Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXK1Q1G)

• DOT Name: Dynamin-1-like protein (DNM1L)
• Synonyms: EC 3.6.5.5; Dnm1p/Vps1p-like protein; DVLP; Dynamin family member proline-rich carboxyl-terminal domain less; Dymple; Dynamin-like protein; Dynamin-like protein 4; Dynamin-like protein IV; HdynIV; Dynamin-related protein 1
• Gene Name: DNM1L
• Related Disease:
  Cardiomyopathy
  Encephalopathy due to mitochondrial and peroxisomal fission defect
  Melanoma
  Pancreatic cancer
  Subarachnoid hemorrhage
  Alzheimer disease
  Amyotrophic lateral sclerosis
  Breast cancer
  Breast carcinoma
  Cardiac failure
  Cerebral infarction
  Chronic renal failure
  Colon cancer
  Colon carcinoma
  Congestive heart failure
  Dilated cardiomyopathy
  Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1
  Epithelial ovarian cancer
  Hepatocellular carcinoma
  High blood pressure
  Huntington disease
  Hyperglycemia
  Isolated congenital microcephaly
  Lactic acidosis
  Lung adenocarcinoma
  Microlissencephaly
  Mitochondrial disease
  Mitochondrial encephalomyopathy
  Multiple sclerosis
  Myocardial infarction
  Myocardial ischemia
  Neoplasm
  Non-insulin dependent diabetes
  Non-small-cell lung cancer
  Optic atrophy 5
  Prostate cancer
  Prostate carcinoma
  Pulmonary fibrosis
  Status epilepticus seizure
  Type-1/2 diabetes
  Diabetic kidney disease
  Parkinson disease
  Autosomal dominant optic atrophy, classic form
  Advanced cancer
  B-cell neoplasm
  Gastric cancer
  Leigh syndrome
  Neuroblastoma
  Stomach cancer
• UniProt ID: DNM1L_HUMAN
• PDB ID: 3W6N; 3W6O; 3W6P; 4BEJ; 4H1U; 4H1V; 5WP9
• EC Number: 3.6.5.5
• Pfam ID: PF01031 ; PF00350 ; PF02212
• Sequence:
  MEALIPVINKLQDVFNTVGADIIQLPQIVVVGTQSSGKSSVLESLVGRDLLPRGTGIVTR
  RPLILQLVHVSQEDKRKTTGEENGVEAEEWGKFLHTKNKLYTDFDEIRQEIENETERISG
  NNKGVSPEPIHLKIFSPNVVNLTLVDLPGMTKVPVGDQPKDIELQIRELILRFISNPNSI
  ILAVTAANTDMATSEALKISREVDPDGRRTLAVITKLDLMDAGTDAMDVLMGRVIPVKLG
  IIGVVNRSQLDINNKKSVTDSIRDEYAFLQKKYPSLANRNGTKYLARTLNRLLMHHIRDC
  LPELKTRINVLAAQYQSLLNSYGEPVDDKSATLLQLITKFATEYCNTIEGTAKYIETSEL
  CGGARICYIFHETFGRTLESVDPLGGLNTIDILTAIRNATGPRPALFVPEVSFELLVKRQ
  IKRLEEPSLRCVELVHEEMQRIIQHCSNYSTQELLRFPKLHDAIVEVVTCLLRKRLPVTN
  EMVHNLVAIELAYINTKHPDFADACGLMNNNIEEQRRNRLARELPSAVSRDKSSKVPSAL
  APASQEPSPAASAEADGKLIQDSRRETKNVASGGGGVGDGVQEPTTGNWRGMLKTSKAEE
  LLAEEKSKPIPIMPASPQKGHAVNLLDVPVPVARKLSAREQRDCEVIERLIKSYFLIVRK
  NIQDSVPKAVMHFLVNHVKDTLQSELVGQLYKSSLLDDLLTESEDMAQRRKEAADMLKAL
  QGASQIIAEIRETHLW
