Details of Drug Off-Target (DOT)

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

• DOT Name: Mannan-binding lectin serine protease 1 (MASP1)
• Synonyms: EC 3.4.21.-; Complement factor MASP-3; Complement-activating component of Ra-reactive factor; Mannose-binding lectin-associated serine protease 1; MASP-1; Mannose-binding protein-associated serine protease; Ra-reactive factor serine protease p100; RaRF; Serine protease 5
• Gene Name: MASP1
• Related Disease:
  3MC syndrome 1
  Non-insulin dependent diabetes
  Rheumatoid arthritis
  Subarachnoid hemorrhage
  3MC syndrome 2
  Alzheimer disease
  Atypical hemolytic uremic syndrome
  Bacterial infection
  Cardiovascular disease
  Cervical cancer
  Cervical carcinoma
  Cystic fibrosis
  Esophageal squamous cell carcinoma
  Glomerulonephritis
  Hepatitis C virus infection
  Inclusion body myopathy with Paget disease of bone and frontotemporal dementia
  Kidney failure
  Lupus
  Multiple sclerosis
  Prostate cancer
  Prostate carcinoma
  Pulmonary tuberculosis
  Systemic lupus erythematosus
  Tuberculosis
  Vascular dementia
  Age-related macular degeneration
  Blindness
  Disseminated intravascular coagulation
  Lung squamous cell carcinoma
  Squamous cell carcinoma
  3MC syndrome
  Amyotrophic lateral sclerosis type 1
  Arthritis
  Fetal growth restriction
  Lewy body dementia
  Neoplasm
  Type-1/2 diabetes
• UniProt ID: MASP1_HUMAN
• PDB ID: 3DEM; 3GOV; 4AQB; 4DJZ; 4IGD; 4IW4; 4KKD; 7PQO
• EC Number: 3.4.21.-
• Pfam ID: PF00431 ; PF00084 ; PF00089
• Sequence:
  MRWLLLYYALCFSLSKASAHTVELNNMFGQIQSPGYPDSYPSDSEVTWNITVPDGFRIKL
  YFMHFNLESSYLCEYDYVKVETEDQVLATFCGRETTDTEQTPGQEVVLSPGSFMSITFRS
  DFSNEERFTGFDAHYMAVDVDECKEREDEELSCDHYCHNYIGGYYCSCRFGYILHTDNRT
  CRVECSDNLFTQRTGVITSPDFPNPYPKSSECLYTIELEEGFMVNLQFEDIFDIEDHPEV
  PCPYDYIKIKVGPKVLGPFCGEKAPEPISTQSHSVLILFHSDNSGENRGWRLSYRAAGNE
  CPELQPPVHGKIEPSQAKYFFKDQVLVSCDTGYKVLKDNVEMDTFQIECLKDGTWSNKIP
  TCKIVDCRAPGELEHGLITFSTRNNLTTYKSEIKYSCQEPYYKMLNNNTGIYTCSAQGVW
  MNKVLGRSLPTCLPVCGLPKFSRKLMARIFNGRPAQKGTTPWIAMLSHLNGQPFCGGSLL
  GSSWIVTAAHCLHQSLDPEDPTLRDSDLLSPSDFKIILGKHWRLRSDENEQHLGVKHTTL
  HPQYDPNTFENDVALVELLESPVLNAFVMPICLPEGPQQEGAMVIVSGWGKQFLQRFPET
  LMEIEIPIVDHSTCQKAYAPLKKKVTRDMICAGEKEGGKDACAGDSGGPMVTLNRERGQW
  YLVGTVSWGDDCGKKDRYGVYSYIHHNKDWIQRVTGVRN
• Function: Functions in the lectin pathway of complement, which performs a key role in innate immunity by recognizing pathogens through patterns of sugar moieties and neutralizing them. The lectin pathway is triggered upon binding of mannan-binding lectin (MBL) and ficolins to sugar moieties which leads to activation of the associated proteases MASP1 and MASP2. Functions as an endopeptidase and may activate MASP2 or C2 or directly activate C3 the key component of complement reaction. Isoform 2 may have an inhibitory effect on the activation of the lectin pathway of complement or may cleave IGFBP5. Also plays a role in development.
• Tissue Specificity: Protein of the plasma which is primarily expressed by liver.
• KEGG Pathway:
  Complement and coagulation cascades (hsa04610)
  Staphylococcus aureus infection (hsa05150)
  Coro.virus disease - COVID-19 (hsa05171)
• Reactome Pathway:
  Initial triggering of complement (R-HSA-166663)
  Ficolins bind to repetitive carbohydrate structures on the target cell surface (R-HSA-2855086)
  Scavenging by Class A Receptors (R-HSA-3000480)
  SARS-CoV-2 activates/modulates innate and adaptive immune responses (R-HSA-9705671)
  Lectin pathway of complement activation (R-HSA-166662)

