Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCV2Q89)

• DOT Name: Protein farnesyltransferase/geranylgeranyltransferase type-1 subunit alpha (FNTA)
• Synonyms: EC 2.5.1.58; EC 2.5.1.59; CAAX farnesyltransferase subunit alpha; FTase-alpha; Ras proteins prenyltransferase subunit alpha; Type I protein geranyl-geranyltransferase subunit alpha; GGTase-I-alpha
• Gene Name: FNTA
• UniProt ID: FNTA_HUMAN
• PDB ID: 1JCQ; 1LD7; 1LD8; 1MZC; 1S63; 1SA4; 1TN6; 2F0Y; 2H6F; 2H6G; 2H6H; 2H6I; 2IEJ; 3E37
• EC Number: 2.5.1.58; 2.5.1.59
• Pfam ID: PF01239
• Sequence:
  MAATEGVGEAAQGGEPGQPAQPPPQPHPPPPQQQHKEEMAAEAGEAVASPMDDGFVSLDS
  PSYVLYRDRAEWADIDPVPQNDGPNPVVQIIYSDKFRDVYDYFRAVLQRDERSERAFKLT
  RDAIELNAANYTVWHFRRVLLKSLQKDLHEEMNYITAIIEEQPKNYQVWHHRRVLVEWLR
  DPSQELEFIADILNQDAKNYHAWQHRQWVIQEFKLWDNELQYVDQLLKEDVRNNSVWNQR
  YFVISNTTGYNDRAVLEREVQYTLEMIKLVPHNESAWNYLKGILQDRGLSKYPNLLNQLL
  DLQPSHSSPYLIAFLVDIYEDMLENQCDNKEDILNKALELCEILAKEKDTIRKEYWRYIG
  RSLQSKHSTENDSPTNVQQ
• Function: Essential subunit of both the farnesyltransferase and the geranylgeranyltransferase complex. Contributes to the transfer of a farnesyl or geranylgeranyl moiety from farnesyl or geranylgeranyl diphosphate to a cysteine at the fourth position from the C-terminus of several proteins having the C-terminal sequence Cys-aliphatic-aliphatic-X. May positively regulate neuromuscular junction development downstream of MUSK via its function in RAC1 prenylation and activation.
• KEGG Pathway: Terpenoid backbone biosynthesis (hsa00900)
• Reactome Pathway:
  Inactivation, recovery and regulation of the phototransduction cascade (R-HSA-2514859)
  RAS processing (R-HSA-9648002)
  Potential therapeutics for SARS (R-HSA-9679191)
  Apoptotic cleavage of cellular proteins (R-HSA-111465)

Molecular Interaction Atlas (MIA) of This DOT

4 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 Protein farnesyltransferase/geranylgeranyltransferase type-1 subunit alpha (FNTA).	[1]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Protein farnesyltransferase/geranylgeranyltransferase type-1 subunit alpha (FNTA).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Protein farnesyltransferase/geranylgeranyltransferase type-1 subunit alpha (FNTA).	[9]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Protein farnesyltransferase/geranylgeranyltransferase type-1 subunit alpha (FNTA).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Protein farnesyltransferase/geranylgeranyltransferase type-1 subunit alpha (FNTA).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein farnesyltransferase/geranylgeranyltransferase type-1 subunit alpha (FNTA).	[3]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Protein farnesyltransferase/geranylgeranyltransferase type-1 subunit alpha (FNTA).	[4]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Protein farnesyltransferase/geranylgeranyltransferase type-1 subunit alpha (FNTA).	[6]
Marinol	DM70IK5	Approved	Marinol increases the expression of Protein farnesyltransferase/geranylgeranyltransferase type-1 subunit alpha (FNTA).	[7]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Protein farnesyltransferase/geranylgeranyltransferase type-1 subunit alpha (FNTA).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Protein farnesyltransferase/geranylgeranyltransferase type-1 subunit alpha (FNTA).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Protein farnesyltransferase/geranylgeranyltransferase type-1 subunit alpha (FNTA).	[11]
GW7647	DM9RD0C	Investigative	GW7647 increases the expression of Protein farnesyltransferase/geranylgeranyltransferase type-1 subunit alpha (FNTA).	[13]

References

• [1] 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.
• [2] 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.
• [3] 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.
• [4] 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.
• [5] 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.
• [6] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [7] JunD is involved in the antiproliferative effect of Delta9-tetrahydrocannabinol on human breast cancer cells. Oncogene. 2008 Aug 28;27(37):5033-44.
• [8] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [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] 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.
• [11] 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.
• [12] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [13] Farnesol induces fatty acid oxidation and decreases triglyceride accumulation in steatotic HepaRG cells. Toxicol Appl Pharmacol. 2019 Feb 15;365:61-70.