Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4DQ82L)

• DOT Name: Dehydrodolichyl diphosphate synthase complex subunit NUS1 (NUS1)
• Synonyms: EC 2.5.1.87; Cis-prenyltransferase subunit NgBR; Nogo-B receptor; NgBR; Nuclear undecaprenyl pyrophosphate synthase 1 homolog
• Gene Name: NUS1
• Related Disease:
  Advanced cancer
  Estrogen-receptor positive breast cancer
  Invasive ductal breast carcinoma
  Breast neoplasm
  Congenital disorder of glycosylation
  Coronary heart disease
  Dilated cardiomyopathy 1A
  Epilepsy
  Fatty liver disease
  Hepatocellular carcinoma
  Intellectual disability, autosomal dominant 55, with seizures
  Neoplasm
  Non-small-cell lung cancer
  Peripheral arterial disease
  Melanoma
  Undetermined early-onset epileptic encephalopathy
  B-cell neoplasm
  Breast cancer
  Breast carcinoma
  Congenital disorder of glycosylation, type IAA
  Erectile dysfunction
  Non-insulin dependent diabetes
• UniProt ID: NGBR_HUMAN
• PDB ID: 6W2L; 6Z1N; 7PAX; 7PAY; 7PB0; 7PB1
• EC Number: 2.5.1.87
• Pfam ID: PF01255
• Sequence:
  MTGLYELVWRVLHALLCLHRTLTSWLRVRFGTWNWIWRRCCRAASAAVLAPLGFTLRKPP
  AVGRNRRHHRHPRGGSCLAAAHHRMRWRADGRSLEKLPVHMGLVITEVEQEPSFSDIASL
  VVWCMAVGISYISVYDHQGIFKRNNSRLMDEILKQQQELLGLDCSKYSPEFANSNDKDDQ
  VLNCHLAVKVLSPEDGKADIVRAAQDFCQLVAQKQKRPTDLDVDTLASLLSSNGCPDPDL
  VLKFGPVDSTLGFLPWHIRLTEIVSLPSHLNISYEDFFSALRQYAACEQRLGK
• Function: With DHDDS, forms the dehydrodolichyl diphosphate synthase (DDS) complex, an essential component of the dolichol monophosphate (Dol-P) biosynthetic machinery. Both subunits contribute to enzymatic activity, i.e. condensation of multiple copies of isopentenyl pyrophosphate (IPP) to farnesyl pyrophosphate (FPP) to produce dehydrodolichyl diphosphate (Dedol-PP), a precursor of dolichol phosphate which is utilized as a sugar carrier in protein glycosylation in the endoplasmic reticulum (ER). Synthesizes long-chain polyprenols, mostly of C95 and C100 chain length. Regulates the glycosylation and stability of nascent NPC2, thereby promoting trafficking of LDL-derived cholesterol. Acts as a specific receptor for the N-terminus of Nogo-B, a neural and cardiovascular regulator.
• KEGG Pathway: Terpenoid backbone biosynthesis (hsa00900)
• Reactome Pathway:
  Defective DHDDS causes RP59 (R-HSA-4755609)
  Synthesis of Dolichyl-phosphate (R-HSA-446199)
• BioCyc Pathway: MetaCyc:ENSG00000153989-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Biomarker	[1]
Estrogen-receptor positive breast cancer	DIS1H502	Definitive	Biomarker	[2]
Invasive ductal breast carcinoma	DIS43J58	Definitive	Biomarker	[1]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[3]
Congenital disorder of glycosylation	DIS400QP	Strong	Genetic Variation	[4]
Coronary heart disease	DIS5OIP1	Strong	Altered Expression	[5]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Biomarker	[1]
Epilepsy	DISBB28L	Strong	Genetic Variation	[6]
Fatty liver disease	DIS485QZ	Strong	Biomarker	[7]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[8]
Intellectual disability, autosomal dominant 55, with seizures	DISXBX9Q	Strong	Autosomal dominant	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[9]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[8]
Peripheral arterial disease	DIS78WFB	Strong	Altered Expression	[5]
Melanoma	DIS1RRCY	moderate	Biomarker	[10]
Undetermined early-onset epileptic encephalopathy	DISISEI2	Supportive	Autosomal dominant	[11]
B-cell neoplasm	DISVY326	Limited	Genetic Variation	[12]
Breast cancer	DIS7DPX1	Limited	Altered Expression	[2]
Breast carcinoma	DIS2UE88	Limited	Altered Expression	[2]
Congenital disorder of glycosylation, type IAA	DISF5H4E	Limited	Autosomal recessive	[13]
Erectile dysfunction	DISD8MTH	Limited	Biomarker	[12]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Biomarker	[14]

