Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVEHG28)

• DOT Name: Geranylgeranyl pyrophosphate synthase (GGPS1)
• Synonyms: GGPP synthase; GGPPSase; EC 2.5.1.-; (2E,6E)-farnesyl diphosphate synthase; Dimethylallyltranstransferase; EC 2.5.1.1; Farnesyl diphosphate synthase; Farnesyltranstransferase; EC 2.5.1.29; Geranylgeranyl diphosphate synthase; Geranyltranstransferase; EC 2.5.1.10
• Gene Name: GGPS1
• Related Disease:
  Matthew-Wood syndrome
  Melanoma
  Pancreatic ductal carcinoma
  Porokeratosis
  Porokeratosis of Mibelli
  Adult glioblastoma
  Advanced cancer
  Carcinoma of liver and intrahepatic biliary tract
  Glioblastoma multiforme
  Hepatitis C virus infection
  Hepatocellular carcinoma
  Hyperinsulinemia
  Liver cancer
  Liver cirrhosis
  Lymphangioleiomyomatosis
  Muscular dystrophy, congenital hearing loss, and ovarian insufficiency syndrome
  Neoplasm
  Non-alcoholic fatty liver disease
  Osteoporosis
  Plasma cell myeloma
  Plasmodium falciparum malaria
  Pneumonia
  Pneumonitis
  Prostate cancer
  Prostate carcinoma
  Pulmonary fibrosis
  Coronary atherosclerosis
  Myocardial ischemia
  Osteoarthritis
  Lymphoid leukemia
  Lung adenocarcinoma
  Metastatic malignant neoplasm
  Toxoplasmosis
• UniProt ID: GGPPS_HUMAN
• PDB ID: 2Q80; 6C56; 6C57; 6G31; 6G32; 6R4V
• EC Number: 2.5.1.-; 2.5.1.1; 2.5.1.10; 2.5.1.29
• Pfam ID: PF00348
• Sequence:
  MEKTQETVQRILLEPYKYLLQLPGKQVRTKLSQAFNHWLKVPEDKLQIIIEVTEMLHNAS
  LLIDDIEDNSKLRRGFPVAHSIYGIPSVINSANYVYFLGLEKVLTLDHPDAVKLFTRQLL
  ELHQGQGLDIYWRDNYTCPTEEEYKAMVLQKTGGLFGLAVGLMQLFSDYKEDLKPLLNTL
  GLFFQIRDDYANLHSKEYSENKSFCEDLTEGKFSFPTIHAIWSRPESTQVQNILRQRTEN
  IDIKKYCVHYLEDVGSFEYTRNTLKELEAKAYKQIDARGGNPELVALVKHLSKMFKEENE
• Function: Catalyzes the trans-addition of the three molecules of IPP onto DMAPP to form geranylgeranyl pyrophosphate, an important precursor of carotenoids and geranylated proteins.
• Tissue Specificity: Abundantly expressed in testis . Found in other tissues to a lower extent . Expressed in dermal fibroblast and skeletal muscle .
• KEGG Pathway:
  Terpenoid backbone biosynthesis (hsa00900)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Activation of gene expression by SREBF (SREBP) (R-HSA-2426168)
  Cholesterol biosynthesis (R-HSA-191273)
• BioCyc Pathway: MetaCyc:HS07859-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

33 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Matthew-Wood syndrome	DISA7HR7	Definitive	Biomarker	[1]
Melanoma	DIS1RRCY	Definitive	Biomarker	[2]
Pancreatic ductal carcinoma	DIS26F9Q	Definitive	Biomarker	[1]
Porokeratosis	DISJPL2I	Definitive	Biomarker	[3]
Porokeratosis of Mibelli	DISF48DQ	Definitive	Biomarker	[3]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[4]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[5]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Altered Expression	[6]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[4]
Hepatitis C virus infection	DISQ0M8R	Strong	Altered Expression	[7]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[6]
Hyperinsulinemia	DISIDWT6	Strong	Biomarker	[6]
Liver cancer	DISDE4BI	Strong	Altered Expression	[6]
Liver cirrhosis	DIS4G1GX	Strong	Biomarker	[6]
Lymphangioleiomyomatosis	DISR0RNB	Strong	Biomarker	[8]
Muscular dystrophy, congenital hearing loss, and ovarian insufficiency syndrome	DISS6JO0	Strong	Autosomal recessive	[9]
Neoplasm	DISZKGEW	Strong	Biomarker	[6]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Altered Expression	[10]
Osteoporosis	DISF2JE0	Strong	Genetic Variation	[11]
Plasma cell myeloma	DIS0DFZ0	Strong	Biomarker	[12]
