Details of Drug Off-Target (DOT)

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

• DOT Name: Protein ERGIC-53 (LMAN1)
• Synonyms: ER-Golgi intermediate compartment 53 kDa protein; Gp58; Intracellular mannose-specific lectin MR60; Lectin mannose-binding 1
• Gene Name: LMAN1
• Related Disease:
  Factor V and factor VIII, combined deficiency of, type 1
  Adenoma
  Carcinoma
  Coagulation defect
  Colorectal neoplasm
  Congenital dyserythropoietic anemia type 2
  Haemophilia A
  Hematologic disease
  IgA nephropathy
  Neoplasm
  Vitamin K-dependent clotting factors, combined deficiency of, type 1
  Combined deficiency of factor V and factor VIII
  Thanatophoric dysplasia type 2
  Allergy
  Coronary atherosclerosis
  Coronary heart disease
  Malaria
• UniProt ID: LMAN1_HUMAN
• PDB ID: 3A4U; 3LCP; 3WHT; 3WHU; 3WNX; 4GKX; 4GKY; 4YGB; 4YGC; 4YGD; 4YGE
• Pfam ID: PF03388
• Sequence:
  MAGSRQRGLRARVRPLFCALLLSLGRFVRGDGVGGDPAVALPHRRFEYKYSFKGPHLVQS
  DGTVPFWAHAGNAIPSSDQIRVAPSLKSQRGSVWTKTKAAFENWEVEVTFRVTGRGRIGA
  DGLAIWYAENQGLEGPVFGSADLWNGVGIFFDSFDNDGKKNNPAIVIIGNNGQIHYDHQN
  DGASQALASCQRDFRNKPYPVRAKITYYQNTLTVMINNGFTPDKNDYEFCAKVENMIIPA
  QGHFGISAATGGLADDHDVLSFLTFQLTEPGKEPPTPDKEISEKEKEKYQEEFEHFQQEL
  DKKKEEFQKGHPDLQGQPAEEIFESVGDRELRQVFEGQNRIHLEIKQLNRQLDMILDEQR
  RYVSSLTEEISKRGAGMPGQHGQITQQELDTVVKTQHEILRQVNEMKNSMSETVRLVSGM
  QHPGSAGGVYETTQHFIDIKEHLHIVKRDIDNLVQRNMPSNEKPKCPELPPFPSCLSTVH
  FIIFVVVQTVLFIGYIMYRSQQEAAAKKFF
• Function: Mannose-specific lectin. May recognize sugar residues of glycoproteins, glycolipids, or glycosylphosphatidyl inositol anchors and may be involved in the sorting or recycling of proteins, lipids, or both. The LMAN1-MCFD2 complex forms a specific cargo receptor for the ER-to-Golgi transport of selected proteins.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway: Protein processing in endoplasmic reticulum (hsa04141)
• Reactome Pathway:
  Cargo concentration in the ER (R-HSA-5694530)
  RHOA GTPase cycle (R-HSA-8980692)
  RHOC GTPase cycle (R-HSA-9013106)
  RAC2 GTPase cycle (R-HSA-9013404)
  RHOD GTPase cycle (R-HSA-9013405)
  RHOG GTPase cycle (R-HSA-9013408)
  RAC3 GTPase cycle (R-HSA-9013423)
  Transport to the Golgi and subsequent modification (R-HSA-948021)
  COPII-mediated vesicle transport (R-HSA-204005)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Factor V and factor VIII, combined deficiency of, type 1	DIS1K6SD	Definitive	Autosomal recessive	[1]
Adenoma	DIS78ZEV	Strong	Altered Expression	[2]
Carcinoma	DISH9F1N	Strong	Altered Expression	[2]
Coagulation defect	DIS9X3H6	Strong	Genetic Variation	[3]
Colorectal neoplasm	DISR1UCN	Strong	Biomarker	[2]
Congenital dyserythropoietic anemia type 2	DIS5RDUE	Strong	Genetic Variation	[4]
Haemophilia A	DIS0RQ2E	Strong	Genetic Variation	[5]
Hematologic disease	DIS9XD9A	Strong	Genetic Variation	[4]
IgA nephropathy	DISZ8MTK	Strong	Biomarker	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Vitamin K-dependent clotting factors, combined deficiency of, type 1	DIS1X7PX	Strong	Biomarker	[7]
Combined deficiency of factor V and factor VIII	DISZM9BG	Supportive	Autosomal recessive	[8]
Thanatophoric dysplasia type 2	DIS2RRO1	Disputed	Biomarker	[9]
Allergy	DIS48ZAP	Limited	Biomarker	[10]
Coronary atherosclerosis	DISKNDYU	Limited	Genetic Variation	[11]
Coronary heart disease	DIS5OIP1	Limited	Genetic Variation	[11]
Malaria	DISQ9Y50	Limited	Genetic Variation	[12]