• Function: Functions in mitochondrial and peroxisomal division. Mediates membrane fission through oligomerization into membrane-associated tubular structures that wrap around the scission site to constrict and sever the mitochondrial membrane through a GTP hydrolysis-dependent mechanism. The specific recruitment at scission sites is mediated by membrane receptors like MFF, MIEF1 and MIEF2 for mitochondrial membranes. While the recruitment by the membrane receptors is GTP-dependent, the following hydrolysis of GTP induces the dissociation from the receptors and allows DNM1L filaments to curl into closed rings that are probably sufficient to sever a double membrane. Acts downstream of PINK1 to promote mitochondrial fission in a PRKN-dependent manner. Plays an important role in mitochondrial fission during mitosis. Through its function in mitochondrial division, ensures the survival of at least some types of postmitotic neurons, including Purkinje cells, by suppressing oxidative damage. Required for normal brain development, including that of cerebellum. Facilitates developmentally regulated apoptosis during neural tube formation. Required for a normal rate of cytochrome c release and caspase activation during apoptosis; this requirement may depend upon the cell type and the physiological apoptotic cues. Required for formation of endocytic vesicles. Proposed to regulate synaptic vesicle membrane dynamics through association with BCL2L1 isoform Bcl-X(L) which stimulates its GTPase activity in synaptic vesicles; the function may require its recruitment by MFF to clathrin-containing vesicles. Required for programmed necrosis execution. Rhythmic control of its activity following phosphorylation at Ser-637 is essential for the circadian control of mitochondrial ATP production ; [Isoform 1]: Inhibits peroxisomal division when overexpressed; [Isoform 4]: Inhibits peroxisomal division when overexpressed.
• Tissue Specificity: Ubiquitously expressed with highest levels found in skeletal muscles, heart, kidney and brain. Isoform 1 is brain-specific. Isoform 2 and isoform 3 are predominantly expressed in testis and skeletal muscles respectively. Isoform 4 is weakly expressed in brain, heart and kidney. Isoform 5 is dominantly expressed in liver, heart and kidney. Isoform 6 is expressed in neurons.
• KEGG Pathway:
  Necroptosis (hsa04217)
  NOD-like receptor sig.ling pathway (hsa04621)
  TNF sig.ling pathway (hsa04668)
• Reactome Pathway: Apoptotic execution phase (R-HSA-75153)