Plasmodium falciparum malaria	DIS3Q9KF	Strong	Altered Expression	[13]
Pneumonia	DIS8EF3M	Strong	Biomarker	[14]
Pneumonitis	DIS88E0K	Strong	Biomarker	[14]
Prostate cancer	DISF190Y	Strong	Biomarker	[15]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[15]
Pulmonary fibrosis	DISQKVLA	Strong	Biomarker	[16]
Coronary atherosclerosis	DISKNDYU	moderate	Biomarker	[17]
Myocardial ischemia	DISFTVXF	moderate	Biomarker	[17]
Osteoarthritis	DIS05URM	moderate	Altered Expression	[18]
Lymphoid leukemia	DIS65TYQ	Disputed	Biomarker	[19]
Lung adenocarcinoma	DISD51WR	Limited	Altered Expression	[20]
Metastatic malignant neoplasm	DIS86UK6	Limited	Altered Expression	[20]
Toxoplasmosis	DISYP8FH	Limited	Biomarker	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Geranylgeranyl pyrophosphate synthase (GGPS1).	[22]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Geranylgeranyl pyrophosphate synthase (GGPS1).	[23]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Geranylgeranyl pyrophosphate synthase (GGPS1).	[24]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Geranylgeranyl pyrophosphate synthase (GGPS1).	[26]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the activity of Geranylgeranyl pyrophosphate synthase (GGPS1).	[27]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Geranylgeranyl pyrophosphate synthase (GGPS1).	[28]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Geranylgeranyl pyrophosphate synthase (GGPS1).	[29]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Geranylgeranyl pyrophosphate synthase (GGPS1).	[28]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Geranylgeranyl pyrophosphate synthase (GGPS1).	[30]
GERANYLGERANYL DIPHOSPHATE	DMJZ0AM	Investigative	GERANYLGERANYL DIPHOSPHATE decreases the activity of Geranylgeranyl pyrophosphate synthase (GGPS1).	[31]
digeranyl bisphosphonate	DMXK8BH	Investigative	digeranyl bisphosphonate decreases the activity of Geranylgeranyl pyrophosphate synthase (GGPS1).	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Geranylgeranyl pyrophosphate synthase (GGPS1).	[25]

References

• [1] Inhibition of geranylgeranyl diphosphate synthase is a novel therapeutic strategy for pancreatic ductal adenocarcinoma.Oncogene. 2019 Jun;38(26):5308-5320. doi: 10.1038/s41388-019-0794-6. Epub 2019 Mar 27.
• [2] HMG-CoA Reductase Inhibition Delays DNA Repair and Promotes Senescence After Tumor Irradiation.Mol Cancer Ther. 2018 Feb;17(2):407-418. doi: 10.1158/1535-7163.MCT-17-0288. Epub 2017 Oct 13.
• [3] Disorder of the mevalonate pathway inhibits calcium-induced differentiation of keratinocytes.Mol Med Rep. 2017 Oct;16(4):4811-4816. doi: 10.3892/mmr.2017.7128. Epub 2017 Aug 1.
• [4] Farnesyl diphosphate synthase is important for the maintenance of glioblastoma stemness.Exp Mol Med. 2018 Oct 17;50(10):1-12. doi: 10.1038/s12276-018-0166-2.
• [5] -Methylation enhances the potency of isoprenoid triazole bisphosphonates as geranylgeranyl diphosphate synthase inhibitors.Bioorg Med Chem. 2018 Jan 15;26(2):376-385. doi: 10.1016/j.bmc.2017.10.023. Epub 2017 Oct 19.
• [6] GGPPS1 predicts the biological character of hepatocellular carcinoma in patients with cirrhosis.BMC Cancer. 2014 Apr 9;14:248. doi: 10.1186/1471-2407-14-248.
• [7] Mevalonate pathway modulation is associated with hepatitis C virus RNA presence in peripheral blood mononuclear cells.Virus Res. 2009 Oct;145(1):141-4. doi: 10.1016/j.virusres.2009.06.001. Epub 2009 Jun 18.
• [8] Evidence for a role of geranylgeranylation in renal angiomyolipoma and renal epithelioid angiomyolipoma.Oncol Lett. 2019 Feb;17(2):1523-1530. doi: 10.3892/ol.2018.9808. Epub 2018 Dec 7.
