Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBTA03N)

• DOT Name: E3 ubiquitin-protein ligase MARCHF6 (MARCHF6)
• Synonyms: EC 2.3.2.27; Doa10 homolog; Membrane-associated RING finger protein 6; Membrane-associated RING-CH protein VI; MARCH-VI; Protein TEB-4; RING finger protein 176; RING-type E3 ubiquitin transferase MARCHF6
• Gene Name: MARCHF6
• Related Disease:
  Bacterial arthritis
  Cardiac failure
  Chronic kidney disease
  Congestive heart failure
  Cutaneous anthrax
  Epilepsy
  Gastric cancer
  Infective arthritis
  Liver cirrhosis
  Polyp
  Prostate cancer
  Prostate carcinoma
  Schizophrenia
  Stomach cancer
  Renal fibrosis
  Benign adult familial myoclonic epilepsy
• UniProt ID: MARH6_HUMAN
• EC Number: 2.3.2.27
• Pfam ID: PF12906
• Sequence:
  MDTAEEDICRVCRSEGTPEKPLYHPCVCTGSIKFIHQECLVQWLKHSRKEYCELCKHRFA
  FTPIYSPDMPSRLPIQDIFAGLVTSIGTAIRYWFHYTLVAFAWLGVVPLTACRIYKCLFT
  GSVSSLLTLPLDMLSTENLLADCLQGCFVVTCTLCAFISLVWLREQIVHGGAPIWLEHAA
  PPFNAAGHHQNEAPAGGNGAENVAADQPANPPAENAVVGENPDAQDDQAEEEEEDNEEED
  DAGVEDAADANNGAQDDMNWNALEWDRAAEELTWERMLGLDGSLVFLEHVFWVVSLNTLF
  ILVFAFCPYHIGHFSLVGLGFEEHVQASHFEGLITTIVGYILLAITLIICHGLATLVKFH
  RSRRLLGVCYIVVKVSLLVVVEIGVFPLICGWWLDICSLEMFDATLKDRELSFQSAPGTT
  MFLHWLVGMVYVFYFASFILLLREVLRPGVLWFLRNLNDPDFNPVQEMIHLPIYRHLRRF
  ILSVIVFGSIVLLMLWLPIRIIKSVLPNFLPYNVMLYSDAPVSELSLELLLLQVVLPALL
  EQGHTRQWLKGLVRAWTVTAGYLLDLHSYLLGDQEENENSANQQVNNNQHARNNNAIPVV
  GEGLHAAHQAILQQGGPVGFQPYRRPLNFPLRIFLLIVFMCITLLIASLICLTLPVFAGR
  WLMSFWTGTAKIHELYTAACGLYVCWLTIRAVTVMVAWMPQGRRVIFQKVKEWSLMIMKT
  LIVAVLLAGVVPLLLGLLFELVIVAPLRVPLDQTPLFYPWQDWALGVLHAKIIAAITLMG
  PQWWLKTVIEQVYANGIRNIDLHYIVRKLAAPVISVLLLSLCVPYVIASGVVPLLGVTAE
  MQNLVHRRIYPFLLMVVVLMAILSFQVRQFKRLYEHIKNDKYLVGQRLVNYERKSGKQGS
  SPPPPQSSQE
• Function: E3 ubiquitin-protein ligase that promotes 'Lys-48'-linked ubiquitination of target proteins, leading to their proteasomal degradation. Promotes ubiquitination of DIO2, leading to its degradation. Promotes ubiquitination of SQLE, leading to its degradation. 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. May cooperate with UBE2G1.
• Tissue Specificity: Present in brain (at protein level).
• KEGG Pathway: Protein processing in endoplasmic reticulum (hsa04141)
• Reactome Pathway: ER Quality Control Compartment (ERQC) (R-HSA-901032)
• BioCyc Pathway: MetaCyc:ENSG00000145495-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bacterial arthritis	DIS8R241	Strong	Biomarker	[1]
Cardiac failure	DISDC067	Strong	Biomarker	[2]
Chronic kidney disease	DISW82R7	Strong	Biomarker	[3]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[2]
Cutaneous anthrax	DISA6ECE	Strong	Biomarker	[4]
Epilepsy	DISBB28L	Strong	Biomarker	[5]
Gastric cancer	DISXGOUK	Strong	Genetic Variation	[6]
Infective arthritis	DIS8YJPR	Strong	Biomarker	[1]
Liver cirrhosis	DIS4G1GX	Strong	Biomarker	[7]
Polyp	DISRSLYF	Strong	Biomarker	[8]
Prostate cancer	DISF190Y	Strong	Biomarker	[9]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[9]
Schizophrenia	DISSRV2N	Strong	Biomarker	[10]
Stomach cancer	DISKIJSX	Strong	Genetic Variation	[6]
Renal fibrosis	DISMHI3I	moderate	Biomarker	[11]
Benign adult familial myoclonic epilepsy	DISIMWOV	Supportive	Autosomal dominant	[12]