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 Dehydrodolichyl diphosphate synthase complex subunit NUS1 (NUS1).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Dehydrodolichyl diphosphate synthase complex subunit NUS1 (NUS1).	[16]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Dehydrodolichyl diphosphate synthase complex subunit NUS1 (NUS1).	[17]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Dehydrodolichyl diphosphate synthase complex subunit NUS1 (NUS1).	[18]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the expression of Dehydrodolichyl diphosphate synthase complex subunit NUS1 (NUS1).	[18]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene decreases the expression of Dehydrodolichyl diphosphate synthase complex subunit NUS1 (NUS1).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Dehydrodolichyl diphosphate synthase complex subunit NUS1 (NUS1).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Dehydrodolichyl diphosphate synthase complex subunit NUS1 (NUS1).	[20]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Dehydrodolichyl diphosphate synthase complex subunit NUS1 (NUS1).	[21]

References

• [1] Correlation of Expression of CHI3L1 and Nogo-A and their Role in Angiogenesis in Invasive Ductal Breast Carcinoma.Anticancer Res. 2019 May;39(5):2341-2350. doi: 10.21873/anticanres.13351.
• [2] Nogo-B receptor increases the resistance of estrogen receptor positive breast cancer to paclitaxel.Cancer Lett. 2018 Apr 10;419:233-244. doi: 10.1016/j.canlet.2018.01.054. Epub 2018 Feb 2.
• [3] Comprehensive proteome quantification reveals NgBR as a new regulator for epithelial-mesenchymal transition of breast tumor cells.J Proteomics. 2015 Jan 1;112:38-52. doi: 10.1016/j.jprot.2014.08.007. Epub 2014 Aug 27.
• [4] Mutation of Nogo-B receptor, a subunit of cis-prenyltransferase, causes a congenital disorder of glycosylation. Cell Metab. 2014 Sep 2;20(3):448-57. doi: 10.1016/j.cmet.2014.06.016. Epub 2014 Jul 24.
• [5] The role of novel cytokines in inflammation: Defining peripheral artery disease among patients with coronary artery disease.Vasc Med. 2018 Oct;23(5):428-436. doi: 10.1177/1358863X18763096. Epub 2018 Apr 11.
• [6] 6q22.1 microdeletion and susceptibility to pediatric epilepsy.Eur J Hum Genet. 2015 Feb;23(2):173-9. doi: 10.1038/ejhg.2014.75. Epub 2014 May 14.
• [7] NogoB receptor in relevant carcinoma: Current achievements, challenges and aims (Review).Int J Oncol. 2018 Nov;53(5):1827-1835. doi: 10.3892/ijo.2018.4520. Epub 2018 Aug 9.
• [8] Nogo-B receptor promotes epithelial-mesenchymal transition in non-small cell lung cancer cells through the Ras/ERK/Snail1 pathway.Cancer Lett. 2018 Apr 1;418:135-146. doi: 10.1016/j.canlet.2018.01.030. Epub 2018 Jan 11.
• [9] Nogo-B Receptor Directs Mitochondria-Associated Membranes to Regulate Vascular Smooth Muscle Cell Proliferation.Int J Mol Sci. 2019 May 10;20(9):2319. doi: 10.3390/ijms20092319.
• [10] Aggressiveness of human melanoma xenograft models is promoted by aneuploidy-driven gene expression deregulation.Oncotarget. 2012 Apr;3(4):399-413. doi: 10.18632/oncotarget.473.
• [11] High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies. Am J Hum Genet. 2017 Nov 2;101(5):664-685. doi: 10.1016/j.ajhg.2017.09.008.
• [12] Silencing Nogo-B receptor inhibits penile corpus cavernosum vascular smooth muscle cell apoptosis of rats with diabetic erectile dysfunction by down-regulating ICAM-1.PLoS One. 2019 Aug 23;14(8):e0220715. doi: 10.1371/journal.pone.0220715. eCollection 2019.
• [13] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [14] Identification of 28 new susceptibility loci for type 2 diabetes in the Japanese population.Nat Genet. 2019 Mar;51(3):379-386. doi: 10.1038/s41588-018-0332-4. Epub 2019 Feb 4.
• [15] 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.
• [16] 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.
• [17] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [18] Comparative gene expression profiling reveals partially overlapping but distinct genomic actions of different antiestrogens in human breast cancer cells. J Cell Biochem. 2006 Aug 1;98(5):1163-84.
• [19] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [20] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [21] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.