• [9] Knockdown of Ggps1 in chondrocyte expedites fracture healing by accelerating the progression of endochondral ossification in mice. J Bone Miner Metab. 2018 Mar;36(2):133-147. doi: 10.1007/s00774-017-0824-9. Epub 2017 Mar 29.
• [10] Geranylgeranyl diphosphate synthase (GGPPS) regulates non-alcoholic fatty liver disease (NAFLD)-fibrosis progression by determining hepatic glucose/fatty acid preference under high-fat diet conditions.J Pathol. 2018 Nov;246(3):277-288. doi: 10.1002/path.5131. Epub 2018 Sep 19.
• [11] Association of farnesyl diphosphate synthase polymorphisms and response to alendronate treatment in Chinese postmenopausal women with osteoporosis.Chin Med J (Engl). 2014;127(4):662-8.
• [12] In Vivo Evaluation of Isoprenoid Triazole Bisphosphonate Inhibitors of Geranylgeranyl Diphosphate Synthase: Impact of Olefin Stereochemistry on Toxicity and Biodistribution.J Pharmacol Exp Ther. 2019 Nov;371(2):327-338. doi: 10.1124/jpet.119.258624. Epub 2019 Aug 16.
• [13] Specific Inhibition of the Bifunctional Farnesyl/Geranylgeranyl Diphosphate Synthase in Malaria Parasites via a New Small-Molecule Binding Site.Cell Chem Biol. 2018 Feb 15;25(2):185-193.e5. doi: 10.1016/j.chembiol.2017.11.010. Epub 2017 Dec 21.
• [14] Inhibition of GGPPS1 attenuated LPS-induced acute lung injury and was associated with NLRP3 inflammasome suppression.Am J Physiol Lung Cell Mol Physiol. 2019 Mar 1;316(3):L567-L577. doi: 10.1152/ajplung.00190.2018. Epub 2019 Jan 17.
• [15] Targeting protein geranylgeranylation slows tumor development in a murine model of prostate cancer metastasis.Cancer Biol Ther. 2017 Nov 2;18(11):872-882. doi: 10.1080/15384047.2016.1219817. Epub 2016 Sep 13.
• [16] Geranylgeranyl diphosphate synthase deficiency aggravates lung fibrosis in mice by modulating TGF-1/BMP-4 signaling.Biol Chem. 2019 Nov 26;400(12):1617-1627. doi: 10.1515/hsz-2019-0168.
• [17] Effect of Geranylgeranyl Pyrophosphate Synthase on Hypoxia/Reoxygenation-Induced Injury in Heart-Derived H9c2 Cells.Int Heart J. 2018 Jul 31;59(4):821-828. doi: 10.1536/ihj.17-218. Epub 2018 May 23.
• [18] The alteration of RhoA geranylgeranylation and Ras farnesylation breaks the integrity of the blood-testis barrier and results in hypospermatogenesis.Cell Death Dis. 2019 Jun 6;10(6):450. doi: 10.1038/s41419-019-1688-9.
• [19] Geranylgeranyl diphosphate synthase inhibition induces apoptosis that is dependent upon GGPP depletion, ERK phosphorylation and caspase activation.Cell Death Dis. 2017 Mar 16;8(3):e2678. doi: 10.1038/cddis.2017.101.
• [20] Overexpression of geranylgeranyl diphosphate synthase contributes to tumour metastasis and correlates with poor prognosis of lung adenocarcinoma.J Cell Mol Med. 2018 Apr;22(4):2177-2189. doi: 10.1111/jcmm.13493. Epub 2018 Jan 29.
• [21] Antiparasitic Activity of Sulfur- and Fluorine-Containing Bisphosphonates against Trypanosomatids and Apicomplexan Parasites.Molecules. 2017 Jan 4;22(1):82. doi: 10.3390/molecules22010082.
• [22] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [23] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [24] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [25] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [26] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [27] Digeranyl bisphosphonate inhibits geranylgeranyl pyrophosphate synthase. Biochem Biophys Res Commun. 2007 Feb 23;353(4):921-5. doi: 10.1016/j.bbrc.2006.12.094. Epub 2006 Dec 21.
• [28] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [29] 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.
• [30] Gene expression changes associated with altered growth and differentiation in benzo[a]pyrene or arsenic exposed normal human epidermal keratinocytes. J Appl Toxicol. 2008 May;28(4):491-508.
• [31] Variously substituted (phosphonoacetamido)oxy analogues of geranylgeranyl diphosphate (GGdP) as GGdP-transferase (GGTase) inhibitors and antiproliferative agents. Med Chem. 2005 May;1(3):239-44. doi: 10.2174/1573406053765512.