Molecular Interaction Atlas (MIA) of This DOT

37 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
3MC syndrome 1	DISXUNXN	Definitive	Autosomal recessive	[1]
Non-insulin dependent diabetes	DISK1O5Z	Definitive	Genetic Variation	[2]
Rheumatoid arthritis	DISTSB4J	Definitive	Biomarker	[3]
Subarachnoid hemorrhage	DISI7I8Y	Definitive	Biomarker	[4]
3MC syndrome 2	DISAXCJJ	Strong	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[5]
Atypical hemolytic uremic syndrome	DIS6FUDJ	Strong	Genetic Variation	[6]
Bacterial infection	DIS5QJ9S	Strong	Biomarker	[7]
Cardiovascular disease	DIS2IQDX	Strong	Biomarker	[8]
Cervical cancer	DISFSHPF	Strong	Biomarker	[9]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[9]
Cystic fibrosis	DIS2OK1Q	Strong	Genetic Variation	[10]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[11]
Glomerulonephritis	DISPZIQ3	Strong	Biomarker	[12]
Hepatitis C virus infection	DISQ0M8R	Strong	Altered Expression	[13]
Inclusion body myopathy with Paget disease of bone and frontotemporal dementia	DISK4S94	Strong	Biomarker	[14]
Kidney failure	DISOVQ9P	Strong	Altered Expression	[15]
Lupus	DISOKJWA	Strong	Biomarker	[12]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[16]
Prostate cancer	DISF190Y	Strong	Biomarker	[17]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[17]
Pulmonary tuberculosis	DIS6FLUM	Strong	Genetic Variation	[18]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[12]
Tuberculosis	DIS2YIMD	Strong	Altered Expression	[18]
Vascular dementia	DISVO82H	Strong	Biomarker	[5]
Age-related macular degeneration	DIS0XS2C	moderate	Biomarker	[19]
Blindness	DISTIM10	moderate	Biomarker	[19]
Disseminated intravascular coagulation	DISCAVOZ	moderate	Biomarker	[20]
Lung squamous cell carcinoma	DISXPIBD	moderate	Biomarker	[21]
Squamous cell carcinoma	DISQVIFL	moderate	Biomarker	[21]
3MC syndrome	DISJUBAL	Supportive	Autosomal recessive	[1]
Amyotrophic lateral sclerosis type 1	DIS5A2M0	Limited	Genetic Variation	[22]
Arthritis	DIST1YEL	Limited	Biomarker	[3]
Fetal growth restriction	DIS5WEJ5	Limited	Biomarker	[23]
Lewy body dementia	DISAE66J	Limited	Biomarker	[24]
Neoplasm	DISZKGEW	Limited	Biomarker	[25]
Type-1/2 diabetes	DISIUHAP	Limited	Altered Expression	[26]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Temozolomide	DMKECZD	Approved	Mannan-binding lectin serine protease 1 (MASP1) affects the response to substance of Temozolomide.	[38]
DTI-015	DMXZRW0	Approved	Mannan-binding lectin serine protease 1 (MASP1) affects the response to substance of DTI-015.	[38]

