Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLBE3CB)

• DOT Name: Protein transport protein Sec61 subunit alpha isoform 1 (SEC61A1)
• Synonyms: Sec61 alpha-1
• Gene Name: SEC61A1
• Related Disease:
  Type-1/2 diabetes
  Chromosomal disorder
  Chronic kidney disease
  Hyperuricemic nephropathy, familial juvenile type 4
  Myelodysplastic syndrome
  Prion disease
  SEC61A1 deficiency
  Anemia
  Colon adenocarcinoma
• UniProt ID: S61A1_HUMAN
• PDB ID: 6W6L; 8B6L; 8DNV; 8DNW; 8DNX; 8DNY; 8DNZ; 8DO0; 8DO1; 8DO2; 8DO3
• Pfam ID: PF10559 ; PF00344
• Sequence:
  MAIKFLEVIKPFCVILPEIQKPERKIQFKEKVLWTAITLFIFLVCCQIPLFGIMSSDSAD
  PFYWMRVILASNRGTLMELGISPIVTSGLIMQLLAGAKIIEVGDTPKDRALFNGAQKLFG
  MIITIGQSIVYVMTGMYGDPSEMGAGICLLITIQLFVAGLIVLLLDELLQKGYGLGSGIS
  LFIATNICETIVWKAFSPTTVNTGRGMEFEGAIIALFHLLATRTDKVRALREAFYRQNLP
  NLMNLIATIFVFAVVIYFQGFRVDLPIKSARYRGQYNTYPIKLFYTSNIPIILQSALVSN
  LYVISQMLSARFSGNLLVSLLGTWSDTSSGGPARAYPVGGLCYYLSPPESFGSVLEDPVH
  AVVYIVFMLGSCAFFSKTWIEVSGSSAKDVAKQLKEQQMVMRGHRETSMVHELNRYIPTA
  AAFGGLCIGALSVLADFLGAIGSGTGILLAVTIIYQYFEIFVKEQSEVGSMGALLF
• Function: Component of SEC61 channel-forming translocon complex that mediates transport of signal peptide-containing precursor polypeptides across the endoplasmic reticulum (ER). Forms a ribosome receptor and a gated pore in the ER membrane, both functions required for cotranslational translocation of nascent polypeptides. May cooperate with auxiliary protein SEC62, SEC63 and HSPA5/BiP to enable post-translational transport of small presecretory proteins. The SEC61 channel is also involved in ER membrane insertion of transmembrane proteins: it mediates membrane insertion of the first few transmembrane segments of proteins, while insertion of subsequent transmembrane regions of multi-pass membrane proteins is mediated by the multi-pass translocon (MPT) complex. The SEC61 channel cooperates with the translocating protein TRAM1 to import nascent proteins into the ER. Controls the passive efflux of calcium ions from the ER lumen to the cytosol through SEC61 channel, contributing to the maintenance of cellular calcium homeostasis. Plays a critical role in nephrogenesis, specifically at pronephros stage.
• Tissue Specificity: Expressed in proximal and distal tubules in kidney (at protein level).
• KEGG Pathway:
  Protein export (hsa03060)
  Protein processing in endoplasmic reticulum (hsa04141)
  Phagosome (hsa04145)
  Vibrio cholerae infection (hsa05110)
• Reactome Pathway:
  SRP-dependent cotranslational protein targeting to membrane (R-HSA-1799339)
  ER-Phagosome pathway (R-HSA-1236974)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Type-1/2 diabetes	DISIUHAP	Definitive	Altered Expression	[1]
Chromosomal disorder	DISM5BB5	Strong	Genetic Variation	[2]
Chronic kidney disease	DISW82R7	Strong	Biomarker	[3]
Hyperuricemic nephropathy, familial juvenile type 4	DISQT12L	Strong	Autosomal dominant	[1]
Myelodysplastic syndrome	DISYHNUI	Strong	Biomarker	[2]
Prion disease	DISOUMB0	Strong	Biomarker	[4]
SEC61A1 deficiency	DISW1LRN	Moderate	Autosomal dominant	[5]
Anemia	DISTVL0C	Limited	Genetic Variation	[3]
Colon adenocarcinoma	DISDRE0J	Limited	Biomarker	[6]

