Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6CKWV5)

• DOT Name: Farnesyl pyrophosphate synthase (FDPS)
• Synonyms: FPP synthase; FPS; EC 2.5.1.10; (2E,6E)-farnesyl diphosphate synthase; Dimethylallyltranstransferase; EC 2.5.1.1; Farnesyl diphosphate synthase; Geranyltranstransferase
• Gene Name: FDPS
• Related Disease:
  Porokeratosis 9, multiple types
  Disseminated superficial actinic porokeratosis
• UniProt ID: FPPS_HUMAN
• PDB ID: 1YQ7 ; 1YV5 ; 1ZW5 ; 2F7M ; 2F89 ; 2F8C ; 2F8Z ; 2F92 ; 2F94 ; 2F9K ; 2OPM ; 2OPN ; 2QIS ; 2RAH ; 2VF6 ; 3B7L ; 3CP6 ; 3N1V ; 3N1W ; 3N3L ; 3N45 ; 3N46 ; 3N49 ; 3N5H ; 3N5J ; 3N6K ; 3RYE ; 3S4J ; 4DEM ; 4GA3 ; 4H5C ; 4H5D ; 4H5E ; 4JVJ ; 4KFA ; 4KPD ; 4KPJ ; 4KQ5 ; 4KQS ; 4KQU ; 4L2X ; 4LFV ; 4LPG ; 4LPH ; 4N1Z ; 4N9U ; 4NFI ; 4NFJ ; 4NFK ; 4NG6 ; 4NKE ; 4NKF ; 4NUA ; 4OGU ; 4P0V ; 4P0W ; 4P0X ; 4PVX ; 4PVY ; 4Q23 ; 4QPF ; 4QXS ; 4RXA ; 4XQR ; 4XQS ; 4XQT ; 5CG5 ; 5CG6 ; 5DGM ; 5DGN ; 5DGS ; 5DIQ ; 5DJP ; 5DJR ; 5DJV ; 5JA0 ; 5JUZ ; 5JV0 ; 5JV1 ; 5JV2 ; 5KSX ; 5YGI ; 6N7Y ; 6N7Z ; 6N82 ; 6N83 ; 6OAG ; 6OAH
• EC Number: 2.5.1.1; 2.5.1.10
• Pfam ID: PF00348
• Sequence:
  MPLSRWLRSVGVFLLPAPYWAPRERWLGSLRRPSLVHGYPVLAWHSARCWCQAWTEEPRA
  LCSSLRMNGDQNSDVYAQEKQDFVQHFSQIVRVLTEDEMGHPEIGDAIARLKEVLEYNAI
  GGKYNRGLTVVVAFRELVEPRKQDADSLQRAWTVGWCVELLQAFFLVADDIMDSSLTRRG
  QICWYQKPGVGLDAINDANLLEACIYRLLKLYCREQPYYLNLIELFLQSSYQTEIGQTLD
  LLTAPQGNVDLVRFTEKRYKSIVKYKTAFYSFYLPIAAAMYMAGIDGEKEHANAKKILLE
  MGEFFQIQDDYLDLFGDPSVTGKIGTDIQDNKCSWLVVQCLQRATPEQYQILKENYGQKE
  AEKVARVKALYEELDLPAVFLQYEEDSYSHIMALIEQYAAPLPPAVFLGLARKIYKRRK
• Function: Key enzyme in isoprenoid biosynthesis which catalyzes the formation of farnesyl diphosphate (FPP), a precursor for several classes of essential metabolites including sterols, dolichols, carotenoids, and ubiquinones. FPP also serves as substrate for protein farnesylation and geranylgeranylation. Catalyzes the sequential condensation of isopentenyl pyrophosphate with the allylic pyrophosphates, dimethylallyl pyrophosphate, and then with the resultant geranylpyrophosphate to the ultimate product farnesyl pyrophosphate.
• KEGG Pathway:
  Terpenoid backbone biosynthesis (hsa00900)
  Metabolic pathways (hsa01100)
  Influenza A (hsa05164)
  Human T-cell leukemia virus 1 infection (hsa05166)
• Reactome Pathway:
  Activation of gene expression by SREBF (SREBP) (R-HSA-2426168)
  Cholesterol biosynthesis (R-HSA-191273)
• BioCyc Pathway: MetaCyc:ENSG00000160752-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Porokeratosis 9, multiple types	DIS8CKGR	Strong	Autosomal dominant	[1]
Disseminated superficial actinic porokeratosis	DISELZ77	Supportive	Autosomal dominant	[2]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Paclitaxel	DMLB81S	Approved	Farnesyl pyrophosphate synthase (FDPS) increases the response to substance of Paclitaxel.	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Farnesyl pyrophosphate synthase (FDPS).	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Farnesyl pyrophosphate synthase (FDPS).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Farnesyl pyrophosphate synthase (FDPS).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Farnesyl pyrophosphate synthase (FDPS).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Farnesyl pyrophosphate synthase (FDPS).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Farnesyl pyrophosphate synthase (FDPS).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Farnesyl pyrophosphate synthase (FDPS).	[9]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Farnesyl pyrophosphate synthase (FDPS).	[10]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Farnesyl pyrophosphate synthase (FDPS).	[11]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Farnesyl pyrophosphate synthase (FDPS).	[12]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Farnesyl pyrophosphate synthase (FDPS).	[13]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Farnesyl pyrophosphate synthase (FDPS).	[14]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of Farnesyl pyrophosphate synthase (FDPS).	[15]
Simvastatin	DM30SGU	Approved	Simvastatin increases the expression of Farnesyl pyrophosphate synthase (FDPS).	[16]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of Farnesyl pyrophosphate synthase (FDPS).	[17]
Curcumin	DMQPH29	Phase 3	Curcumin increases the expression of Farnesyl pyrophosphate synthase (FDPS).	[18]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of Farnesyl pyrophosphate synthase (FDPS).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Farnesyl pyrophosphate synthase (FDPS).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Farnesyl pyrophosphate synthase (FDPS).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Farnesyl pyrophosphate synthase (FDPS).	[21]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Farnesyl pyrophosphate synthase (FDPS).	[22]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Farnesyl pyrophosphate synthase (FDPS).	[23]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the expression of Farnesyl pyrophosphate synthase (FDPS).	[24]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE decreases the expression of Farnesyl pyrophosphate synthase (FDPS).	[10]
Okadaic acid	DM47CO1	Investigative	Okadaic acid decreases the expression of Farnesyl pyrophosphate synthase (FDPS).	[25]
Ganoderic acid A	DM42EVG	Investigative	Ganoderic acid A decreases the expression of Farnesyl pyrophosphate synthase (FDPS).	[26]

