Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2JC9YR)

• DOT Name: Mitochondrial ubiquitin ligase activator of NFKB 1 (MUL1)
• Synonyms: EC 2.3.2.27; E3 SUMO-protein ligase MUL1; E3 ubiquitin-protein ligase MUL1; Growth inhibition and death E3 ligase; Mitochondrial-anchored protein ligase; Protein Hades; Putative NF-kappa-B-activating protein 266; RING finger protein 218; RING-type E3 ubiquitin transferase NFKB 1
• Gene Name: MUL1
• Related Disease:
  Clear cell renal carcinoma
  Endometrial carcinoma
  Lafora disease
  Acute myelogenous leukaemia
  Adult glioblastoma
  Adult lymphoma
  Angelman syndrome
  Autism
  Autoimmune disease
  Cerebellar ataxia
  Charcot marie tooth disease
  Colorectal carcinoma
  Epithelial ovarian cancer
  Fanconi anemia complementation group A
  Fanconi's anemia
  Gastric cancer
  Glioblastoma multiforme
  Head and neck cancer
  Head and neck carcinoma
  Hepatitis B virus infection
  Hepatocellular carcinoma
  Herpes simplex infection
  Intellectual disability
  Liver cancer
  Lung cancer
  Lung carcinoma
  Lymphoma
  Metastatic malignant neoplasm
  Neoplasm
  Neurodevelopmental disorder
  Non-small-cell lung cancer
  Ovarian cancer
  Ovarian neoplasm
  Pancreatic cancer
  Parkinson disease
  Pediatric lymphoma
  Plasma cell myeloma
  Prion disease
  Renal cell carcinoma
  Small lymphocytic lymphoma
  Stomach cancer
  Type-1/2 diabetes
  Von hippel-lindau disease
  Young-onset Parkinson disease
  Autosomal recessive juvenile Parkinson disease 2
  Breast neoplasm
  Liver cirrhosis
  Melanoma
  Rheumatoid arthritis
  Triple negative breast cancer
• UniProt ID: MUL1_HUMAN
• PDB ID: 6K2K; 6M2C; 6M2D
• EC Number: 2.3.2.27
• Pfam ID: PF12483 ; PF13920
• Sequence:
  MESGGRPSLCQFILLGTTSVVTAALYSVYRQKARVSQELKGAKKVHLGEDLKSILSEAPG
  KCVPYAVIEGAVRSVKETLNSQFVENCKGVIQRLTLQEHKMVWNRTTHLWNDCSKIIHQR
  TNTVPFDLVPHEDGVDVAVRVLKPLDSVDLGLETVYEKFHPSIQSFTDVIGHYISGERPK
  GIQETEEMLKVGATLTGVGELVLDNNSVRLQPPKQGMQYYLSSQDFDSLLQRQESSVRLW
  KVLALVFGFATCATLFFILRKQYLQRQERLRLKQMQEEFQEHEAQLLSRAKPEDRESLKS
  ACVVCLSSFKSCVFLECGHVCSCTECYRALPEPKKCPICRQAITRVIPLYNS
• Function: Exhibits weak E3 ubiquitin-protein ligase activity. E3 ubiquitin ligases accept ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfer the ubiquitin to targeted substrates. Can ubiquitinate AKT1 preferentially at 'Lys-284' involving 'Lys-48'-linked polyubiquitination and seems to be involved in regulation of Akt signaling by targeting phosphorylated Akt to proteasomal degradation. Mediates polyubiquitination of cytoplasmic TP53 at 'Lys-24' which targets TP53 for proteasomal degradation, thus reducing TP53 levels in the cytoplasm and mitochondrion. Proposed to preferentially act as a SUMO E3 ligase at physiological concentrations. Plays a role in the control of mitochondrial morphology by promoting mitochondrial fragmentation, and influences mitochondrial localization. Likely to promote mitochondrial fission through negatively regulating the mitochondrial fusion proteins MFN1 and MFN2, acting in a pathway that is parallel to the PRKN/PINK1 regulatory pathway. May also be involved in the sumoylation of the membrane fission protein DNM1L. Inhibits cell growth. When overexpressed, activates JNK through MAP3K7/TAK1 and induces caspase-dependent apoptosis. Involved in the modulation of innate immune defense against viruses by inhibiting RIGI-dependent antiviral response. Can mediate RIGI sumoylation and disrupt its polyubiquitination.
• Tissue Specificity: Widely expressed with highest levels in the heart, skeletal muscle, placenta, kidney and liver. Barely detectable in colon and thymus.
• KEGG Pathway: Mitophagy - animal (hsa04137)
• Reactome Pathway:
  Neddylation (R-HSA-8951664)
  KEAP1-NFE2L2 pathway (R-HSA-9755511)
  Ub-specific processing proteases (R-HSA-5689880)

