Details of Drug Off-Target (DOT)

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

• DOT Name: Dematin (DMTN)
• Synonyms: Dematin actin-binding protein; Erythrocyte membrane protein band 4.9
• Gene Name: DMTN
• Related Disease:
  Tuberculosis
  Advanced cancer
  Anemia
  Anxiety
  Anxiety disorder
  Colorectal carcinoma
  Fuchs' endothelial dystrophy
  Gonorrhea
  Hemolytic anemia
  Hereditary spherocytosis
  Mixed anxiety and depressive disorder
  Mood disorder
  Multiple sclerosis
  Prostate adenocarcinoma
  Prostate cancer
  Prostate carcinoma
  Prostate neoplasm
  Alcohol dependence
• UniProt ID: DEMA_HUMAN
• PDB ID: 1QZP; 1ZV6
• Pfam ID: PF16182 ; PF02209
• Sequence:
  MERLQKQPLTSPGSVSPSRDSSVPGSPSSIVAKMDNQVLGYKDLAAIPKDKAILDIERPD
  LMIYEPHFTYSLLEHVELPRSRERSLSPKSTSPPPSPEVWADSRSPGIISQASAPRTTGT
  PRTSLPHFHHPETSRPDSNIYKKPPIYKQRESVGGSPQTKHLIEDLIIESSKFPAAQPPD
  PNQPAKIETDYWPCPPSLAVVETEWRKRKASRRGAEEEEEEEDDDSGEEMKALRERQREE
  LSKVTSNLGKMILKEEMEKSLPIRRKTRSLPDRTPFHTSLHQGTSKSSSLPAYGRTTLSR
  LQSTEFSPSGSETGSPGLQNGEGQRGRMDRGNSLPCVLEQKIYPYEMLVVTNKGRTKLPP
  GVDRMRLERHLSAEDFSRVFAMSPEEFGKLALWKRNELKKKASLF
• Function: Membrane-cytoskeleton-associated protein with F-actin-binding activity that induces F-actin bundles formation and stabilization. Its F-actin-bundling activity is reversibly regulated upon its phosphorylation by the cAMP-dependent protein kinase A (PKA). Binds to the erythrocyte membrane glucose transporter-1 SLC2A1/GLUT1, and hence stabilizes and attaches the spectrin-actin network to the erythrocytic plasma membrane. Plays a role in maintaining the functional integrity of PKA-activated erythrocyte shape and the membrane mechanical properties. Also plays a role as a modulator of actin dynamics in fibroblasts; acts as a negative regulator of the RhoA activation pathway. In platelets, functions as a regulator of internal calcium mobilization across the dense tubular system that affects platelet granule secretion pathways and aggregation. Also required for the formation of a diverse set of cell protrusions, such as filopodia and lamellipodia, necessary for platelet cell spreading, motility and migration. Acts as a tumor suppressor and inhibits malignant cell transformation.
• Tissue Specificity: Expressed in platelets (at protein level). Expressed in heart, brain, lung, skeletal muscle, and kidney.
• Reactome Pathway: Miscellaneous transport and binding events (R-HSA-5223345)

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Tuberculosis	DIS2YIMD	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Anemia	DISTVL0C	Strong	Biomarker	[3]
Anxiety	DISIJDBA	Strong	Genetic Variation	[4]
Anxiety disorder	DISBI2BT	Strong	Genetic Variation	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[2]
Fuchs' endothelial dystrophy	DISL7TXC	Strong	Genetic Variation	[5]
Gonorrhea	DISQ5AO6	Strong	Genetic Variation	[6]
Hemolytic anemia	DIS803XQ	Strong	Genetic Variation	[7]
Hereditary spherocytosis	DISQYJP5	Strong	Genetic Variation	[8]
Mixed anxiety and depressive disorder	DISV809X	Strong	Biomarker	[4]
Mood disorder	DISLVMWO	Strong	Biomarker	[6]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[9]
Prostate adenocarcinoma	DISBZYU8	Strong	Biomarker	[8]
Prostate cancer	DISF190Y	Strong	Biomarker	[8]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[8]
Prostate neoplasm	DISHDKGQ	Strong	Genetic Variation	[8]
Alcohol dependence	DIS4ZSCO	moderate	Genetic Variation	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Dematin (DMTN).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Dematin (DMTN).	[17]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Dematin (DMTN).	[20]

