Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZ25I2W)

• DOT Name: Geranylgeranyl transferase type-2 subunit beta (RABGGTB)
• Synonyms: EC 2.5.1.60; Geranylgeranyl transferase type II subunit beta; GGTase-II-beta; Rab geranyl-geranyltransferase subunit beta; Rab GG transferase beta; Rab GGTase beta; Rab geranylgeranyltransferase subunit beta; Type II protein geranyl-geranyltransferase subunit beta
• Gene Name: RABGGTB
• Related Disease: Multiple sclerosis
• UniProt ID: PGTB2_HUMAN
• PDB ID: 6J6X; 6J74; 6J7F; 6J7X; 6O60
• EC Number: 2.5.1.60
• Pfam ID: PF00432
• Sequence:
  MGTPQKDVIIKSDAPDTLLLEKHADYIASYGSKKDDYEYCMSEYLRMSGIYWGLTVMDLM
  GQLHRMNREEILAFIKSCQHECGGISASIGHDPHLLYTLSAVQILTLYDSINVIDVNKVV
  EYVKGLQKEDGSFAGDIWGEIDTRFSFCAVATLALLGKLDAINVEKAIEFVLSCMNFDGG
  FGCRPGSESHAGQIYCCTGFLAITSQLHQVNSDLLGWWLCERQLPSGGLNGRPEKLPDVC
  YSWWVLASLKIIGRLHWIDREKLRNFILACQDEETGGFADRPGDMVDPFHTLFGIAGLSL
  LGEEQIKPVNPVFCMPEEVLQRVNVQPELVS
• Function: Catalyzes the transfer of a geranylgeranyl moiety from geranylgeranyl diphosphate to both cysteines of Rab proteins with the C-terminal sequence -XXCC, -XCXC and -CCXX, such as RAB1A, RAB3A, RAB5A and RAB7A.
• Reactome Pathway:
  RAB geranylgeranylation (R-HSA-8873719)
  TP53 regulates transcription of several additional cell death genes whose specific roles in p53-dependent apoptosis remain uncertain (R-HSA-6803205)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Multiple sclerosis	DISB2WZI	Strong	Altered Expression	[1]

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 Geranylgeranyl transferase type-2 subunit beta (RABGGTB).	[2]

15 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 Geranylgeranyl transferase type-2 subunit beta (RABGGTB).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Geranylgeranyl transferase type-2 subunit beta (RABGGTB).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Geranylgeranyl transferase type-2 subunit beta (RABGGTB).	[5]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Geranylgeranyl transferase type-2 subunit beta (RABGGTB).	[6]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Geranylgeranyl transferase type-2 subunit beta (RABGGTB).	[7]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Geranylgeranyl transferase type-2 subunit beta (RABGGTB).	[8]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Geranylgeranyl transferase type-2 subunit beta (RABGGTB).	[9]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene decreases the expression of Geranylgeranyl transferase type-2 subunit beta (RABGGTB).	[4]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Geranylgeranyl transferase type-2 subunit beta (RABGGTB).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Geranylgeranyl transferase type-2 subunit beta (RABGGTB).	[11]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Geranylgeranyl transferase type-2 subunit beta (RABGGTB).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Geranylgeranyl transferase type-2 subunit beta (RABGGTB).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Geranylgeranyl transferase type-2 subunit beta (RABGGTB).	[14]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Geranylgeranyl transferase type-2 subunit beta (RABGGTB).	[15]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Geranylgeranyl transferase type-2 subunit beta (RABGGTB).	[16]

References

• [1] Assessment of Protein Prenylation Pathway in Multiple Sclerosis Patients.J Mol Neurosci. 2018 Apr;64(4):581-590. doi: 10.1007/s12031-018-1052-z. Epub 2018 Mar 25.
• [2] 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.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [5] 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.
• [6] 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.
• [7] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [8] The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009 Jun;23(6):1019-28.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
• [11] 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.
• [12] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [13] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [14] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [15] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [16] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.