Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTID6YNN)

• DOT Name: Glomulin (GLMN)
• Synonyms: FK506-binding protein-associated protein; FAP; FKBP-associated protein
• Gene Name: GLMN
• Related Disease: Glomuvenous malformation
• UniProt ID: GLMN_HUMAN
• PDB ID: 4F52
• Pfam ID: PF08568
• Sequence:
  MAVEELQSIIKRCQILEEQDFKEEDFGLFQLAGQRCIEEGHTDQLLEIIQNEKNKVIIKN
  MGWNLVGPVVRCLLCKDKEDSKRKVYFLIFDLLVKLCNPKELLLGLLELIEEPSGKQISQ
  SILLLLQPLQTVIQKLHNKAYSIGLALSTLWNQLSLLPVPYSKEQIQMDDYGLCQCCKAL
  IEFTKPFVEEVIDNKENSLENEKLKDELLKFCFKSLKCPLLTAQFFEQSEEGGNDPFRYF
  ASEIIGFLSAIGHPFPKMIFNHGRKKRTWNYLEFEEEENKQLADSMASLAYLVFVQGIHI
  DQLPMVLSPLYLLQFNMGHIEVFLQRTEESVISKGLELLENSLLRIEDNSLLYQYLEIKS
  FLTVPQGLVKVMTLCPIETLRKKSLAMLQLYINKLDSQGKYTLFRCLLNTSNHSGVEAFI
  IQNIKNQIDMSLKRTRNNKWFTGPQLISLLDLVLFLPEGAETDLLQNSDRIMASLNLLRY
  LVIKDNENDNQTGLWTELGNIENNFLKPLHIGLNMSKAHYEAEIKNSQEAQKSKDLCSIT
  VSGEEIPNMPPEMQLKVLHSALFTFDLIESVLARVEELIEIKTKSTSEENIGIK
• Function: [Isoform 1]: Regulatory component of cullin-RING-based SCF (SKP1-Cullin-F-box protein) E3 ubiquitin-protein ligase complexes. Inhibits E3 ubiquitin ligase activity by binding to RBX1 (via RING domain) and inhibiting its interaction with the E2 ubiquitin-conjugating enzyme CDC34. Inhibits RBX1-mediated neddylation of CUL1. Required for normal stability and normal cellular levels of key components of SCF ubiquitin ligase complexes, including FBXW7, RBX1, CUL1, CUL2, CUL3, CUL4A, and thereby contributes to the regulation of CCNE1 and MYC levels. Essential for normal development of the vasculature. Contributes to the regulation of RPS6KB1 phosphorylation.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway: Shigellosis (hsa05131)
• Reactome Pathway: Antigen processing (R-HSA-983168)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Glomuvenous malformation	DIS5UNDD	Definitive	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Glomulin (GLMN).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Glomulin (GLMN).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Glomulin (GLMN).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Glomulin (GLMN).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Glomulin (GLMN).	[6]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Glomulin (GLMN).	[7]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Glomulin (GLMN).	[8]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Glomulin (GLMN).	[8]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Glomulin (GLMN).	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Glomulin (GLMN).	[12]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Glomulin (GLMN).	[13]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Glomulin (GLMN).	[14]

2 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 affects the methylation of Glomulin (GLMN).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Glomulin (GLMN).	[11]

References

• [1] Linkage disequilibrium narrows locus for venous malformation with glomus cells (VMGLOM) to a single 1.48 Mbp YAC. Eur J Hum Genet. 2001 Jan;9(1):34-8. doi: 10.1038/sj.ejhg.5200576.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [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] 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.
• [8] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [9] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [10] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [11] 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.
• [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] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [14] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.