Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBZMED0)

• DOT Name: Spermatogenesis-defective protein 39 homolog
• Synonyms: hSPE-39; VPS33B-interacting protein in apical-basolateral polarity regulator; VPS33B-interacting protein in polarity and apical restriction
• Gene Name: VIPAS39
• Related Disease:
  Arthrogryposis, renal dysfunction, and cholestasis 2
  Arthrogryposis-renal dysfunction-cholestasis syndrome
• UniProt ID: SPE39_HUMAN
• Pfam ID: PF04840
• Sequence:
  MNRTKGDEEEYWNSSKFKAFTFDDEDDELSQLKESKRAVNSLRDFVDDDDDDDLERVSWS
  GEPVGSISWSIRETAGNSGSTHEGREQLKSRNSFSSYAQLPKPTSTYSLSSFFRGRTRPG
  SFQSLSDALSDTPAKSYAPELGRPKGEYRDYSNDWSPSDTVRRLRKGKVCSLERFRSLQD
  KLQLLEEAVSMHDGNVITAVLIFLKRTLSKEILFRELEVRQVALRHLIHFLKEIGDQKLL
  LDLFRFLDRTEELALSHYREHLNIQDPDKRKEFLKTCVGLPFSAEDSAHIQDHYTLLERQ
  IIIEANDRHLESAGQTEIFRKHPRKASILNMPLVTTLFYSCFYHYTEAEGTFSSPVNLKK
  TFKIPDKQYVLTALAARAKLRAWNDVDALFTTKNWLGYTKKRAPIGFHRVVEILHKNNAP
  VQILQEYVNLVEDVDTKLNLATKFKCHDVVIDTYRDLKDRQQLLAYRSKVDKGSAEEEKI
  DALLSSSQIRWKN
• Function: Proposed to be involved in endosomal maturation implicating in part VPS33B. In epithelial cells, the VPS33B:VIPAS39 complex may play a role in the apical RAB11A-dependent recycling pathway and in the maintenance of the apical-basolateral polarity. May play a role in lysosomal trafficking, probably via association with the core HOPS complex in a discrete population of endosomes; the functions seems to be independent of VPS33B. May play a role in vesicular trafficking during spermatogenesis. May be involved in direct or indirect transcriptional regulation of E-cadherin.

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arthrogryposis, renal dysfunction, and cholestasis 2	DISMOIC2	Definitive	Autosomal recessive	[1]
Arthrogryposis-renal dysfunction-cholestasis syndrome	DISRQJH4	Supportive	Autosomal recessive	[2]

5 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 Spermatogenesis-defective protein 39 homolog.	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Spermatogenesis-defective protein 39 homolog.	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Spermatogenesis-defective protein 39 homolog.	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Spermatogenesis-defective protein 39 homolog.	[6]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Spermatogenesis-defective protein 39 homolog.	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Spermatogenesis-defective protein 39 homolog.	[8]

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] Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome: from molecular genetics to clinical features. Ital J Pediatr. 2014 Sep 20;40:77. doi: 10.1186/s13052-014-0077-3.
• [3] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [4] 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.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] 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.
• [7] 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.
• [8] 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.