):1825-31. doi: 10.1136/gut.2004.042713.
• [11] Genetic variant in folate homeostasis is associated with lower warfarin dose in African Americans. Blood. 2014 Oct 2;124(14):2298-305. doi: 10.1182/blood-2014-04-568436. Epub 2014 Jul 30.
• [12] A randomized, double-blind, phase II study of two doses of pemetrexed as first-line chemotherapy for advanced breast cancer. Clin Cancer Res. 2007 Jun 15;13(12):3652-9. doi: 10.1158/1078-0432.CCR-06-2377.