Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1NG8V7)

• DOT Name: Kelch-like protein 2 (KLHL2)
• Synonyms: Actin-binding protein Mayven
• Gene Name: KLHL2
• Related Disease:
  Encephalitis
  Hepatocellular carcinoma
  Intrahepatic cholangiocarcinoma
  Neoplasm
  Pneumonia
  Pneumonitis
  Viral encephalitis
  Wilms tumor
  Tuberculosis
• UniProt ID: KLHL2_HUMAN
• PDB ID: 2XN4; 4CHB
• Pfam ID: PF07707 ; PF00651 ; PF01344
• Sequence:
  METPPLPPACTKQGHQKPLDSKDDNTEKHCPVTVNPWHMKKAFKVMNELRSQNLLCDVTI
  VAEDMEISAHRVVLAACSPYFHAMFTGEMSESRAKRVRIKEVDGWTLRMLIDYVYTAEIQ
  VTEENVQVLLPAAGLLQLQDVKKTCCEFLESQLHPVNCLGIRAFADMHACTDLLNKANTY
  AEQHFADVVLSEEFLNLGIEQVCSLISSDKLTISSEEKVFEAVIAWVNHDKDVRQEFMAR
  LMEHVRLPLLPREYLVQRVEEEALVKNSSACKDYLIEAMKYHLLPTEQRILMKSVRTRLR
  TPMNLPKLMVVVGGQAPKAIRSVECYDFKEERWHQVAELPSRRCRAGMVYMAGLVFAVGG
  FNGSLRVRTVDSYDPVKDQWTSVANMRDRRSTLGAAVLNGLLYAVGGFDGSTGLSSVEAY
  NIKSNEWFHVAPMNTRRSSVGVGVVGGLLYAVGGYDGASRQCLSTVECYNATTNEWTYIA
  EMSTRRSGAGVGVLNNLLYAVGGHDGPLVRKSVEVYDPTTNAWRQVADMNMCRRNAGVCA
  VNGLLYVVGGDDGSCNLASVEYYNPTTDKWTVVSSCMSTGRSYAGVTVIDKPL
• Function: Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that mediates the ubiquitination of target proteins, such as NPTXR, WNK1, WNK3 and WNK4, leading most often to their proteasomal degradation. The BCR(KLHL2) complex catalyzes ubiquitination and degradation of NPTXR. Responsible for degradative ubiquitination of the WNK kinases WNK1, WNK3 and WNK4. Plays a role in the reorganization of the actin cytoskeleton. Promotes growth of cell projections in oligodendrocyte precursors.
• Tissue Specificity: Ubiquitous. Detected throughout the brain.
• Reactome Pathway:
  Antigen processing (R-HSA-983168)
  Neddylation (R-HSA-8951664)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Encephalitis	DISLD1RL	Strong	Biomarker	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[2]
Intrahepatic cholangiocarcinoma	DIS6GOC8	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Pneumonia	DIS8EF3M	Strong	Altered Expression	[3]
Pneumonitis	DIS88E0K	Strong	Altered Expression	[3]
Viral encephalitis	DIS9G09S	Strong	Biomarker	[1]
Wilms tumor	DISB6T16	Strong	Biomarker	[4]
Tuberculosis	DIS2YIMD	Limited	Biomarker	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Kelch-like protein 2 (KLHL2).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Kelch-like protein 2 (KLHL2).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Kelch-like protein 2 (KLHL2).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Kelch-like protein 2 (KLHL2).	[9]
Clorgyline	DMCEUJD	Approved	Clorgyline increases the expression of Kelch-like protein 2 (KLHL2).	[10]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Kelch-like protein 2 (KLHL2).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Kelch-like protein 2 (KLHL2).	[13]

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 Kelch-like protein 2 (KLHL2).	[12]

References

• [1] A Protective Role for Interleukin-1 Signaling during Mouse Adenovirus Type 1-Induced Encephalitis.J Virol. 2017 Jan 31;91(4):e02106-16. doi: 10.1128/JVI.02106-16. Print 2017 Feb 15.
• [2] HRAS, EGFR, MET, and RON Genes Are Recurrently Activated by Provirus Insertion in Liver Tumors Induced by the Retrovirus Myeloblastosis-Associated Virus 2.J Virol. 2017 Sep 27;91(20):e00467-17. doi: 10.1128/JVI.00467-17. Print 2017 Oct 15.
• [3] Fas activity mediates airway inflammation during mouse adenovirus type 1 respiratory infection.Virology. 2018 Aug;521:129-137. doi: 10.1016/j.virol.2018.06.002. Epub 2018 Jun 13.
• [4] Deletions within the U3 long terminal repeat alter the tumorigenic potential of myeloblastosis associated virus type 1(N).Virology. 2003 Nov 10;316(1):84-9. doi: 10.1016/j.virol.2003.07.005.
• [5] Identification of virulence determinants of Mycobacterium avium that impact on the ability to resist host killing mechanisms.J Med Microbiol. 2010 Jan;59(Pt 1):8-16. doi: 10.1099/jmm.0.012864-0.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [7] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [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] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [10] Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells. BMC Med Genomics. 2009 Aug 20;2:55. doi: 10.1186/1755-8794-2-55.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] 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.
• [13] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.