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 Mannan-binding lectin serine protease 1 (MASP1).	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Mannan-binding lectin serine protease 1 (MASP1).	[28]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Mannan-binding lectin serine protease 1 (MASP1).	[29]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Mannan-binding lectin serine protease 1 (MASP1).	[30]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Mannan-binding lectin serine protease 1 (MASP1).	[31]
Decitabine	DMQL8XJ	Approved	Decitabine decreases the expression of Mannan-binding lectin serine protease 1 (MASP1).	[32]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Mannan-binding lectin serine protease 1 (MASP1).	[33]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Mannan-binding lectin serine protease 1 (MASP1).	[34]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 decreases the expression of Mannan-binding lectin serine protease 1 (MASP1).	[35]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Mannan-binding lectin serine protease 1 (MASP1).	[36]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Mannan-binding lectin serine protease 1 (MASP1).	[37]

References

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• [4] Changes in the Lectin Pathway Following Intracerebral or Spontaneous Subarachnoid Hemorrhage.Mol Neurobiol. 2019 Jan;56(1):78-87. doi: 10.1007/s12035-018-1066-0. Epub 2018 Apr 19.
• [5] N-homocysteinylation of tau and MAP1 is increased in autopsy specimens of Alzheimer's disease and vascular dementia.J Pathol. 2019 Jul;248(3):291-303. doi: 10.1002/path.5254. Epub 2019 Mar 19.
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• [7] Molecular and functional characterization of a mannose-binding lectin/ficolin-associated protein (MAp44) from Nile tilapia (Oreochromis niloticus) involved in the immune response to bacterial infection.Dev Comp Immunol. 2019 Dec;101:103438. doi: 10.1016/j.dci.2019.103438. Epub 2019 Jul 9.
• [8] Distinct Longitudinal Associations of MBL, MASP-1, MASP-2, MASP-3, and MAp44 With Endothelial Dysfunction and Intima-Media Thickness: The Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) Study.Arterioscler Thromb Vasc Biol. 2016 Jun;36(6):1278-85. doi: 10.1161/ATVBAHA.115.306552. Epub 2016 Apr 7.
• [9] MASP-1 and MASP-2 Serum Levels Are Associated With Worse Prognostic in Cervical Cancer Progression.Front Immunol. 2018 Nov 23;9:2742. doi: 10.3389/fimmu.2018.02742. eCollection 2018.
• [10] Polymorphisms in the lectin pathway genes as a possible cause of early chronic Pseudomonas aeruginosa colonization in cystic fibrosis patients.Hum Immunol. 2012 Nov;73(11):1175-83. doi: 10.1016/j.humimm.2012.08.010. Epub 2012 Aug 29.
• [11] High p53 and MAP1 light chain 3A co-expression predicts poor prognosis in patients with esophageal squamous cell carcinoma.Mol Med Rep. 2013 Jul;8(1):41-6. doi: 10.3892/mmr.2013.1451. Epub 2013 Apr 30.
• [12] Essential Roles for Mannose-Binding Lectin-Associated Serine Protease-1/3 in the Development of Lupus-Like Glomerulonephritis in MRL/lpr Mice.Front Immunol. 2018 May 28;9:1191. doi: 10.3389/fimmu.2018.01191. eCollection 2018.
• [13] Mannan binding lectin-associated serine protease 1 is induced by hepatitis C virus infection and activates human hepatic stellate cells.Clin Exp Immunol. 2013 Nov;174(2):265-73. doi: 10.1111/cei.12174.
• [14] Valosin-containing protein (VCP) is required for autophagy and is disrupted in VCP disease.J Cell Biol. 2009 Dec 14;187(6):875-88. doi: 10.1083/jcb.200908115.