9 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 Dematin (DMTN).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Dematin (DMTN).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Dematin (DMTN).	[14]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Dematin (DMTN).	[15]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of Dematin (DMTN).	[16]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Dematin (DMTN).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Dematin (DMTN).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Dematin (DMTN).	[21]
cinnamaldehyde	DMZDUXG	Investigative	cinnamaldehyde increases the expression of Dematin (DMTN).	[22]

References

• [1] A Multistage Subunit Vaccine Effectively Protects Mice Against Primary Progressive Tuberculosis, Latency and Reactivation.EBioMedicine. 2017 Aug;22:143-154. doi: 10.1016/j.ebiom.2017.07.005. Epub 2017 Jul 8.
• [2] Hypermethylation of DMTN promotes the metastasis of colorectal cancer cells by regulating the actin cytoskeleton through Rac1 signaling activation.J Exp Clin Cancer Res. 2018 Dec 4;37(1):299. doi: 10.1186/s13046-018-0958-1.
• [3] Headpiece domain of dematin is required for the stability of the erythrocyte membrane.Proc Natl Acad Sci U S A. 2002 May 14;99(10):6637-42. doi: 10.1073/pnas.052155999.
• [4] 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) used in a naturalistic group setting is associated with unintended improvements in depression and anxiety.Am J Drug Alcohol Abuse. 2019;45(2):161-169. doi: 10.1080/00952990.2018.1545024. Epub 2019 Mar 1.
• [5] Regenerative Therapy for Fuchs Endothelial Corneal Dystrophy.Cornea. 2018 Apr;37(4):523-527. doi: 10.1097/ICO.0000000000001518.
• [6] A Single Dose of 5-MeO-DMT Stimulates Cell Proliferation, Neuronal Survivability, Morphological and Functional Changes in Adult Mice Ventral Dentate Gyrus.Front Mol Neurosci. 2018 Sep 4;11:312. doi: 10.3389/fnmol.2018.00312. eCollection 2018.
• [7] Combined deletion of mouse dematin-headpiece and beta-adducin exerts a novel effect on the spectrin-actin junctions leading to erythrocyte fragility and hemolytic anemia.J Biol Chem. 2007 Feb 9;282(6):4124-35. doi: 10.1074/jbc.M610231200. Epub 2006 Dec 2.
• [8] Loss of heterozygosity on 8p in prostate cancer implicates a role for dematin in tumor progression.Cancer Genet Cytogenet. 1999 Nov;115(1):65-9. doi: 10.1016/s0165-4608(99)00081-3.
• [9] Use of the new oral disease-modifying therapies for multiple sclerosis in British Columbia, Canada: the first five-years.Mult Scler Relat Disord. 2018 Oct;25:57-60. doi: 10.1016/j.msard.2018.07.012. Epub 2018 Jul 9.
• [10] The epidemiology of 5-methoxy- N, N-dimethyltryptamine (5-MeO-DMT) use: Benefits, consequences, patterns of use, subjective effects, and reasons for consumption.J Psychopharmacol. 2018 Jul;32(7):779-792. doi: 10.1177/0269881118769063. Epub 2018 Apr 30.
• [11] 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.
• [12] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [13] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [14] 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.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [17] 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.
• [18] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [19] 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.
• [20] 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.
• [21] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [22] Comparative DNA microarray analysis of human monocyte derived dendritic cells and MUTZ-3 cells exposed to the moderate skin sensitizer cinnamaldehyde. Toxicol Appl Pharmacol. 2009 Sep 15;239(3):273-83.