Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTC4TDHU)

• DOT Name: Protein O-mannosyl-transferase TMTC4 (TMTC4)
• Synonyms: EC 2.4.1.109; Transmembrane O-mannosyltransferase targeting cadherins 4; Transmembrane and tetratricopeptide repeat-containing 4
• Gene Name: TMTC4
• UniProt ID: TMTC4_HUMAN
• EC Number: 2.4.1.109
• Pfam ID: PF08409 ; PF13432 ; PF13431 ; PF13181
• Sequence:
  MAVLDTDLDHILPSSVLPPFWAKLVVGSVAIVCFARSYDGDFVFDDSEAIVNNKDLQAET
  PLGDLWHHDFWGSRLSSNTSHKSYRPLTVLTFRINYYLSGGFHPVGFHVVNILLHSGISV
  LMVDVFSVLFGGLQYTSKGRRLHLAPRASLLAALLFAVHPVHTECVAGVVGRADLLCALF
  FLLSFLGYCKAFRESNKEGAHSSTFWVLLSIFLGAVAMLCKEQGITVLGLNAVFDILVIG
  KFNVLEIVQKVLHKDKSLENLGMLRNGGLLFRMTLLTSGGAGMLYVRWRIMGTGPPAFTE
  VDNPASFADSMLVRAVNYNYYYSLNAWLLLCPWWLCFDWSMGCIPLIKSISDWRVIALAA
  LWFCLIGLICQALCSEDGHKRRILTLGLGFLVIPFLPASNLFFRVGFVVAERVLYLPSVG
  YCVLLTFGFGALSKHTKKKKLIAAVVLGILFINTLRCVLRSGEWRSEEQLFRSALSVCPL
  NAKVHYNIGKNLADKGNQTAAIRYYREAVRLNPKYVHAMNNLGNILKERNELQEAEELLS
  LAVQIQPDFAAAWMNLGIVQNSLKRFEAAEQSYRTAIKHRRKYPDCYYNLGRLYADLNRH
  VDALNAWRNATVLKPEHSLAWNNMIILLDNTGNLAQAEAVGREALELIPNDHSLMFSLAN
  VLGKSQKYKESEALFLKAIKANPNAASYHGNLAVLYHRWGHLDLAKKHYEISLQLDPTAS
  GTKENYGLLRRKLELMQKKAV
• Function: Transfers mannosyl residues to the hydroxyl group of serine or threonine residues. The 4 members of the TMTC family are O-mannosyl-transferases dedicated primarily to the cadherin superfamily, each member seems to have a distinct role in decorating the cadherin domains with O-linked mannose glycans at specific regions. Also acts as O-mannosyl-transferase on other proteins such as PDIA3.

Molecular Interaction Atlas (MIA) of This DOT

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 Protein O-mannosyl-transferase TMTC4 (TMTC4).	[1]

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 Protein O-mannosyl-transferase TMTC4 (TMTC4).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Protein O-mannosyl-transferase TMTC4 (TMTC4).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Protein O-mannosyl-transferase TMTC4 (TMTC4).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Protein O-mannosyl-transferase TMTC4 (TMTC4).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Protein O-mannosyl-transferase TMTC4 (TMTC4).	[6]
Marinol	DM70IK5	Approved	Marinol increases the expression of Protein O-mannosyl-transferase TMTC4 (TMTC4).	[7]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Protein O-mannosyl-transferase TMTC4 (TMTC4).	[8]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Protein O-mannosyl-transferase TMTC4 (TMTC4).	[9]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Protein O-mannosyl-transferase TMTC4 (TMTC4).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Protein O-mannosyl-transferase TMTC4 (TMTC4).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Protein O-mannosyl-transferase TMTC4 (TMTC4).	[12]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Protein O-mannosyl-transferase TMTC4 (TMTC4).	[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] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [7] Delta9-tetrahydrocannabinol inhibits cytotrophoblast cell proliferation and modulates gene transcription. Mol Hum Reprod. 2006 May;12(5):321-33. doi: 10.1093/molehr/gal036. Epub 2006 Apr 5.
• [8] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [11] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [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] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.