• [15] Factors involved in initiation and regulation of complement lectin pathway influence postoperative outcome after pediatric cardiac surgery involving cardiopulmonary bypass.Sci Rep. 2019 Feb 27;9(1):2930. doi: 10.1038/s41598-019-39742-w.
• [16] Close Encounters of the First Kind: Innate Sensors and Multiple Sclerosis.Mol Neurobiol. 2017 Jan;54(1):101-114. doi: 10.1007/s12035-015-9665-5. Epub 2016 Jan 5.
• [17] A novel role for MAP1 LC3 in nonautophagic cytoplasmic vacuolation death of cancer cells.Oncogene. 2009 Jul 16;28(28):2556-68. doi: 10.1038/onc.2009.118. Epub 2009 May 18.
• [18] AmpliSeq Screening of Genes Encoding the C-Type Lectin Receptors and Their Signaling Components Reveals a Common Variant in MASP1 Associated with Pulmonary Tuberculosis in an Indian Population.Front Immunol. 2018 Feb 20;9:242. doi: 10.3389/fimmu.2018.00242. eCollection 2018.
• [19] Proteomics-based identification and validation of novel plasma biomarkers phospholipid transfer protein and mannan-binding lectin serine protease-1 in age-related macular degeneration.Sci Rep. 2016 Sep 8;6:32548. doi: 10.1038/srep32548.
• [20] Reduced Mannose-Binding Lectin-Associated Serine Protease (MASP)-1 is Associated with Disturbed Coagulation in Septic Shock.Thromb Haemost. 2019 Jun;119(6):952-961. doi: 10.1055/s-0039-1685140. Epub 2019 Apr 15.
• [21] Identification of novel candidate target genes, including EPHB3, MASP1 and SST at 3q26.2-q29 in squamous cell carcinoma of the lung.BMC Cancer. 2009 Jul 16;9:237. doi: 10.1186/1471-2407-9-237.
• [22] Genome-wide association study combining pathway analysis for typical sporadic amyotrophic lateral sclerosis in Chinese Han populations.Neurobiol Aging. 2014 Jul;35(7):1778.e9-1778.e23. doi: 10.1016/j.neurobiolaging.2014.01.014. Epub 2014 Jan 17.
• [23] Lectin pathway proteins of the complement system in normotensive pregnancy and pre-eclampsia.Am J Reprod Immunol. 2019 Apr;81(4):e13092. doi: 10.1111/aji.13092. Epub 2019 Feb 23.
• [24] Localization of MAP1-LC3 in vulnerable neurons and Lewy bodies in brains of patients with dementia with Lewy bodies.J Neuropathol Exp Neurol. 2011 Apr;70(4):264-80. doi: 10.1097/NEN.0b013e318211c86a.
• [25] The tumor suppressor RASSF1A and MAP-1 link death receptor signaling to Bax conformational change and cell death.Mol Cell. 2005 Jun 10;18(6):637-50. doi: 10.1016/j.molcel.2005.05.010.
• [26] Plasma levels of MASP-1, MASP-3 and MAp44 in patients with type 2 diabetes: influence of glycaemic control, body composition and polymorphisms in the MASP1 gene.Clin Exp Immunol. 2017 Jul;189(1):103-112. doi: 10.1111/cei.12963. Epub 2017 Apr 20.
• [27] 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.
• [28] 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.
• [29] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [30] 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.
• [31] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [32] The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009 Jun;23(6):1019-28.
• [33] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [34] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [35] Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cells. PLoS One. 2022 Apr 29;17(4):e0266966. doi: 10.1371/journal.pone.0266966. eCollection 2022.
• [36] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [37] Comparison of the global gene expression profiles produced by methylparaben, n-butylparaben and 17beta-oestradiol in MCF7 human breast cancer cells. J Appl Toxicol. 2007 Jan-Feb;27(1):67-77. doi: 10.1002/jat.1200.
• [38] Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas. J Clin Oncol. 2006 Jan 10;24(2):274-87. doi: 10.1200/JCO.2005.02.9405. Epub 2005 Dec 19.