Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTM3H5OA)

• DOT Name: Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1)
• Synonyms: EC 3.4.22.-; MALT lymphoma-associated translocation; Paracaspase
• Gene Name: MALT1
• Related Disease: Combined immunodeficiency due to MALT1 deficiency
• UniProt ID: MALT1_HUMAN
• PDB ID: 2G7R; 3BFO; 3K0W; 3UO8; 3UOA; 3V4O; 3V55; 4I1P; 4I1R; 6F7I; 6GK2; 6H4A; 6YN8; 6YN9; 7A41; 7AK0; 7AK1; 7PAV; 7PAW; 8CZO
• EC Number: 3.4.22.-
• Pfam ID: PF13895 ; PF13927 ; PF18703 ; PF00656
• Sequence:
  MSLLGDPLQALPPSAAPTGPLLAPPAGATLNRLREPLLRRLSELLDQAPEGRGWRRLAEL
  AGSRGRLRLSCLDLEQCSLKVLEPEGSPSLCLLKLMGEKGCTVTELSDFLQAMEHTEVLQ
  LLSPPGIKITVNPESKAVLAGQFVKLCCRATGHPFVQYQWFKMNKEIPNGNTSELIFNAV
  HVKDAGFYVCRVNNNFTFEFSQWSQLDVCDIPESFQRSVDGVSESKLQICVEPTSQKLMP
  GSTLVLQCVAVGSPIPHYQWFKNELPLTHETKKLYMVPYVDLEHQGTYWCHVYNDRDSQD
  SKKVEIIIGRTDEAVECTEDELNNLGHPDNKEQTTDQPLAKDKVALLIGNMNYREHPKLK
  APLVDVYELTNLLRQLDFKVVSLLDLTEYEMRNAVDEFLLLLDKGVYGLLYYAGHGYENF
  GNSFMVPVDAPNPYRSENCLCVQNILKLMQEKETGLNVFLLDMCRKRNDYDDTIPILDAL
  KVTANIVFGYATCQGAEAFEIQHSGLANGIFMKFLKDRLLEDKKITVLLDEVAEDMGKCH
  LTKGKQALEIRSSLSEKRALTDPIQGTEYSAESLVRNLQWAKAHELPESMCLKFDCGVQI
  QLGFAAEFSNVMIIYTSIVYKPPEIIMCDAYVTDFPLDLDIDPKDANKGTPEETGSYLVS
  KDLPKHCLYTRLSSLQKLKEHLVFTVCLSYQYSGLEDTVEDKQEVNVGKPLIAKLDMHRG
  LGRKTCFQTCLMSNGPYQSSAATSGGAGHYHSLQDPFHGVYHSHPGNPSNVTPADSCHCS
  RTPDAFISSFAHHASCHFSRSNVPVETTDEIPFSFSDRLRISEK
• Function: Protease that enhances BCL10-induced activation: acts via formation of CBM complexes that channel adaptive and innate immune signaling downstream of CARD domain-containing proteins (CARD9, CARD11 and CARD14) to activate NF-kappa-B and MAP kinase p38 pathways which stimulate expression of genes encoding pro-inflammatory cytokines and chemokines. Mediates BCL10 cleavage: MALT1-dependent BCL10 cleavage plays an important role in T-cell antigen receptor-induced integrin adhesion. Involved in the induction of T helper 17 cells (Th17) differentiation. Cleaves RC3H1 and ZC3H12A in response to T-cell receptor (TCR) stimulation which releases their cooperatively repressed targets to promote Th17 cell differentiation. Also mediates cleavage of N4BP1 in T-cells following TCR-mediated activation, leading to N4BP1 inactivation. May also have ubiquitin ligase activity: binds to TRAF6, inducing TRAF6 oligomerization and activation of its ligase activity.
• Tissue Specificity: Highly expressed in peripheral blood mononuclear cells. Detected at lower levels in bone marrow, thymus and lymph node, and at very low levels in colon and lung.
• KEGG Pathway:
  NF-kappa B sig.ling pathway (hsa04064)
  C-type lectin receptor sig.ling pathway (hsa04625)
  T cell receptor sig.ling pathway (hsa04660)
  B cell receptor sig.ling pathway (hsa04662)
  Shigellosis (hsa05131)
  Tuberculosis (hsa05152)
• Reactome Pathway:
  Downstream TCR signaling (R-HSA-202424)
  FCERI mediated NF-kB activation (R-HSA-2871837)
  CLEC7A (Dectin-1) signaling (R-HSA-5607764)
  CLEC7A/inflammasome pathway (R-HSA-5660668)
  Activation of NF-kappaB in B cells (R-HSA-1169091)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Combined immunodeficiency due to MALT1 deficiency	DIS2QVF0	Definitive	Autosomal recessive	[1]

18 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 Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1).	[6]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1).	[9]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1).	[10]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1).	[10]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1).	[11]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1).	[12]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1).	[13]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1).	[14]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1).	[15]
LY294002	DMY1AFS	Phase 1	LY294002 decreases the activity of Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1).	[16]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1).	[19]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1).	[20]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1).	[18]

References

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• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Cyclosporine A--induced oxidative stress in human renal mesangial cells: a role for ERK 1/2 MAPK signaling. Toxicol Sci. 2012 Mar;126(1):101-13.
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• [6] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
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• [8] 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.
• [9] 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.
• [10] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [11] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [12] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [13] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [14] Comparison of gene expression in HCT116 treatment derivatives generated by two different 5-fluorouracil exposure protocols. Mol Cancer. 2004 Apr 26;3:11.
• [15] 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.
• [16] Critical role of PI3K signaling for NF-kappaB-dependent survival in a subset of activated B-cell-like diffuse large B-cell lymphoma cells. Proc Natl Acad Sci U S A. 2011 Jan 4;108(1):272-7. doi: 10.1073/pnas.1008969108. Epub 2010 Dec 20.
• [17] 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.
• [18] 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.
• [19] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [20] CD34+ derived macrophage and dendritic cells display differential responses to paraquat. Toxicol In Vitro. 2021 Sep;75:105198. doi: 10.1016/j.tiv.2021.105198. Epub 2021 Jun 9.