Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTI8X2WQ)

• DOT Name: Dynamin-1 (DNM1)
• Synonyms: EC 3.6.5.5; Dynamin; Dynamin I
• Gene Name: DNM1
• Related Disease:
  Infantile spasm
  Developmental and epileptic encephalopathy 31B
  Developmental and epileptic encephalopathy, 31
  LennoxGastaut syndrome
  Undetermined early-onset epileptic encephalopathy
• UniProt ID: DYN1_HUMAN
• PDB ID: 1DYN; 2DYN; 2X2E; 2X2F; 3SNH; 3ZYC; 3ZYS; 4UUD; 4UUK; 5D3Q; 6DLU; 6DLV; 6S9A; 7AX3
• EC Number: 3.6.5.5
• Pfam ID: PF01031 ; PF00350 ; PF02212 ; PF00169
• Sequence:
  MGNRGMEDLIPLVNRLQDAFSAIGQNADLDLPQIAVVGGQSAGKSSVLENFVGRDFLPRG
  SGIVTRRPLVLQLVNATTEYAEFLHCKGKKFTDFEEVRLEIEAETDRVTGTNKGISPVPI
  NLRVYSPHVLNLTLVDLPGMTKVPVGDQPPDIEFQIRDMLMQFVTKENCLILAVSPANSD
  LANSDALKVAKEVDPQGQRTIGVITKLDLMDEGTDARDVLENKLLPLRRGYIGVVNRSQK
  DIDGKKDITAALAAERKFFLSHPSYRHLADRMGTPYLQKVLNQQLTNHIRDTLPGLRNKL
  QSQLLSIEKEVEEYKNFRPDDPARKTKALLQMVQQFAVDFEKRIEGSGDQIDTYELSGGA
  RINRIFHERFPFELVKMEFDEKELRREISYAIKNIHGIRTGLFTPDMAFETIVKKQVKKI
  REPCLKCVDMVISELISTVRQCTKKLQQYPRLREEMERIVTTHIREREGRTKEQVMLLID
  IELAYMNTNHEDFIGFANAQQRSNQMNKKKTSGNQDEILVIRKGWLTINNIGIMKGGSKE
  YWFVLTAENLSWYKDDEEKEKKYMLSVDNLKLRDVEKGFMSSKHIFALFNTEQRNVYKDY
  RQLELACETQEEVDSWKASFLRAGVYPERVGDKEKASETEENGSDSFMHSMDPQLERQVE
  TIRNLVDSYMAIVNKTVRDLMPKTIMHLMINNTKEFIFSELLANLYSCGDQNTLMEESAE
  QAQRRDEMLRMYHALKEALSIIGDINTTTVSTPMPPPVDDSWLQVQSVPAGRRSPTSSPT
  PQRRAPAVPPARPGSRGPAPGPPPAGSALGGAPPVPSRPGASPDPFGPPPQVPSRPNRAP
  PGVPSRSGQASPSRPESPRPPFDL
• Function: Catalyzes the hydrolysis of GTP and utilizes this energy to mediate vesicle scission and participates in many forms of endocytosis, such as clathrin-mediated endocytosis or synaptic vesicle endocytosis as well as rapid endocytosis (RE). Associates to the membrane, through lipid binding, and self-assembles into rings and stacks of interconnected rings through oligomerization to form a helical polymer around the vesicle membrane leading to constriction of invaginated coated pits around their necks. Self-assembly of the helical polymer induces membrane tubules narrowing until the polymer reaches a length sufficient to trigger GTP hydrolysis. Depending on the curvature imposed on the tubules, membrane detachment from the helical polymer upon GTP hydrolysis can cause spontaneous hemifission followed by complete fission. May play a role in regulating early stages of clathrin-mediated endocytosis in non-neuronal cells through its activation by dephosphorylation via the signaling downstream of EGFR. Controls vesicle size at a step before fission, during formation of membrane pits, at hippocampal synapses. Controls plastic adaptation of the synaptic vesicle recycling machinery to high levels of activity. Mediates rapid endocytosis (RE), a Ca(2+)-dependent and clathrin- and K(+)-independent process in chromaffin cells. Microtubule-associated force-producing protein involved in producing microtubule bundles and able to bind and hydrolyze GTP. Through its interaction with DNAJC6, acts during the early steps of clathrin-coated vesicle (CCV) formation.
• KEGG Pathway:
  Phospholipase D sig.ling pathway (hsa04072)
  Endocytosis (hsa04144)
  Sy.ptic vesicle cycle (hsa04721)
  Endocrine and other factor-regulated calcium reabsorption (hsa04961)
  Bacterial invasion of epithelial cells (hsa05100)
• Reactome Pathway:
  Retrograde neurotrophin signalling (R-HSA-177504)
  Gap junction degradation (R-HSA-190873)
  Formation of annular gap junctions (R-HSA-196025)
  MHC class II antigen presentation (R-HSA-2132295)
  EPH-ephrin mediated repulsion of cells (R-HSA-3928665)
  Recycling pathway of L1 (R-HSA-437239)
  Clathrin-mediated endocytosis (R-HSA-8856828)
  Toll Like Receptor 4 (TLR4) Cascade (R-HSA-166016)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Infantile spasm	DISZSKDG	Definitive	Autosomal dominant	[1]
Developmental and epileptic encephalopathy 31B	DISF2TMI	Strong	Autosomal recessive	[2]
Developmental and epileptic encephalopathy, 31	DISVPP9Z	Strong	Autosomal dominant	[3]
LennoxGastaut syndrome	DISOTGO5	Supportive	Autosomal dominant	[4]
Undetermined early-onset epileptic encephalopathy	DISISEI2	Supportive	Autosomal dominant	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Dynamin-1 (DNM1).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Dynamin-1 (DNM1).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Dynamin-1 (DNM1).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Dynamin-1 (DNM1).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Dynamin-1 (DNM1).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Dynamin-1 (DNM1).	[10]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Dynamin-1 (DNM1).	[11]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Dynamin-1 (DNM1).	[12]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Dynamin-1 (DNM1).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Dynamin-1 (DNM1).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Dynamin-1 (DNM1).	[15]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Dynamin-1 (DNM1).	[17]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Dynamin-1 (DNM1).	[18]
Butanoic acid	DMTAJP7	Investigative	Butanoic acid increases the expression of Dynamin-1 (DNM1).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Dynamin-1 (DNM1).	[16]

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] Loss-of-function variants in DNM1 cause a specific form of developmental and epileptic encephalopathy only in biallelic state. J Med Genet. 2022 Jun;59(6):549-553. doi: 10.1136/jmedgenet-2021-107769. Epub 2021 Jun 25.
• [3] A selective activity-dependent requirement for dynamin 1 in synaptic vesicle endocytosis. Science. 2007 Apr 27;316(5824):570-4. doi: 10.1126/science.1140621.
• [4] De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies. Am J Hum Genet. 2014 Oct 2;95(4):360-70. doi: 10.1016/j.ajhg.2014.08.013. Epub 2014 Sep 25.
• [5] 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.
• [6] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [7] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [8] 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.
• [9] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [10] 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.
• [11] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [12] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [13] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [18] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.
• [19] MS4A3-HSP27 target pathway reveals potential for haematopoietic disorder treatment in alimentary toxic aleukia. Cell Biol Toxicol. 2023 Feb;39(1):201-216. doi: 10.1007/s10565-021-09639-4. Epub 2021 Sep 28.