19 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 Protein ERGIC-53 (LMAN1).	[13]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Protein ERGIC-53 (LMAN1).	[14]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Protein ERGIC-53 (LMAN1).	[15]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Protein ERGIC-53 (LMAN1).	[16]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Protein ERGIC-53 (LMAN1).	[17]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Protein ERGIC-53 (LMAN1).	[18]
Phenobarbital	DMXZOCG	Approved	Phenobarbital increases the expression of Protein ERGIC-53 (LMAN1).	[19]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Protein ERGIC-53 (LMAN1).	[20]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Protein ERGIC-53 (LMAN1).	[21]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Protein ERGIC-53 (LMAN1).	[20]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Protein ERGIC-53 (LMAN1).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Protein ERGIC-53 (LMAN1).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Protein ERGIC-53 (LMAN1).	[22]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Protein ERGIC-53 (LMAN1).	[23]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Protein ERGIC-53 (LMAN1).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Protein ERGIC-53 (LMAN1).	[25]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Protein ERGIC-53 (LMAN1).	[26]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Protein ERGIC-53 (LMAN1).	[27]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Protein ERGIC-53 (LMAN1).	[28]

References

• [1] 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.
• [2] High frequency of LMAN1 abnormalities in colorectal tumors with microsatellite instability.Cancer Res. 2009 Jan 1;69(1):292-9. doi: 10.1158/0008-5472.CAN-08-3314.
• [3] Combined deficiency of coagulation factors V and VIII: an update.Semin Thromb Hemost. 2013 Sep;39(6):613-20. doi: 10.1055/s-0033-1349223. Epub 2013 Jul 12.
• [4] The COPII pathway and hematologic disease.Blood. 2012 Jul 5;120(1):31-8. doi: 10.1182/blood-2012-01-292086. Epub 2012 May 14.
• [5] The first case of combined coagulation factor V and coagulation factor VIII deficiency in Poland due to a novel p.Tyr135Asn missense mutation in the MCFD2 gene.Blood Coagul Fibrinolysis. 2008 Sep;19(6):531-534. doi: 10.1097/MBC.0b013e3283061103.
• [6] IgA nephropathy-specific expression of the IgA Fc receptors (CD89) on blood phagocytic cells.Clin Exp Immunol. 1997 Nov;110(2):226-32. doi: 10.1111/j.1365-2249.1997.tb08321.x.
• [7] Familial multiple coagulation factor deficiencies: new biologic insight from rare genetic bleeding disorders.J Thromb Haemost. 2004 Sep;2(9):1564-72. doi: 10.1111/j.1538-7836.2004.00857.x.
• [8] Mutations in the ER-Golgi intermediate compartment protein ERGIC-53 cause combined deficiency of coagulation factors V and VIII. Cell. 1998 Apr 3;93(1):61-70. doi: 10.1016/s0092-8674(00)81146-0.
• [9] Transient dimerization and interaction with ERGIC-53 occur in the fibroblast growth factor receptor 3 early secretory pathway.Int J Biochem Cell Biol. 2008;40(11):2649-59. doi: 10.1016/j.biocel.2008.05.017. Epub 2008 Jun 5.
• [10] Role of collectins in innate immunity against aspergillosis.Med Mycol. 2005 May;43 Suppl 1:S155-63. doi: 10.1080/13693780500088408.
• [11] Successful percutaneous coronary intervention in a patient with combined deficiency of FV and FVIII due to novel compound heterozygous mutations in LMAN1.Haemophilia. 2013 Jul;19(4):607-10. doi: 10.1111/hae.12128. Epub 2013 Apr 5.
• [12] Restricted polymorphisms of the mannose-binding lectin gene in a population of Papua New Guinea.Mutat Res. 2002 Aug 29;505(1-2):87-91. doi: 10.1016/s0027-5107(02)00142-2.
• [13] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [14] 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.
• [15] 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.
• [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] 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.
• [18] 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.
• [19] Proteomic analysis of hepatic effects of phenobarbital in mice with humanized liver. Arch Toxicol. 2022 Oct;96(10):2739-2754. doi: 10.1007/s00204-022-03338-7. Epub 2022 Jul 26.
• [20] 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.
• [21] 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.
• [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] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [24] Heat shock induces preferential translation of ERGIC-53 and affects its recycling pathway. J Biol Chem. 2004 Oct 8;279(41):42535-44. doi: 10.1074/jbc.M401860200. Epub 2004 Jul 29.
• [25] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.
• [26] 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.
• [27] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [28] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.