Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTW3VW8D)

• DOT Name: Rab proteins geranylgeranyltransferase component A 2 (CHML)
• Synonyms: Choroideremia-like protein; Rab escort protein 2; REP-2
• Gene Name: CHML
• Related Disease:
  Allergic asthma
  Blindness
  Spinal muscular atrophy
  Zika virus infection
  Biotinidase deficiency
  Choroideremia
  Usher syndrome type 2
  Usher syndrome type 2D
• UniProt ID: RAE2_HUMAN
• Pfam ID: PF00996
• Sequence:
  MADNLPTEFDVVIIGTGLPESILAAACSRSGQRVLHIDSRSYYGGNWASFSFSGLLSWLK
  EYQQNNDIGEESTVVWQDLIHETEEAITLRKKDETIQHTEAFCYASQDMEDNVEEIGALQ
  KNPSLGVSNTFTEVLDSALPEESQLSYFNSDEMPAKHTQKSDTEISLEVTDVEESVEKEK
  YCGDKTCMHTVSDKDGDKDESKSTVEDKADEPIRNRITYSQIVKEGRRFNIDLVSKLLYS
  QGLLIDLLIKSDVSRYVEFKNVTRILAFREGKVEQVPCSRADVFNSKELTMVEKRMLMKF
  LTFCLEYEQHPDEYQAFRQCSFSEYLKTKKLTPNLQHFVLHSIAMTSESSCTTIDGLNAT
  KNFLQCLGRFGNTPFLFPLYGQGEIPQGFCRMCAVFGGIYCLRHKVQCFVVDKESGRCKA
  IIDHFGQRINAKYFIVEDSYLSEETCSNVQYKQISRAVLITDQSILKTDLDQQTSILIVP
  PAEPGACAVRVTELCSSTMTCMKDTYLVHLTCSSSKTAREDLESVVKKLFTPYTETEINE
  EELTKPRLLWALYFNMRDSSGISRSSYNGLPSNVYVCSGPDCGLGNEHAVKQAETLFQEI
  FPTEEFCPPPPNPEDIIFDGDDKQPEAPGTNNVVMAKLESSEESKNLESPEKHLQN
• Function: Substrate-binding subunit (component A) of the Rab geranylgeranyltransferase (GGTase) complex. Binds unprenylated Rab proteins and presents the substrate peptide to the catalytic component B. The component A is thought to be regenerated by transferring its prenylated Rab back to the donor membrane. Less effective than CHM in supporting prenylation of Rab3 family.
• Reactome Pathway:
  RAB GEFs exchange GTP for GDP on RABs (R-HSA-8876198)
  RAB geranylgeranylation (R-HSA-8873719)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Allergic asthma	DISHF0H3	Strong	Genetic Variation	[1]
Blindness	DISTIM10	Strong	Biomarker	[2]
Spinal muscular atrophy	DISTLKOB	Strong	Altered Expression	[3]
Zika virus infection	DISQUCTY	Strong	Altered Expression	[4]
Biotinidase deficiency	DISFHBBV	moderate	Genetic Variation	[5]
Choroideremia	DISH4N9B	Limited	Biomarker	[6]
Usher syndrome type 2	DIS3LO3C	Limited	Biomarker	[7]
Usher syndrome type 2D	DISHEVUD	Limited	Genetic Variation	[7]

3 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 Rab proteins geranylgeranyltransferase component A 2 (CHML).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Rab proteins geranylgeranyltransferase component A 2 (CHML).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Rab proteins geranylgeranyltransferase component A 2 (CHML).	[21]

12 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 Rab proteins geranylgeranyltransferase component A 2 (CHML).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Rab proteins geranylgeranyltransferase component A 2 (CHML).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Rab proteins geranylgeranyltransferase component A 2 (CHML).	[11]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Rab proteins geranylgeranyltransferase component A 2 (CHML).	[12]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Rab proteins geranylgeranyltransferase component A 2 (CHML).	[13]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Rab proteins geranylgeranyltransferase component A 2 (CHML).	[14]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Rab proteins geranylgeranyltransferase component A 2 (CHML).	[15]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Rab proteins geranylgeranyltransferase component A 2 (CHML).	[16]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Rab proteins geranylgeranyltransferase component A 2 (CHML).	[17]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Rab proteins geranylgeranyltransferase component A 2 (CHML).	[18]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Rab proteins geranylgeranyltransferase component A 2 (CHML).	[20]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Rab proteins geranylgeranyltransferase component A 2 (CHML).	[17]

References

• [1] Identification of a novel asthma susceptibility gene on chromosome 1qter and its functional evaluation.Hum Mol Genet. 2008 Jul 1;17(13):1890-903. doi: 10.1093/hmg/ddn087. Epub 2008 Mar 15.
• [2] REP-2, a Rab escort protein encoded by the choroideremia-like gene.J Biol Chem. 1994 Jan 21;269(3):2111-7.
• [3] Genome-wide analysis shows association of epigenetic changes in regulators of Rab and Rho GTPases with spinal muscular atrophy severity.Eur J Hum Genet. 2013 Sep;21(9):988-93. doi: 10.1038/ejhg.2012.293. Epub 2013 Jan 9.
• [4] Determination of system level alterations in host transcriptome due to Zika virus (ZIKV) Infection in retinal pigment epithelium.Sci Rep. 2018 Jul 25;8(1):11209. doi: 10.1038/s41598-018-29329-2.
• [5] Corrigendum to "First contiguous gene deletion causing biotinidase deficiency: The enzyme deficiency in three Sri Lankan children" [Mol. Genet. Metab. Rep. 2 (2016) 81-84].Mol Genet Metab Rep. 2016 Apr 12;11:95. doi: 10.1016/j.ymgmr.2016.04.001. eCollection 2017 Jun.
• [6] High expression of CHML predicts poor prognosis of multiple myeloma.J Cancer. 2019 Oct 15;10(24):6048-6056. doi: 10.7150/jca.34465. eCollection 2019.
• [7] Mapping of the choroideremia-like (CHML) gene at 1q42-qter and mutation analysis in patients with Usher syndrome type II.Genomics. 1994 Jan 15;19(2):385-7. doi: 10.1006/geno.1994.1077.
• [8] 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.
• [9] 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.
• [10] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [13] Drinking-water arsenic exposure modulates gene expression in human lymphocytes from a U.S. population. Environ Health Perspect. 2008 Apr;116(4):524-31. doi: 10.1289/ehp.10861.
• [14] 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.
• [15] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [16] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [17] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [18] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [19] 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.
• [20] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [21] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.