7 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 E3 ubiquitin-protein ligase MARCHF6 (MARCHF6).	[13]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of E3 ubiquitin-protein ligase MARCHF6 (MARCHF6).	[15]
Selenium	DM25CGV	Approved	Selenium decreases the expression of E3 ubiquitin-protein ligase MARCHF6 (MARCHF6).	[16]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of E3 ubiquitin-protein ligase MARCHF6 (MARCHF6).	[17]
Irinotecan	DMP6SC2	Approved	Irinotecan increases the expression of E3 ubiquitin-protein ligase MARCHF6 (MARCHF6).	[18]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of E3 ubiquitin-protein ligase MARCHF6 (MARCHF6).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of E3 ubiquitin-protein ligase MARCHF6 (MARCHF6).	[20]

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 E3 ubiquitin-protein ligase MARCHF6 (MARCHF6).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Simvastatin	DM30SGU	Approved	Simvastatin increases the degradation of E3 ubiquitin-protein ligase MARCHF6 (MARCHF6).	[19]
Betaine	DMGRZW2	Approved	Betaine decreases the stability of E3 ubiquitin-protein ligase MARCHF6 (MARCHF6).	[19]
ANW-32821	DMMJOZD	Phase 2	ANW-32821 increases the stability of E3 ubiquitin-protein ligase MARCHF6 (MARCHF6).	[19]
CB-5083	DM12GN7	Phase 1	CB-5083 increases the stability of E3 ubiquitin-protein ligase MARCHF6 (MARCHF6).	[19]
MG-132	DMKA2YS	Preclinical	MG-132 increases the stability of E3 ubiquitin-protein ligase MARCHF6 (MARCHF6).	[19]
25-hydroxycholesterol	DMCHAQ7	Investigative	25-hydroxycholesterol increases the stability of E3 ubiquitin-protein ligase MARCHF6 (MARCHF6).	[19]
Desmosterol	DMV8SUM	Investigative	Desmosterol increases the stability of E3 ubiquitin-protein ligase MARCHF6 (MARCHF6).	[19]
Lanosterol	DMHN74V	Investigative	Lanosterol increases the stability of E3 ubiquitin-protein ligase MARCHF6 (MARCHF6).	[19]

References

• [1] Outbreak of Septic Arthritis Associated with Intra-Articular Injections at an Outpatient Practice - New Jersey, 2017.MMWR Morb Mortal Wkly Rep. 2017 Jul 28;66(29):777-779. doi: 10.15585/mmwr.mm6629a3.
• [2] Can Functional Testing for Ischemia and Viability Guide Revascularization?.JACC Cardiovasc Imaging. 2017 Mar;10(3):354-364. doi: 10.1016/j.jcmg.2016.12.011.
• [3] Treatment of Uremic Pruritus: A Systematic Review.Am J Kidney Dis. 2017 Nov;70(5):638-655. doi: 10.1053/j.ajkd.2017.05.018. Epub 2017 Jul 15.
• [4] Suspected cutaneous anthrax in a laboratory worker--Texas, 2002.MMWR Morb Mortal Wkly Rep. 2002 Apr 5;51(13):279-81.
• [5] FAME 3: a novel form of progressive myoclonus and epilepsy.Neurology. 2007 Apr 24;68(17):1382-9. doi: 10.1212/01.wnl.0000260063.46425.7e.
• [6] Association between tumor necrosis factor-alpha 857C/T polymorphism and gastric cancer: a meta-analysis.Tumour Biol. 2013 Dec;34(6):3383-8. doi: 10.1007/s13277-013-0910-0. Epub 2013 Jul 3.
• [7] Alcohol Consumption and Risk of Liver Cirrhosis: A Systematic Review and Meta-Analysis.Am J Gastroenterol. 2019 Oct;114(10):1574-1586. doi: 10.14309/ajg.0000000000000340.
• [8] Serrated polyps of the large intestine: a morphologic and molecular review of an evolving concept.Am J Clin Pathol. 2005 Sep;124(3):380-91. doi: 10.1309/V2EP-TPLJ-RB3F-GHJL.
• [9] Consulting prostate cancer cohort data uncovers transcriptional control: Regulation of the MARCH6 gene.Biochim Biophys Acta Mol Cell Biol Lipids. 2019 Nov;1864(11):1656-1668. doi: 10.1016/j.bbalip.2019.08.006. Epub 2019 Aug 15.
• [10] Cognitive behavioural therapy plus standard care versus standard care for people with schizophrenia.Cochrane Database Syst Rev. 2018 Dec 20;12(12):CD007964. doi: 10.1002/14651858.CD007964.pub2.
• [11] Calcium-sensing receptor activation attenuates collagen expression in renal proximal tubular epithelial cells.Am J Physiol Renal Physiol. 2019 May 1;316(5):F1006-F1015. doi: 10.1152/ajprenal.00413.2018. Epub 2019 Mar 6.
• [12] Unstable TTTTA/TTTCA expansions in MARCH6 are associated with Familial Adult Myoclonic Epilepsy type 3. Nat Commun. 2019 Oct 29;10(1):4919. doi: 10.1038/s41467-019-12763-9.
• [13] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [14] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [15] 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.
• [16] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [17] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [18] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [19] Cholesterol increases protein levels of the E3 ligase MARCH6 and thereby stimulates protein degradation. J Biol Chem. 2019 Feb 15;294(7):2436-2448. doi: 10.1074/jbc.RA118.005069. Epub 2018 Dec 13.
• [20] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.