Molecular Interaction Atlas (MIA) of This DOT

50 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Clear cell renal carcinoma	DISBXRFJ	Definitive	Altered Expression	[1]
Endometrial carcinoma	DISXR5CY	Definitive	Genetic Variation	[2]
Lafora disease	DIS83JHH	Definitive	Biomarker	[3]
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[4]
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[5]
Adult lymphoma	DISK8IZR	Strong	Altered Expression	[6]
Angelman syndrome	DIS4QVXO	Strong	Genetic Variation	[7]
Autism	DISV4V1Z	Strong	Genetic Variation	[8]
Autoimmune disease	DISORMTM	Strong	Altered Expression	[9]
Cerebellar ataxia	DIS9IRAV	Strong	Biomarker	[10]
Charcot marie tooth disease	DIS3BT2L	Strong	Genetic Variation	[11]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[12]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[13]
Fanconi anemia complementation group A	DIS8PZLI	Strong	Biomarker	[14]
Fanconi's anemia	DISGW6Q8	Strong	Biomarker	[14]
Gastric cancer	DISXGOUK	Strong	Biomarker	[15]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[5]
Head and neck cancer	DISBPSQZ	Strong	Altered Expression	[16]
Head and neck carcinoma	DISOU1DS	Strong	Altered Expression	[16]
Hepatitis B virus infection	DISLQ2XY	Strong	Altered Expression	[17]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[18]
Herpes simplex infection	DISL1SAV	Strong	Biomarker	[19]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[20]
Liver cancer	DISDE4BI	Strong	Biomarker	[21]
Lung cancer	DISCM4YA	Strong	Altered Expression	[22]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[22]
Lymphoma	DISN6V4S	Strong	Altered Expression	[6]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[23]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[24]
Neurodevelopmental disorder	DIS372XH	Strong	Genetic Variation	[25]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[26]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[13]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[13]
Pancreatic cancer	DISJC981	Strong	Altered Expression	[27]
Parkinson disease	DISQVHKL	Strong	Genetic Variation	[28]
Pediatric lymphoma	DIS51BK2	Strong	Altered Expression	[6]
Plasma cell myeloma	DIS0DFZ0	Strong	Altered Expression	[29]
Prion disease	DISOUMB0	Strong	Biomarker	[30]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[1]
Small lymphocytic lymphoma	DIS30POX	Strong	Genetic Variation	[31]
Stomach cancer	DISKIJSX	Strong	Biomarker	[15]
Type-1/2 diabetes	DISIUHAP	Strong	Genetic Variation	[32]
Von hippel-lindau disease	DIS6ZFQQ	Strong	Biomarker	[33]
Young-onset Parkinson disease	DIS05LFS	Strong	Genetic Variation	[34]
Autosomal recessive juvenile Parkinson disease 2	DISNSTD1	Limited	Altered Expression	[35]
Breast neoplasm	DISNGJLM	Limited	Altered Expression	[36]
Liver cirrhosis	DIS4G1GX	Limited	Biomarker	[37]
Melanoma	DIS1RRCY	Limited	Biomarker	[38]
Rheumatoid arthritis	DISTSB4J	Limited	Biomarker	[39]
Triple negative breast cancer	DISAMG6N	Limited	Biomarker	[40]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Mitochondrial ubiquitin ligase activator of NFKB 1 (MUL1).	[41]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Mitochondrial ubiquitin ligase activator of NFKB 1 (MUL1).	[42]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Mitochondrial ubiquitin ligase activator of NFKB 1 (MUL1).	[44]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Mitochondrial ubiquitin ligase activator of NFKB 1 (MUL1).	[43]

References

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