3 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 transport protein Sec61 subunit alpha isoform 1 (SEC61A1).	[7]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Protein transport protein Sec61 subunit alpha isoform 1 (SEC61A1).	[15]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Protein transport protein Sec61 subunit alpha isoform 1 (SEC61A1).	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Protein transport protein Sec61 subunit alpha isoform 1 (SEC61A1).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Protein transport protein Sec61 subunit alpha isoform 1 (SEC61A1).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein transport protein Sec61 subunit alpha isoform 1 (SEC61A1).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Protein transport protein Sec61 subunit alpha isoform 1 (SEC61A1).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Protein transport protein Sec61 subunit alpha isoform 1 (SEC61A1).	[12]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Protein transport protein Sec61 subunit alpha isoform 1 (SEC61A1).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Protein transport protein Sec61 subunit alpha isoform 1 (SEC61A1).	[14]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Protein transport protein Sec61 subunit alpha isoform 1 (SEC61A1).	[16]
Marinol	DM70IK5	Approved	Marinol increases the expression of Protein transport protein Sec61 subunit alpha isoform 1 (SEC61A1).	[17]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Protein transport protein Sec61 subunit alpha isoform 1 (SEC61A1).	[18]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Protein transport protein Sec61 subunit alpha isoform 1 (SEC61A1).	[19]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Protein transport protein Sec61 subunit alpha isoform 1 (SEC61A1).	[20]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Protein transport protein Sec61 subunit alpha isoform 1 (SEC61A1).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Protein transport protein Sec61 subunit alpha isoform 1 (SEC61A1).	[22]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Protein transport protein Sec61 subunit alpha isoform 1 (SEC61A1).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Protein transport protein Sec61 subunit alpha isoform 1 (SEC61A1).	[24]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Protein transport protein Sec61 subunit alpha isoform 1 (SEC61A1).	[25]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Protein transport protein Sec61 subunit alpha isoform 1 (SEC61A1).	[26]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Protein transport protein Sec61 subunit alpha isoform 1 (SEC61A1).	[13]

References

• [1] A point mutation in Sec61alpha1 leads to diabetes and hepatosteatosis in mice. Diabetes. 2010 Feb;59(2):460-70. doi: 10.2337/db08-1362. Epub 2009 Nov 23.
• [2] Cytogenetic abnormalities and genomic copy number variations in EPO (7q22) and SEC-61(7p11) genes in primary myelodysplastic syndromes.Blood Cells Mol Dis. 2016 Jul;59:52-7. doi: 10.1016/j.bcmd.2016.04.005. Epub 2016 Apr 13.
• [3] Heterozygous Loss-of-Function SEC61A1 Mutations Cause Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia.Am J Hum Genet. 2016 Jul 7;99(1):174-87. doi: 10.1016/j.ajhg.2016.05.028.
• [4] Impaired transport of intrinsically disordered proteins through the Sec61 and SecY translocon; implications for prion diseases.Prion. 2018 Mar 4;12(2):88-92. doi: 10.1080/19336896.2018.1435936. Epub 2018 Mar 29.
• [5] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [6] E2F1-mediated MNX1-AS1-miR-218-5p-SEC61A1 feedback loop contributes to the progression of colon adenocarcinoma.J Cell Biochem. 2019 Apr;120(4):6145-6153. doi: 10.1002/jcb.27902. Epub 2018 Oct 25.
• [7] 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.
• [8] 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.
• [9] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [10] 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.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] 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.
• [13] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [14] 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.
• [15] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [16] 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.
• [17] JunD is involved in the antiproliferative effect of Delta9-tetrahydrocannabinol on human breast cancer cells. Oncogene. 2008 Aug 28;27(37):5033-44.
• [18] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [19] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [20] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [21] Changes in gene expressions elicited by physiological concentrations of genistein on human endometrial cancer cells. Mol Carcinog. 2006 Oct;45(10):752-63.
• [22] 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.
• [23] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [24] 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.
• [25] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [26] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [27] 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.