Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTC0SFS9)

• DOT Name: Kelch-like protein 20 (KLHL20)
• Synonyms: Kelch-like ECT2-interacting protein; Kelch-like protein X
• Gene Name: KLHL20
• Related Disease: Alzheimer disease
• UniProt ID: KLH20_HUMAN
• PDB ID: 5YQ4; 6GY5; 8CIA
• Pfam ID: PF07707 ; PF00651 ; PF01344
• Sequence:
  MEGKPMRRCTNIRPGETGMDVTSRCTLGDPNKLPEGVPQPARMPYISDKHPRQTLEVINL
  LRKHRELCDVVLVVGAKKIYAHRVILSACSPYFRAMFTGELAESRQTEVVIRDIDERAME
  LLIDFAYTSQITVEEGNVQTLLPAACLLQLAEIQEACCEFLKRQLDPSNCLGIRAFADTH
  SCRELLRIADKFTQHNFQEVMESEEFMLLPANQLIDIISSDELNVRSEEQVFNAVMAWVK
  YSIQERRPQLPQVLQHVRLPLLSPKFLVGTVGSDPLIKSDEECRDLVDEAKNYLLLPQER
  PLMQGPRTRPRKPIRCGEVLFAVGGWCSGDAISSVERYDPQTNEWRMVASMSKRRCGVGV
  SVLDDLLYAVGGHDGSSYLNSVERYDPKTNQWSSDVAPTSTCRTSVGVAVLGGFLYAVGG
  QDGVSCLNIVERYDPKENKWTRVASMSTRRLGVAVAVLGGFLYAVGGSDGTSPLNTVERY
  NPQENRWHTIAPMGTRRKHLGCAVYQDMIYAVGGRDDTTELSSAERYNPRTNQWSPVVAM
  TSRRSGVGLAVVNGQLMAVGGFDGTTYLKTIEVFDPDANTWRLYGGMNYRRLGGGVGVIK
  MTHCESHIW
• Function: Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex involved in interferon response and anterograde Golgi to endosome transport. The BCR(KLHL20) E3 ubiquitin ligase complex mediates the ubiquitination of DAPK1, leading to its degradation by the proteasome, thereby acting as a negative regulator of apoptosis. The BCR(KLHL20) E3 ubiquitin ligase complex also specifically mediates 'Lys-33'-linked ubiquitination. Involved in anterograde Golgi to endosome transport by mediating 'Lys-33'-linked ubiquitination of CORO7, promoting interaction between CORO7 and EPS15, thereby facilitating actin polymerization and post-Golgi trafficking. Also acts as a regulator of endothelial migration during angiogenesis by controlling the activation of Rho GTPases. The BCR(KLHL20) E3 ubiquitin ligase complex acts as a regulator of neurite outgrowth by mediating ubiquitination and degradation of PDZ-RhoGEF/ARHGEF11. In case of tumor, the BCR(KLHL20) E3 ubiquitin ligase complex is involved in tumor hypoxia: following hypoxia, the BCR(KLHL20)complex mediates ubiquitination and degradation of PML, potentiating HIF-1 signaling and cancer progression.
• Reactome Pathway:
  Antigen processing (R-HSA-983168)
  Neddylation (R-HSA-8951664)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Biomarker	[1]

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 Kelch-like protein 20 (KLHL20).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Kelch-like protein 20 (KLHL20).	[3]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Kelch-like protein 20 (KLHL20).	[4]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Kelch-like protein 20 (KLHL20).	[5]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Kelch-like protein 20 (KLHL20).	[6]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Kelch-like protein 20 (KLHL20).	[7]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Kelch-like protein 20 (KLHL20).	[4]

References

• [1] Structural Basis for Recruitment of DAPK1 to the KLHL20 E3 Ligase.Structure. 2019 Sep 3;27(9):1395-1404.e4. doi: 10.1016/j.str.2019.06.005. Epub 2019 Jul 3.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] 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.
• [4] 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.
• [5] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [6] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [7] 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.