Molecular Interaction Atlas (MIA) of This DOT

49 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cardiomyopathy	DISUPZRG	Definitive	Altered Expression	[1]
Encephalopathy due to mitochondrial and peroxisomal fission defect	DIS7RGZ4	Definitive	Autosomal dominant	[2]
Melanoma	DIS1RRCY	Definitive	Biomarker	[3]
Pancreatic cancer	DISJC981	Definitive	Genetic Variation	[4]
Subarachnoid hemorrhage	DISI7I8Y	Definitive	Biomarker	[5]
Alzheimer disease	DISF8S70	Strong	Biomarker	[6]
Amyotrophic lateral sclerosis	DISF7HVM	Strong	Altered Expression	[7]
Breast cancer	DIS7DPX1	Strong	Biomarker	[8]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[8]
Cardiac failure	DISDC067	Strong	Altered Expression	[9]
Cerebral infarction	DISR1WNP	Strong	Biomarker	[10]
Chronic renal failure	DISGG7K6	Strong	Therapeutic	[11]
Colon cancer	DISVC52G	Strong	Posttranslational Modification	[12]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[12]
Congestive heart failure	DIS32MEA	Strong	Altered Expression	[9]
Dilated cardiomyopathy	DISX608J	Strong	Biomarker	[13]
Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1	DISFGI5B	Strong	Autosomal recessive	[14]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[15]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[16]
High blood pressure	DISY2OHH	Strong	Biomarker	[17]
Huntington disease	DISQPLA4	Strong	Biomarker	[18]
Hyperglycemia	DIS0BZB5	Strong	Biomarker	[10]
Isolated congenital microcephaly	DISUXHZ6	Strong	Genetic Variation	[19]
Lactic acidosis	DISZI1ZK	Strong	Biomarker	[20]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[21]
Microlissencephaly	DISUCKNT	Strong	Biomarker	[20]
Mitochondrial disease	DISKAHA3	Strong	Biomarker	[22]
Mitochondrial encephalomyopathy	DISA6PTN	Strong	Biomarker	[20]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[23]
Myocardial infarction	DIS655KI	Strong	Biomarker	[24]
Myocardial ischemia	DISFTVXF	Strong	Biomarker	[25]
Neoplasm	DISZKGEW	Strong	Altered Expression	[26]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[27]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[28]
Optic atrophy 5	DISE932D	Strong	Autosomal dominant	[29]
Prostate cancer	DISF190Y	Strong	Altered Expression	[30]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[30]
Pulmonary fibrosis	DISQKVLA	Strong	Biomarker	[31]
Status epilepticus seizure	DISY3BIC	Strong	Genetic Variation	[32]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[33]
Diabetic kidney disease	DISJMWEY	moderate	Biomarker	[34]
Parkinson disease	DISQVHKL	moderate	Biomarker	[35]
Autosomal dominant optic atrophy, classic form	DISXUAV9	Supportive	Autosomal dominant	[29]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[36]
B-cell neoplasm	DISVY326	Limited	Altered Expression	[37]
Gastric cancer	DISXGOUK	Limited	Biomarker	[38]
Leigh syndrome	DISWQU45	Limited	Autosomal recessive	[2]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[39]
Stomach cancer	DISKIJSX	Limited	Biomarker	[38]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Dynamin-1-like protein (DNM1L) increases the response to substance of Cisplatin.	[65]
Azide	DM5XZYB	Investigative	Dynamin-1-like protein (DNM1L) increases the response to substance of Azide.	[65]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Dynamin-1-like protein (DNM1L).	[40]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Dynamin-1-like protein (DNM1L).	[41]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Dynamin-1-like protein (DNM1L).	[42]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Dynamin-1-like protein (DNM1L).	[44]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Dynamin-1-like protein (DNM1L).	[45]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Dynamin-1-like protein (DNM1L).	[46]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Dynamin-1-like protein (DNM1L).	[47]
Simvastatin	DM30SGU	Approved	Simvastatin increases the expression of Dynamin-1-like protein (DNM1L).	[48]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Dynamin-1-like protein (DNM1L).	[51]
CERC-801	DM3SZ7P	Phase 2	CERC-801 increases the expression of Dynamin-1-like protein (DNM1L).	[52]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Dynamin-1-like protein (DNM1L).	[54]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Dynamin-1-like protein (DNM1L).	[50]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Dynamin-1-like protein (DNM1L).	[55]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Dynamin-1-like protein (DNM1L).	[56]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Dynamin-1-like protein (DNM1L).	[46]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Dynamin-1-like protein (DNM1L).	[57]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of Dynamin-1-like protein (DNM1L).	[58]
D-glucose	DMMG2TO	Investigative	D-glucose increases the expression of Dynamin-1-like protein (DNM1L).	[59]
Forskolin	DM6ITNG	Investigative	Forskolin decreases the expression of Dynamin-1-like protein (DNM1L).	[60]
Cycloheximide	DMGDA3C	Investigative	Cycloheximide increases the expression of Dynamin-1-like protein (DNM1L).	[61]
Sanggenon C	DMSF5DW	Investigative	Sanggenon C decreases the expression of Dynamin-1-like protein (DNM1L).	[64]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Estradiol increases the phosphorylation of Dynamin-1-like protein (DNM1L).	[43]
Sodium phenylbutyrate	DMXLBCQ	Approved	Sodium phenylbutyrate increases the phosphorylation of Dynamin-1-like protein (DNM1L).	[49]
Verapamil	DMA7PEW	Phase 2/3 Trial	Verapamil increases the phosphorylation of Dynamin-1-like protein (DNM1L).	[43]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Dynamin-1-like protein (DNM1L).	[53]
Oleic acid	DM54O1Z	Investigative	Oleic acid affects the phosphorylation of Dynamin-1-like protein (DNM1L).	[62]
aconitine	DMFOZ60	Investigative	aconitine increases the phosphorylation of Dynamin-1-like protein (DNM1L).	[63]
PHTPP	DMBHKAV	Investigative	PHTPP decreases the phosphorylation of Dynamin-1-like protein (DNM1L).	[43]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Efavirenz	DMC0GSJ	Approved	Efavirenz affects the localization of Dynamin-1-like protein (DNM1L).	[50]

References

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