Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHT028D)

• DOT Name: Rabankyrin-5 (ANKFY1)
• Synonyms: Rank-5; Ankyrin repeat and FYVE domain-containing protein 1; Ankyrin repeats hooked to a zinc finger motif
• Gene Name: ANKFY1
• Related Disease:
  Charlevoix-Saguenay spastic ataxia
  Nephrotic syndrome, type 2
  Non-insulin dependent diabetes
  Urinary bladder cancer
  Urinary bladder neoplasm
  Familial idiopathic steroid-resistant nephrotic syndrome
• UniProt ID: ANFY1_HUMAN
• Pfam ID: PF00023 ; PF12796 ; PF00651 ; PF01363
• Sequence:
  MAEEEVAKLEKHLMLLRQEYVKLQKKLAETEKRCALLAAQANKESSSESFISRLLAIVAD
  LYEQEQYSDLKIKVGDRHISAHKFVLAARSDSWSLANLSSTKELDLSDANPEVTMTMLRW
  IYTDELEFREDDVFLTELMKLANRFQLQLLRERCEKGVMSLVNVRNCIRFYQTAEELNAS
  TLMNYCAEIIASHWDDLRKEDFSSMSAQLLYKMIKSKTEYPLHKAIKVEREDVVFLYLIE
  MDSQLPGKLNEADHNGDLALDLALSRRLESIATTLVSHKADVDMVDKSGWSLLHKGIQRG
  DLFAATFLIKNGAFVNAATLGAQETPLHLVALYSSKKHSADVMSEMAQIAEALLQAGANP
  NMQDSKGRTPLHVSIMAGNEYVFSQLLQCKQLDLELKDHEGSTALWLAVQHITVSSDQSV
  NPFEDVPVVNGTSFDENSFAARLIQRGSHTDAPDTATGNCLLQRAAGAGNEAAALFLATN
  GAHVNHRNKWGETPLHTACRHGLANLTAELLQQGANPNLQTEEALPLPKEAASLTSLADS
  VHLQTPLHMAIAYNHPDVVSVILEQKANALHATNNLQIIPDFSLKDSRDQTVLGLALWTG
  MHTIAAQLLGSGAAINDTMSDGQTLLHMAIQRQDSKSALFLLEHQADINVRTQDGETALQ
  LAIRNQLPLVVDAICTRGADMSVPDEKGNPPLWLALANNLEDIASTLVRHGCDATCWGPG
  PGGCLQTLLHRAIDENNEPTACFLIRSGCDVNSPRQPGANGEGEEEARDGQTPLHLAASW
  GLEETVQCLLEFGANVNAQDAEGRTPIHVAISSQHGVIIQLLVSHPDIHLNVRDRQGLTP
  FACAMTFKNNKSAEAILKRESGAAEQVDNKGRNFLHVAVQNSDIESVLFLISVHANVNSR
  VQDASKLTPLHLAVQAGSEIIVRNLLLAGAKVNELTKHRQTALHLAAQQDLPTICSVLLE
  NGVDFAAVDENGNNALHLAVMHGRLNNIRVLLTECTVDAEAFNLRGQSPLHILGQYGKEN
  AAAIFDLFLECMPGYPLDKPDADGSTVLLLAYMKGNANLCRAIVRSGARLGVNNNQGVNI
  FNYQVATKQLLFRLLDMLSKEPPWCDGSYCYECTARFGVTTRKHHCRHCGRLLCHKCSTK
  EIPIIKFDLNKPVRVCNICFDVLTLGGVS
• Function: Proposed effector of Rab5. Binds to phosphatidylinositol 3-phosphate (PI(3)P). Involved in homotypic early endosome fusion and to a lesser extent in heterotypic fusion of chlathrin-coated vesicles with early endosomes. Involved in macropinocytosis; the function is dependent on Rab5-GTP. Required for correct endosomal localization. Involved in the internalization and trafficking of activated tyrosine kinase receptors such as PDGFRB. Regulates the subcellular localization of the retromer complex in a EHD1-dependent manner. Involved in endosome-to-Golgi transport and biosynthetic transport to late endosomes and lysosomes indicative for a regulation of retromer complex-mediated retrograde transport.
• Tissue Specificity: High expression in whole adult brain and intermediate expression in all other tissues and specific brain regions examined, including fetal brain.
• Reactome Pathway: RHOD GTPase cycle (R-HSA-9013405)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Charlevoix-Saguenay spastic ataxia	DISE8X81	Strong	Biomarker	[1]
Nephrotic syndrome, type 2	DISIRFO1	Strong	GermlineCausalMutation	[2]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[3]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[4]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[4]
Familial idiopathic steroid-resistant nephrotic syndrome	DISQ53RS	Supportive	Autosomal dominant	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Rabankyrin-5 (ANKFY1).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Rabankyrin-5 (ANKFY1).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Rabankyrin-5 (ANKFY1).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Rabankyrin-5 (ANKFY1).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Rabankyrin-5 (ANKFY1).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Rabankyrin-5 (ANKFY1).	[10]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Rabankyrin-5 (ANKFY1).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Rabankyrin-5 (ANKFY1).	[13]
crotylaldehyde	DMTWRQI	Investigative	crotylaldehyde decreases the expression of Rabankyrin-5 (ANKFY1).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Rabankyrin-5 (ANKFY1).	[4]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Rabankyrin-5 (ANKFY1).	[14]

References

• [1] Purkinje Cell Degeneration and Motor Coordination Deficits in a New Mouse Model of Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay.Front Mol Neurosci. 2017 May 1;10:121. doi: 10.3389/fnmol.2017.00121. eCollection 2017.
• [2] GAPVD1 and ANKFY1 Mutations Implicate RAB5 Regulation in Nephrotic Syndrome. J Am Soc Nephrol. 2018 Aug;29(8):2123-2138. doi: 10.1681/ASN.2017121312. Epub 2018 Jun 29.
• [3] Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
• [4] Identification of novel gene targets and putative regulators of arsenic-associated DNA methylation in human urothelial cells and bladder cancer. Chem Res Toxicol. 2015 Jun 15;28(6):1144-55. doi: 10.1021/tx500393y. Epub 2015 Jun 3.
• [5] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [6] 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.
• [7] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [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 novel gene targets and putative regulators of arsenic-associated DNA methylation in human urothelial cells and bladder cancer. Chem Res Toxicol. 2015 Jun 15;28(6):1144-55. doi: 10.1021/tx500393y. Epub 2015 Jun 3.
• [12] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [13] 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.
• [14] 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.
• [15] Gene expression profile and cytotoxicity of human bronchial epithelial cells exposed to crotonaldehyde. Toxicol Lett. 2010 Aug 16;197(2):113-22.