Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUYU2U3)

• DOT Name: Dynamin-2 (DNM2)
• Synonyms: EC 3.6.5.5; Dynamin 2; Dynamin II
• Gene Name: DNM2
• Related Disease:
  Autosomal dominant centronuclear myopathy
  Charcot marie tooth disease
  Charcot-Marie-Tooth disease dominant intermediate B
  Autosomal dominant Charcot-Marie-Tooth disease type 2M
  Fetal akinesia-cerebral and retinal hemorrhage syndrome
  Hereditary spastic paraplegia
• UniProt ID: DYN2_HUMAN
• PDB ID: 2YS1
• EC Number: 3.6.5.5
• Pfam ID: PF01031 ; PF00350 ; PF02212 ; PF00169
• Sequence:
  MGNRGMEELIPLVNKLQDAFSSIGQSCHLDLPQIAVVGGQSAGKSSVLENFVGRDFLPRG
  SGIVTRRPLILQLIFSKTEHAEFLHCKSKKFTDFDEVRQEIEAETDRVTGTNKGISPVPI
  NLRVYSPHVLNLTLIDLPGITKVPVGDQPPDIEYQIKDMILQFISRESSLILAVTPANMD
  LANSDALKLAKEVDPQGLRTIGVITKLDLMDEGTDARDVLENKLLPLRRGYIGVVNRSQK
  DIEGKKDIRAALAAERKFFLSHPAYRHMADRMGTPHLQKTLNQQLTNHIRESLPALRSKL
  QSQLLSLEKEVEEYKNFRPDDPTRKTKALLQMVQQFGVDFEKRIEGSGDQVDTLELSGGA
  RINRIFHERFPFELVKMEFDEKDLRREISYAIKNIHGVRTGLFTPDLAFEAIVKKQVVKL
  KEPCLKCVDLVIQELINTVRQCTSKLSSYPRLREETERIVTTYIREREGRTKDQILLLID
  IEQSYINTNHEDFIGFANAQQRSTQLNKKRAIPNQGEILVIRRGWLTINNISLMKGGSKE
  YWFVLTAESLSWYKDEEEKEKKYMLPLDNLKIRDVEKGFMSNKHVFAIFNTEQRNVYKDL
  RQIELACDSQEDVDSWKASFLRAGVYPEKDQAENEDGAQENTFSMDPQLERQVETIRNLV
  DSYVAIINKSIRDLMPKTIMHLMINNTKAFIHHELLAYLYSSADQSSLMEESADQAQRRD
  DMLRMYHALKEALNIIGDISTSTVSTPVPPPVDDTWLQSASSHSPTPQRRPVSSIHPPGR
  PPAVRGPTPGPPLIPVPVGAAASFSAPPIPSRPGPQSVFANSDLFPAPPQIPSRPVRIPP
  GIPPGVPSRRPPAAPSRPTIIRPAEPSLLD
• Function: Catalyzes the hydrolysis of GTP and utilizes this energy to mediate vesicle scission at plasma membrane during endocytosis and filament remodeling at many actin structures during organization of the actin cytoskeleton. Plays an important role in vesicular trafficking processes, namely clathrin-mediated endocytosis (CME), exocytic and clathrin-coated vesicle from the trans-Golgi network, and PDGF stimulated macropinocytosis. During vesicular trafficking process, associates to the membrane, through lipid binding, and self-assembles into ring-like structure through oligomerization to form a helical polymer around the vesicle membrane and leading to vesicle scission. Plays a role in organization of the actin cytoskeleton by mediating arrangement of stress fibers and actin bundles in podocytes. During organization of the actin cytoskeleton, self-assembles into ring-like structure that directly bundles actin filaments to form typical membrane tubules decorated with dynamin spiral polymers. Self-assembly increases GTPase activity and the GTP hydrolysis causes the rapid depolymerization of dynamin spiral polymers, and results in dispersion of actin bundles. Remodels, through its interaction with CTTN, bundled actin filaments in a GTPase-dependent manner and plays a role in orchestrating the global actomyosin cytoskeleton. The interaction with CTTN stabilizes the interaction of DNM2 and actin filaments and stimulates the intrinsic GTPase activity that results in actin filament-barbed ends and increases the sensitivity of filaments in bundles to the actin depolymerizing factor, CFL1. Plays a role in the autophagy process, by participating in the formation of ATG9A vesicles destined for the autophagosomes through its interaction with SNX18 , by mediating recycling endosome scission leading to autophagosome release through MAP1LC3B interaction. Also regulates maturation of apoptotic cell corpse-containing phagosomes by recruiting PIK3C3 to the phagosome membrane. Also plays a role in cytokinesis. May participate in centrosome cohesion through its interaction with TUBG1. Plays a role in the regulation of neuron morphology, axon growth and formation of neuronal growth cones. Involved in membrane tubulation.
• Tissue Specificity: Widely expressed . Expressed in skeletal muscle and the peripheral nerve .
• KEGG Pathway:
  Phospholipase D sig.ling pathway (hsa04072)
  Endocytosis (hsa04144)
  Fc gamma R-mediated phagocytosis (hsa04666)
  Sy.ptic vesicle cycle (hsa04721)
  Endocrine and other factor-regulated calcium reabsorption (hsa04961)
  Bacterial invasion of epithelial cells (hsa05100)
  Salmonella infection (hsa05132)
• Reactome Pathway:
  Retrograde neurotrophin signalling (R-HSA-177504)
  Gap junction degradation (R-HSA-190873)
  Formation of annular gap junctions (R-HSA-196025)
  NOSTRIN mediated eNOS trafficking (R-HSA-203641)
  MHC class II antigen presentation (R-HSA-2132295)
  Lysosome Vesicle Biogenesis (R-HSA-432720)
  Golgi Associated Vesicle Biogenesis (R-HSA-432722)
  Recycling pathway of L1 (R-HSA-437239)
  Clathrin-mediated endocytosis (R-HSA-8856828)
  NGF-stimulated transcription (R-HSA-9031628)
  Toll Like Receptor 4 (TLR4) Cascade (R-HSA-166016)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal dominant centronuclear myopathy	DISF2XWP	Definitive	Autosomal dominant	[1]
Charcot marie tooth disease	DIS3BT2L	Definitive	Autosomal dominant	[1]
Charcot-Marie-Tooth disease dominant intermediate B	DIS98MAN	Strong	Autosomal dominant	[2]
Autosomal dominant Charcot-Marie-Tooth disease type 2M	DISH8AXJ	Supportive	Autosomal dominant	[3]
Fetal akinesia-cerebral and retinal hemorrhage syndrome	DISKHTKC	Supportive	Autosomal recessive	[4]
Hereditary spastic paraplegia	DISGZQV1	Limited	Autosomal dominant	[5]

