Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTB323OZ)

• DOT Name: Legumain (LGMN)
• Synonyms: EC 3.4.22.34; Asparaginyl endopeptidase; AEP; Protease, cysteine 1
• Gene Name: LGMN
• UniProt ID: LGMN_HUMAN
• PDB ID: 4AW9; 4AWA; 4AWB; 4FGU; 4N6N; 4N6O; 5LU8; 5LU9; 5LUA; 5LUB; 7FQH; 7FQI; 7FQJ; 7FQK; 7FQL; 7O50; 8AE4; 8AE5
• EC Number: 3.4.22.34
• Pfam ID: PF20985 ; PF01650
• Sequence:
  MVWKVAVFLSVALGIGAVPIDDPEDGGKHWVVIVAGSNGWYNYRHQADACHAYQIIHRNG
  IPDEQIVVMMYDDIAYSEDNPTPGIVINRPNGTDVYQGVPKDYTGEDVTPQNFLAVLRGD
  AEAVKGIGSGKVLKSGPQDHVFIYFTDHGSTGILVFPNEDLHVKDLNETIHYMYKHKMYR
  KMVFYIEACESGSMMNHLPDNINVYATTAANPRESSYACYYDEKRSTYLGDWYSVNWMED
  SDVEDLTKETLHKQYHLVKSHTNTSHVMQYGNKTISTMKVMQFQGMKRKASSPVPLPPVT
  HLDLTPSPDVPLTIMKRKLMNTNDLEESRQLTEEIQRHLDARHLIEKSVRKIVSLLAASE
  AEVEQLLSERAPLTGHSCYPEALLHFRTHCFNWHSPTYEYALRHLYVLVNLCEKPYPLHR
  IKLSMDHVCLGHY
• Function: Has a strict specificity for hydrolysis of asparaginyl bonds. Can also cleave aspartyl bonds slowly, especially under acidic conditions. Involved in the processing of proteins for MHC class II antigen presentation in the lysosomal/endosomal system. Also involved in MHC class I antigen presentation in cross-presenting dendritic cells by mediating cleavage and maturation of Perforin-2 (MPEG1), thereby promoting antigen translocation in the cytosol. Required for normal lysosomal protein degradation in renal proximal tubules. Required for normal degradation of internalized EGFR. Plays a role in the regulation of cell proliferation via its role in EGFR degradation.
• Tissue Specificity: Ubiquitous. Particularly abundant in kidney, heart and placenta.
• KEGG Pathway:
  Lysosome (hsa04142)
  Antigen processing and presentation (hsa04612)
• Reactome Pathway:
  Vitamin D (calciferol) metabolism (R-HSA-196791)
  MHC class II antigen presentation (R-HSA-2132295)
  Trafficking and processing of endosomal TLR (R-HSA-1679131)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Legumain (LGMN).	[1]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Legumain (LGMN).	[2]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Legumain (LGMN).	[3]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Legumain (LGMN).	[4]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Legumain (LGMN).	[5]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Legumain (LGMN).	[6]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Legumain (LGMN).	[7]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Legumain (LGMN).	[9]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Legumain (LGMN).	[11]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Legumain (LGMN).	[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 affects the methylation of Legumain (LGMN).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Legumain (LGMN).	[10]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] 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.
• [3] 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.
• [4] 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.
• [5] Changes in gene expression profiles of multiple myeloma cells induced by arsenic trioxide (ATO): possible mechanisms to explain ATO resistance in vivo. Br J Haematol. 2005 Mar;128(5):636-44.
• [6] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [7] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [8] 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.
• [9] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [10] 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.
• [11] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [12] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.