Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIEAN7F)

• DOT Name: Rab proteins geranylgeranyltransferase component A 1 (CHM)
• Synonyms: Choroideremia protein; Rab escort protein 1; REP-1; TCD protein
• Gene Name: CHM
• Related Disease: Choroideremia
• UniProt ID: RAE1_HUMAN
• Pfam ID: PF00996
• Sequence:
  MADTLPSEFDVIVIGTGLPESIIAAACSRSGRRVLHVDSRSYYGGNWASFSFSGLLSWLK
  EYQENSDIVSDSPVWQDQILENEEAIALSRKDKTIQHVEVFCYASQDLHEDVEEAGALQK
  NHALVTSANSTEAADSAFLPTEDESLSTMSCEMLTEQTPSSDPENALEVNGAEVTGEKEN
  HCDDKTCVPSTSAEDMSENVPIAEDTTEQPKKNRITYSQIIKEGRRFNIDLVSKLLYSRG
  LLIDLLIKSNVSRYAEFKNITRILAFREGRVEQVPCSRADVFNSKQLTMVEKRMLMKFLT
  FCMEYEKYPDEYKGYEEITFYEYLKTQKLTPNLQYIVMHSIAMTSETASSTIDGLKATKN
  FLHCLGRYGNTPFLFPLYGQGELPQCFCRMCAVFGGIYCLRHSVQCLVVDKESRKCKAII
  DQFGQRIISEHFLVEDSYFPENMCSRVQYRQISRAVLITDRSVLKTDSDQQISILTVPAE
  EPGTFAVRVIELCSSTMTCMKGTYLVHLTCTSSKTAREDLESVVQKLFVPYTEMEIENEQ
  VEKPRILWALYFNMRDSSDISRSCYNDLPSNVYVCSGPDCGLGNDNAVKQAETLFQEICP
  NEDFCPPPPNPEDIILDGDSLQPEASESSAIPEANSETFKESTNLGNLEESSE
• Function: Substrate-binding subunit of the Rab geranylgeranyltransferase (GGTase) complex. Binds unprenylated Rab proteins and presents the substrate peptide to the catalytic component B composed of RABGGTA and RABGGTB, and remains bound to it after the geranylgeranyl transfer reaction. The component A is thought to be regenerated by transferring its prenylated Rab back to the donor membrane. Besides, a pre-formed complex consisting of CHM and the Rab GGTase dimer (RGGT or component B) can bind to and prenylate Rab proteins; this alternative pathway is proposed to be the predominant pathway for Rab protein geranylgeranylation.
• Reactome Pathway:
  RAB geranylgeranylation (R-HSA-8873719)
  RAB GEFs exchange GTP for GDP on RABs (R-HSA-8876198)
  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
Choroideremia	DISH4N9B	Definitive	X-linked	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Rab proteins geranylgeranyltransferase component A 1 (CHM).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Rab proteins geranylgeranyltransferase component A 1 (CHM).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Rab proteins geranylgeranyltransferase component A 1 (CHM).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Rab proteins geranylgeranyltransferase component A 1 (CHM).	[5]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Rab proteins geranylgeranyltransferase component A 1 (CHM).	[6]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Rab proteins geranylgeranyltransferase component A 1 (CHM).	[7]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Rab proteins geranylgeranyltransferase component A 1 (CHM).	[8]
Clorgyline	DMCEUJD	Approved	Clorgyline increases the expression of Rab proteins geranylgeranyltransferase component A 1 (CHM).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Rab proteins geranylgeranyltransferase component A 1 (CHM).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Rab proteins geranylgeranyltransferase component A 1 (CHM).	[12]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Rab proteins geranylgeranyltransferase component A 1 (CHM).	[8]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Rab proteins geranylgeranyltransferase component A 1 (CHM).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Rab proteins geranylgeranyltransferase component A 1 (CHM).	[10]

References

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• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [4] 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.
• [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] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [7] 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.
• [8] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [9] Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells. BMC Med Genomics. 2009 Aug 20;2:55. doi: 10.1186/1755-8794-2-55.
• [10] 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.
• [11] Involvement of the Endocrine-Disrupting Chemical Bisphenol A (BPA) in Human Placentation. J Clin Med. 2020 Feb 3;9(2):405. doi: 10.3390/jcm9020405.
• [12] 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.
• [13] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.