References

• [1] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [2] Genomic variations of the mevalonate pathway in porokeratosis. Elife. 2015 Jul 23;4:e06322. doi: 10.7554/eLife.06322.
• [3] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [4] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [5] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [9] 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.
• [10] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [11] Gene expression profile induced by arsenic trioxide in chronic lymphocytic leukemia cells reveals a central role for heme oxygenase-1 in apoptosis and regulation of matrix metalloproteinase-9. Oncotarget. 2016 Dec 13;7(50):83359-83377.
• [12] Coordinate up-regulation of TMEM97 and cholesterol biosynthesis genes in normal ovarian surface epithelial cells treated with progesterone: implications for pathogenesis of ovarian cancer. BMC Cancer. 2007 Dec 11;7:223.
• [13] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [14] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [15] Drug-induced activation of SREBP-controlled lipogenic gene expression in CNS-related cell lines: marked differences between various antipsychotic drugs. BMC Neurosci. 2006 Oct 20;7:69.
• [16] Resveratrol potentiates effect of simvastatin on inhibition of mevalonate pathway in human endometrial stromal cells. J Clin Endocrinol Metab. 2013 Mar;98(3):E455-62.
• [17] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [18] Curcumin induces changes in expression of genes involved in cholesterol homeostasis. J Nutr Biochem. 2007 Feb;18(2):113-9.
• [19] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [20] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [21] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [22] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [23] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [24] Classification of heavy-metal toxicity by human DNA microarray analysis. Environ Sci Technol. 2007 May 15;41(10):3769-74.
• [25] Whole genome mRNA transcriptomics analysis reveals different modes of action of the diarrheic shellfish poisons okadaic acid and dinophysis toxin-1 versus azaspiracid-1 in Caco-2 cells. Toxicol In Vitro. 2018 Feb;46:102-112.
• [26] Ganoderic Acid A improves high fat diet-induced obesity, lipid accumulation and insulin sensitivity through regulating SREBP pathway. Chem Biol Interact. 2018 Jun 25;290:77-87.
• [27] cDNA microarray analysis of isogenic paclitaxel- and doxorubicin-resistant breast tumor cell lines reveals distinct drug-specific genetic signatures of resistance. Breast Cancer Res Treat. 2006 Mar;96(1):17-39. doi: 10.1007/s10549-005-9026-6. Epub 2005 Dec 2.