Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTEJ6850)

• DOT Name: Kelch-like protein 3 (KLHL3)
• Gene Name: KLHL3
• Related Disease:
  Autosomal dominant pseudohypoaldosteronism type 1
  Malaria
  Non-insulin dependent diabetes
  Pseudohypoaldosteronism type 2D
  Gordon syndrome
  High blood pressure
  Congenital heart disease
• UniProt ID: KLHL3_HUMAN
• PDB ID: 4CH9; 4HXI; 5NKP
• Pfam ID: PF07707 ; PF00651 ; PF01344
• Sequence:
  MEGESVKLSSQTLIQAGDDEKNQRTITVNPAHMGKAFKVMNELRSKQLLCDVMIVAEDVE
  IEAHRVVLAACSPYFCAMFTGDMSESKAKKIEIKDVDGQTLSKLIDYIYTAEIEVTEENV
  QVLLPAASLLQLMDVRQNCCDFLQSQLHPTNCLGIRAFADVHTCTDLLQQANAYAEQHFP
  EVMLGEEFLSLSLDQVCSLISSDKLTVSSEEKVFEAVISWINYEKETRLEHMAKLMEHVR
  LPLLPRDYLVQTVEEEALIKNNNTCKDFLIEAMKYHLLPLDQRLLIKNPRTKPRTPVSLP
  KVMIVVGGQAPKAIRSVECYDFEEDRWDQIAELPSRRCRAGVVFMAGHVYAVGGFNGSLR
  VRTVDVYDGVKDQWTSIASMQERRSTLGAAVLNDLLYAVGGFDGSTGLASVEAYSYKTNE
  WFFVAPMNTRRSSVGVGVVEGKLYAVGGYDGASRQCLSTVEQYNPATNEWIYVADMSTRR
  SGAGVGVLSGQLYATGGHDGPLVRKSVEVYDPGTNTWKQVADMNMCRRNAGVCAVNGLLY
  VVGGDDGSCNLASVEYYNPVTDKWTLLPTNMSTGRSYAGVAVIHKSL
• Function: Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that acts as a regulator of ion transport in the distal nephron. The BCR(KLHL3) complex acts by mediating ubiquitination and degradation of WNK1 and WNK4, two activators of Na-Cl cotransporter SLC12A3/NCC in distal convoluted tubule cells of kidney, thereby regulating NaCl reabsorption. The BCR(KLHL3) complex also mediates ubiquitination and degradation of WNK3. The BCR(KLHL3) complex also mediates ubiquitination of CLDN8, a tight-junction protein required for paracellular chloride transport in the kidney, leading to its degradation.
• Tissue Specificity: Widely expressed.
• Reactome Pathway:
  Antigen processing (R-HSA-983168)
  Neddylation (R-HSA-8951664)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal dominant pseudohypoaldosteronism type 1	DIS4FXQ4	Strong	Biomarker	[1]
Malaria	DISQ9Y50	Strong	Genetic Variation	[2]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[3]
Pseudohypoaldosteronism type 2D	DIS2AO4N	Strong	Autosomal dominant	[4]
Gordon syndrome	DISVMP0Y	Disputed	Genetic Variation	[5]
High blood pressure	DISY2OHH	Disputed	Genetic Variation	[6]
Congenital heart disease	DISQBA23	Limited	Biomarker	[7]

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 3 (KLHL3).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Kelch-like protein 3 (KLHL3).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Kelch-like protein 3 (KLHL3).	[10]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Kelch-like protein 3 (KLHL3).	[11]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Kelch-like protein 3 (KLHL3).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Kelch-like protein 3 (KLHL3).	[14]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of Kelch-like protein 3 (KLHL3).	[15]

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 increases the methylation of Kelch-like protein 3 (KLHL3).	[12]

References

• [1] KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron.Nat Genet. 2012 Mar 11;44(4):456-60, S1-3. doi: 10.1038/ng.2218.
• [2] Novel genetic polymorphisms associated with severe malaria and under selective pressure in North-eastern Tanzania.PLoS Genet. 2018 Jan 30;14(1):e1007172. doi: 10.1371/journal.pgen.1007172. eCollection 2018 Jan.
• [3] Inhibition of Sodium Glucose Cotransporter 2 Attenuates the Dysregulation of Kelch-Like 3 and NaCl Cotransporter in Obese Diabetic Mice.J Am Soc Nephrol. 2019 May;30(5):782-794. doi: 10.1681/ASN.2018070703. Epub 2019 Mar 26.
• [4] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [5] Three cases of Gordon syndrome with dominant KLHL3 mutations.J Pediatr Endocrinol Metab. 2017 Mar 1;30(3):361-364. doi: 10.1515/jpem-2016-0309.
• [6] Calcineurin dephosphorylates Kelch-like 3, reversing phosphorylation by angiotensin II and regulating renal electrolyte handling.Proc Natl Acad Sci U S A. 2019 Feb 19;116(8):3155-3160. doi: 10.1073/pnas.1817281116. Epub 2019 Feb 4.
• [7] cMyBP-C was decreased via KLHL3-mediated proteasomal degradation in congenital heart diseases.Exp Cell Res. 2017 Jun 1;355(1):18-25. doi: 10.1016/j.yexcr.2017.03.025. Epub 2017 Mar 16.
• [8] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [9] 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.
• [10] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [11] Cannabidiol enhances cytotoxicity of anti-cancer drugs in human head and neck squamous cell carcinoma. Sci Rep. 2020 Nov 26;10(1):20622. doi: 10.1038/s41598-020-77674-y.
• [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] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [14] 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.
• [15] Persistence of epigenomic effects after recovery from repeated treatment with two nephrocarcinogens. Front Genet. 2018 Dec 3;9:558.