Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3KCK0U)

• DOT Name: DDRGK domain-containing protein 1 (DDRGK1)
• Synonyms: Dashurin; UFM1-binding and PCI domain-containing protein 1
• Gene Name: DDRGK1
• Related Disease:
  Osteochondrodysplasia
  Parkinson disease
  Skeletal dysplasia
  Spondyloepimetaphyseal dysplasia, Shohat type
  Thrombocytopenia
  Gastric cancer
  Neoplasm
  Spondyloepimetaphyseal dysplasia
  Stomach cancer
• UniProt ID: DDRGK_HUMAN
• PDB ID: 7W3N; 8B9X
• Pfam ID: PF09756
• Sequence:
  MVAPVWYLVAAALLVGFILFLTRSRGRAASAGQEPLHNEELAGAGRVAQPGPLEPEEPRA
  GGRPRRRRDLGSRLQAQRRAQRVAWAEADENEEEAVILAQEEEGVEKPAETHLSGKIGAK
  KLRKLEEKQARKAQREAEEAEREERKRLESQREAEWKKEEERLRLEEEQKEEEERKAREE
  QAQREHEEYLKLKEAFVVEEEGVGETMTEEQSQSFLTEFINYIKQSKVVLLEDLASQVGL
  RTQDTINRIQDLLAEGTITGVIDDRGKFIYITPEELAAVANFIRQRGRVSIAELAQASNS
  LIAWGRESPAQAPA
• Function: Substrate adapter for ufmylation, the covalent attachment of the ubiquitin-like modifier UFM1 to substrate proteins, which plays a key role in reticulophagy (also called ER-phagy). In response to endoplasmic reticulum stress, promotes recruitment of the E3 UFM1-protein ligase UFL1 to the endoplasmic reticulum membrane: in turn, UFL1 mediates ufmylation of proteins such as RPN1 and RPL26/uL24, promoting reticulophagy of endoplasmic reticulum sheets. Ufmylation-dependent reticulophagy inhibits the unfolded protein response (UPR) by regulating ERN1/IRE1-alpha stability. Ufmylation in response to endoplasmic reticulum stress is essential for processes such as hematopoiesis or inflammatory response. Required for TRIP4 ufmylation, thereby regulating nuclear receptors-mediated. transcription. May play a role in NF-kappa-B-mediated transcription through regulation of the phosphorylation and the degradation of NFKBIA, the inhibitor of NF-kappa-B. Plays a role in cartilage development through SOX9, inhibiting the ubiquitin-mediated proteasomal degradation of this transcriptional regulator.
• Tissue Specificity: Widely expressed (at protein level). In the brain, highest levels in medulla oblongata, followed by cerebral cortex, cerebellum and frontal lobe.
• Reactome Pathway: RHOA GTPase cycle (R-HSA-8980692)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Osteochondrodysplasia	DIS9SPWW	Strong	Altered Expression	[1]
Parkinson disease	DISQVHKL	Strong	Genetic Variation	[2]
Skeletal dysplasia	DIS5Z8U6	Strong	Altered Expression	[1]
Spondyloepimetaphyseal dysplasia, Shohat type	DISN2QMB	Strong	Autosomal recessive	[1]
Thrombocytopenia	DISU61YW	Strong	Genetic Variation	[3]
Gastric cancer	DISXGOUK	Limited	Altered Expression	[4]
Neoplasm	DISZKGEW	Limited	Altered Expression	[4]
Spondyloepimetaphyseal dysplasia	DISO4L5A	Limited	Biomarker	[1]
Stomach cancer	DISKIJSX	Limited	Altered Expression	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of DDRGK domain-containing protein 1 (DDRGK1).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of DDRGK domain-containing protein 1 (DDRGK1).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of DDRGK domain-containing protein 1 (DDRGK1).	[7]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of DDRGK domain-containing protein 1 (DDRGK1).	[8]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of DDRGK domain-containing protein 1 (DDRGK1).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of DDRGK domain-containing protein 1 (DDRGK1).	[12]

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 increases the methylation of DDRGK domain-containing protein 1 (DDRGK1).	[9]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of DDRGK domain-containing protein 1 (DDRGK1).	[10]

References

• [1] Loss of DDRGK1 modulates SOX9 ubiquitination in spondyloepimetaphyseal dysplasia. J Clin Invest. 2017 Apr 3;127(4):1475-1484. doi: 10.1172/JCI90193. Epub 2017 Mar 6.
• [2] Association analyses of variants of SIPA1L2, MIR4697, GCH1, VPS13C, and DDRGK1 with Parkinson's disease in East Asians.Neurobiol Aging. 2018 Aug;68:159.e7-159.e14. doi: 10.1016/j.neurobiolaging.2018.03.005. Epub 2018 Mar 10.
• [3] Genome-wide association study identified ITPA/DDRGK1 variants reflecting thrombocytopenia in pegylated interferon and ribavirin therapy for chronic hepatitis C.Hum Mol Genet. 2011 Sep 1;20(17):3507-16. doi: 10.1093/hmg/ddr249. Epub 2011 Jun 9.
• [4] Low expression of CDK5RAP3 and DDRGK1 indicates a poor prognosis in patients with gastric cancer.World J Gastroenterol. 2018 Sep 14;24(34):3898-3907. doi: 10.3748/wjg.v24.i34.3898.
• [5] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [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] 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.
• [8] Quantitative proteomics and transcriptomics addressing the estrogen receptor subtype-mediated effects in T47D breast cancer cells exposed to the phytoestrogen genistein. Mol Cell Proteomics. 2011 Jan;10(1):M110.002170.
• [9] 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.
• [10] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [11] Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides. J Biol Chem. 2018 Apr 13;293(15):5600-5612.
• [12] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.