Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYMG99C)

• DOT Name: Geranylgeranyl transferase type-2 subunit alpha (RABGGTA)
• Synonyms: EC 2.5.1.60; Geranylgeranyl transferase type II subunit alpha; Rab geranyl-geranyltransferase subunit alpha; Rab GG transferase alpha; Rab GGTase alpha; Rab geranylgeranyltransferase subunit alpha
• Gene Name: RABGGTA
• Related Disease:
  Gray platelet syndrome
  Multiple sclerosis
• UniProt ID: PGTA_HUMAN
• EC Number: 2.5.1.60
• Pfam ID: PF00560 ; PF01239 ; PF07711
• Sequence:
  MHGRLKVKTSEEQAEAKRLEREQKLKLYQSATQAVFQKRQAGELDESVLELTSQILGANP
  DFATLWNCRREVLQQLETQKSPEELAALVKAELGFLESCLRVNPKSYGTWHHRCWLLGRL
  PEPNWTRELELCARFLEVDERNFHCWDYRRFVATQAAVPPAEELAFTDSLITRNFSNYSS
  WHYRSCLLPQLHPQPDSGPQGRLPEDVLLKELELVQNAFFTDPNDQSAWFYHRWLLGRAD
  PQDALRCLHVSRDEACLTVSFSRPLLVGSRMEILLLMVDDSPLIVEWRTPDGRNRPSHVW
  LCDLPAASLNDQLPQHTFRVIWTAGDVQKECVLLKGRQEGWCRDSTTDEQLFRCELSVEK
  STVLQSELESCKELQELEPENKWCLLTIILLMRALDPLLYEKETLQYFQTLKAVDPMRAT
  YLDDLRSKFLLENSVLKMEYAEVRVLHLAHKDLTVLCHLEQLLLVTHLDLSHNRLRTLPP
  ALAALRCLEVLQASDNAIESLDGVTNLPRLQELLLCNNRLQQPAVLQPLASCPRLVLLNL
  QGNPLCQAVGILEQLAELLPSVSSVLT
• 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

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Gray platelet syndrome	DISLOTCW	Strong	Genetic Variation	[1]
Multiple sclerosis	DISB2WZI	Strong	Altered Expression	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Geranylgeranyl transferase type-2 subunit alpha (RABGGTA).	[3]

9 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 Geranylgeranyl transferase type-2 subunit alpha (RABGGTA).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Geranylgeranyl transferase type-2 subunit alpha (RABGGTA).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Geranylgeranyl transferase type-2 subunit alpha (RABGGTA).	[6]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Geranylgeranyl transferase type-2 subunit alpha (RABGGTA).	[7]
Aspirin	DM672AH	Approved	Aspirin increases the expression of Geranylgeranyl transferase type-2 subunit alpha (RABGGTA).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Geranylgeranyl transferase type-2 subunit alpha (RABGGTA).	[9]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Geranylgeranyl transferase type-2 subunit alpha (RABGGTA).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Geranylgeranyl transferase type-2 subunit alpha (RABGGTA).	[11]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Geranylgeranyl transferase type-2 subunit alpha (RABGGTA).	[12]

References

• [1] 5'-UTR structural organization, transcript expression, and mutational analysis of the human Rab geranylgeranyl transferase alpha-subunit (RABGGTA) gene.Mol Genet Metab. 2000 Dec;71(4):599-608. doi: 10.1006/mgme.2000.3091.
• [2] 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.
• [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] 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.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] 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.
• [7] 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.
• [8] Expression profile analysis of colon cancer cells in response to sulindac or aspirin. Biochem Biophys Res Commun. 2002 Mar 29;292(2):498-512.
• [9] 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.
• [10] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [11] 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.
• [12] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.