Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTF8T3JM)

• DOT Name: Matrix metalloproteinase-24 (MMP24)
• Synonyms: MMP-24; EC 3.4.24.-; Membrane-type matrix metalloproteinase 5; MT-MMP 5; MTMMP5; Membrane-type-5 matrix metalloproteinase; MT5-MMP; MT5MMP
• Gene Name: MMP24
• Related Disease:
  Multiple sclerosis
  Alzheimer disease
  Brain neoplasm
  Chronic renal failure
  End-stage renal disease
  Endometriosis
  Glioblastoma multiforme
  Plasma cell myeloma
  Type-1/2 diabetes
  Gastric cancer
  Stomach cancer
  Neoplasm
• UniProt ID: MMP24_HUMAN
• EC Number: 3.4.24.-
• Pfam ID: PF11857 ; PF00045 ; PF00413 ; PF01471
• Sequence:
  MPRSRGGRAAPGPPPPPPPPGQAPRWSRWRVPGRLLLLLLPALCCLPGAARAAAAAAGAG
  NRAAVAVAVARADEAEAPFAGQNWLKSYGYLLPYDSRASALHSAKALQSAVSTMQQFYGI
  PVTGVLDQTTIEWMKKPRCGVPDHPHLSRRRRNKRYALTGQKWRQKHITYSIHNYTPKVG
  ELDTRKAIRQAFDVWQKVTPLTFEEVPYHEIKSDRKEADIMIFFASGFHGDSSPFDGEGG
  FLAHAYFPGPGIGGDTHFDSDEPWTLGNANHDGNDLFLVAVHELGHALGLEHSSDPSAIM
  APFYQYMETHNFKLPQDDLQGIQKIYGPPAEPLEPTRPLPTLPVRRIHSPSERKHERQPR
  PPRPPLGDRPSTPGTKPNICDGNFNTVALFRGEMFVFKDRWFWRLRNNRVQEGYPMQIEQ
  FWKGLPARIDAAYERADGRFVFFKGDKYWVFKEVTVEPGYPHSLGELGSCLPREGIDTAL
  RWEPVGKTYFFKGERYWRYSEERRATDPGYPKPITVWKGIPQAPQGAFISKEGYYTYFYK
  GRDYWKFDNQKLSVEPGYPRNILRDWMGCNQKEVERRKERRLPQDDVDIMVTINDVPGSV
  NAVAVVIPCILSLCILVLVYTIFQFKNKTGPQPVTYYKRPVQEWV
• Function: Metalloprotease that mediates cleavage of N-cadherin (CDH2) and acts as a regulator of neuro-immune interactions and neural stem cell quiescence. Involved in cell-cell interactions between nociceptive neurites and mast cells, possibly by mediating cleavage of CDH2, thereby acting as a mediator of peripheral thermal nociception and inflammatory hyperalgesia. Key regulator of neural stem cells quiescence by mediating cleavage of CDH2, affecting CDH2-mediated anchorage of neural stem cells to ependymocytes in the adult subependymal zone, leading to modulate their quiescence. May play a role in axonal growth. Able to activate progelatinase A. May also be a proteoglycanase involved in degradation of proteoglycans, such as dermatan sulfate and chondroitin sulfate proteoglycans. Cleaves partially fibronectin, but not collagen type I, nor laminin.
• Tissue Specificity: Predominantly expressed in brain, kidney, pancreas and lung. Overexpressed in a series of brain tumors, including astrocytomas and glioblastomas.
• KEGG Pathway: Parathyroid hormone synthesis, secretion and action (hsa04928)
• Reactome Pathway: Activation of Matrix Metalloproteinases (R-HSA-1592389)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Multiple sclerosis	DISB2WZI	Definitive	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[2]
Brain neoplasm	DISY3EKS	Strong	Altered Expression	[3]
Chronic renal failure	DISGG7K6	Strong	Biomarker	[4]
End-stage renal disease	DISXA7GG	Strong	Biomarker	[4]
Endometriosis	DISX1AG8	Strong	Biomarker	[5]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[3]
Plasma cell myeloma	DIS0DFZ0	Strong	Biomarker	[6]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[4]
Gastric cancer	DISXGOUK	moderate	Biomarker	[7]
Stomach cancer	DISKIJSX	moderate	Biomarker	[7]
Neoplasm	DISZKGEW	Disputed	Biomarker	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Matrix metalloproteinase-24 (MMP24).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Matrix metalloproteinase-24 (MMP24).	[10]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Matrix metalloproteinase-24 (MMP24).	[11]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Matrix metalloproteinase-24 (MMP24).	[12]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Matrix metalloproteinase-24 (MMP24).	[13]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Matrix metalloproteinase-24 (MMP24).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Matrix metalloproteinase-24 (MMP24).	[16]

1 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 Matrix metalloproteinase-24 (MMP24).	[15]

References

• [1] Inflammatory proprotein convertase-matrix metalloproteinase proteolytic pathway in antigen-presenting cells as a step to autoimmune multiple sclerosis.J Biol Chem. 2009 Oct 30;284(44):30615-26. doi: 10.1074/jbc.M109.041244. Epub 2009 Sep 2.
• [2] Emerging Alternative Proteinases in APP Metabolism and Alzheimer's Disease Pathogenesis: A Focus on MT1-MMP and MT5-MMP.Front Aging Neurosci. 2019 Sep 24;11:244. doi: 10.3389/fnagi.2019.00244. eCollection 2019.
• [3] Identification and characterization of human MT5-MMP, a new membrane-bound activator of progelatinase a overexpressed in brain tumors.Cancer Res. 1999 Jun 1;59(11):2570-6.
• [4] Upregulated expression of human membrane type-5 matrix metalloproteinase in kidneys from diabetic patients.Am J Physiol Renal Physiol. 2001 Aug;281(2):F309-17. doi: 10.1152/ajprenal.2001.281.2.F309.
• [5] Expression of membrane-type 5 matrix metalloproteinase in human endometrium and endometriosis.Gynecol Endocrinol. 2007 Oct;23(10):567-73. doi: 10.1080/09513590701556921.
• [6] Human beta-defensin-1 and -2 and matrix metalloproteinase-25 and -26 expression in chronic and aggressive periodontitis and in peri-implantitis.Arch Oral Biol. 2008 Feb;53(2):175-86. doi: 10.1016/j.archoralbio.2007.09.010. Epub 2007 Nov 9.
• [7] Inactivation of Capicua drives cancer metastasis.Nat Genet. 2017 Jan;49(1):87-96. doi: 10.1038/ng.3728. Epub 2016 Nov 21.
• [8] Extracellular gamma-synuclein promotes tumor cell motility by activating 1 integrin-focal adhesion kinase signaling pathway and increasing matrix metalloproteinase-24, -2 protein secretion.J Exp Clin Cancer Res. 2018 Jun 15;37(1):117. doi: 10.1186/s13046-018-0783-6.
• [9] 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.
• [10] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [11] Inhibition of invasion and induction of apoptosis by selenium in human malignant brain tumour cells in vitro. Int J Oncol. 2007 May;30(5):1263-71.
• [12] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] 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.
• [15] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [16] 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.