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 Dynamin-2 (DNM2).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Dynamin-2 (DNM2).	[10]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Dynamin-2 (DNM2).	[12]

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 Dynamin-2 (DNM2).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Dynamin-2 (DNM2).	[8]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Dynamin-2 (DNM2).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Dynamin-2 (DNM2).	[11]
NS398	DMINUWH	Terminated	NS398 increases the expression of Dynamin-2 (DNM2).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Dynamin-2 (DNM2).	[14]
Z-Pro-Prolinal	DM43O2U	Investigative	Z-Pro-Prolinal increases the expression of Dynamin-2 (DNM2).	[15]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Dominant intermediate Charcot-Marie-Tooth neuropathy maps to chromosome 19p12-p13.2. Am J Hum Genet. 2001 Oct;69(4):883-8. doi: 10.1086/323743. Epub 2001 Aug 28.
• [3] A novel mutation in the dynamin 2 gene in a Charcot-Marie-Tooth type 2 patient: clinical and pathological findings. Neuromuscul Disord. 2008 Apr;18(4):334-8. doi: 10.1016/j.nmd.2008.01.005. Epub 2008 Apr 3.
• [4] Dynamin 2 homozygous mutation in humans with a lethal congenital syndrome. Eur J Hum Genet. 2013 Jun;21(6):637-42. doi: 10.1038/ejhg.2012.226. Epub 2012 Oct 24.
• [5] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] Detection of differentially expressed genes in human colon carcinoma cells treated with a selective COX-2 inhibitor. Oncogene. 2001 Jul 27;20(33):4450-6. doi: 10.1038/sj.onc.1204588.
• [14] MCM-2 is a therapeutic target of Trichostatin A in colon cancer cells. Toxicol Lett. 2013 Jul 31;221(1):23-30. doi: 10.1016/j.toxlet.2013.05.643. Epub 2013 Jun 13.
• [15] Prolyl endopeptidase is involved in cellular signalling in human neuroblastoma SH-SY5Y cells. Neurosignals. 2011;19(2):97-109. doi: 10.1159/000326342. Epub 2011 Apr 10.