Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRQ0A4W)

DOT Name E3 ubiquitin-protein ligase NHLRC1 (NHLRC1)
Synonyms EC 2.3.2.27; Malin; NHL repeat-containing protein 1; RING-type E3 ubiquitin transferase NHLRC1
Gene Name NHLRC1
Related Disease
Lafora disease ( )
Action myoclonus-renal failure syndrome ( )
Dentatorubral-pallidoluysian atrophy ( )
Epilepsy ( )
Progressive myoclonus epilepsy ( )
UniProt ID
NHLC1_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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EC Number
2.3.2.27
Pfam ID
PF14634
Sequence
MAAEASESGPALHELMREAEISLLECKVCFEKFGHRQQRRPRNLSCGHVVCLACVAALAH
PRTLALECPFCRRACRGCDTSDCLPVLHLIELLGSALRQSPAAHRAAPSAPGALTCHHTF
GGWGTLVNPTGLALCPKTGRVVVVHDGRRRVKIFDSGGGCAHQFGEKGDAAQDIRYPVDV
TITNDCHVVVTDAGDRSIKVFDFFGQIKLVIGGQFSLPWGVETTPQNGIVVTDAEAGSLH
LLDVDFAEGVLRRTERLQAHLCNPRGVAVSWLTGAIAVLEHPLALGTGVCSTRVKVFSSS
MQLVGQVDTFGLSLYFPSKITASAVTFDHQGNVIVADTSGPAILCLGKPEEFPVPKPMVT
HGLSHPVALTFTKENSLLVLDTASHSIKVYKVDWG
Function
E3 ubiquitin-protein ligase. Together with the phosphatase EPM2A/laforin, appears to be involved in the clearance of toxic polyglucosan and protein aggregates via multiple pathways. In complex with EPM2A/laforin and HSP70, suppresses the cellular toxicity of misfolded proteins by promoting their degradation through the ubiquitin-proteasome system (UPS). Ubiquitinates the glycogen-targeting protein phosphatase subunits PPP1R3C/PTG and PPP1R3D in a laforin-dependent manner and targets them for proteasome-dependent degradation, thus decreasing glycogen accumulation. Polyubiquitinates EPM2A/laforin and ubiquitinates AGL and targets them for proteasome-dependent degradation. Also promotes proteasome-independent protein degradation through the macroautophagy pathway.
Tissue Specificity Expressed in brain, cerebellum, spinal cord, medulla, heart, liver, skeletal muscle and pancreas.
KEGG Pathway
Ubiquitin mediated proteolysis (hsa04120 )
Reactome Pathway
Myoclonic epilepsy of Lafora (R-HSA-3785653 )
Glycogen synthesis (R-HSA-3322077 )

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Lafora disease DIS83JHH Definitive Autosomal recessive [1]
Action myoclonus-renal failure syndrome DISI2BZN Strong Biomarker [2]
Dentatorubral-pallidoluysian atrophy DISHWE0K Strong Biomarker [2]
Epilepsy DISBB28L Strong Biomarker [3]
Progressive myoclonus epilepsy DISAMCNS Strong Genetic Variation [4]
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Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
2 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
Valproate DMCFE9I Approved Valproate decreases the methylation of E3 ubiquitin-protein ligase NHLRC1 (NHLRC1). [5]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene increases the methylation of E3 ubiquitin-protein ligase NHLRC1 (NHLRC1). [9]
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3 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Cisplatin DMRHGI9 Approved Cisplatin increases the expression of E3 ubiquitin-protein ligase NHLRC1 (NHLRC1). [6]
Pantothenic acid DM091H2 Approved Pantothenic acid increases the expression of E3 ubiquitin-protein ligase NHLRC1 (NHLRC1). [7]
Urethane DM7NSI0 Phase 4 Urethane decreases the expression of E3 ubiquitin-protein ligase NHLRC1 (NHLRC1). [8]
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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 A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy. Nat Genet. 2015 Jan;47(1):39-46. doi: 10.1038/ng.3144. Epub 2014 Nov 17.
3 Lafora progressive myoclonus epilepsy: disease course homogeneity in a genetic isolate.J Child Neurol. 2008 Feb;23(2):240-2. doi: 10.1177/0883073807309245.
4 Lafora disease.Epileptic Disord. 2016 Sep 1;18(S2):38-62. doi: 10.1684/epd.2016.0842.
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 Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
7 Calcium pantothenate modulates gene expression in proliferating human dermal fibroblasts. Exp Dermatol. 2009 Nov;18(11):969-78. doi: 10.1111/j.1600-0625.2009.00884.x. Epub 2009 Apr 8.
8 Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
9 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.