Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTU5M06J)

• DOT Name: Kelch domain-containing protein 3 (KLHDC3)
• Synonyms: Testis intracellular mediator protein
• Gene Name: KLHDC3
• UniProt ID: KLDC3_HUMAN
• Pfam ID: PF01344 ; PF07646 ; PF13418 ; PF13964
• Sequence:
  MLRWTVHLEGGPRRVNHAAVAVGHRVYSFGGYCSGEDYETLRQIDVHIFNAVSLRWTKLP
  PVKSAIRGQAPVVPYMRYGHSTVLIDDTVLLWGGRNDTEGACNVLYAFDVNTHKWFTPRV
  SGTVPGARDGHSACVLGKIMYIFGGYEQQADCFSNDIHKLDTSTMTWTLICTKGSPARWR
  DFHSATMLGSHMYVFGGRADRFGPFHSNNEIYCNRIRVFDTRTEAWLDCPPTPVLPEGRR
  SHSAFGYNGELYIFGGYNARLNRHFHDLWKFNPVSFTWKKIEPKGKGPCPRRRQCCCIVG
  DKIVLFGGTSPSPEEGLGDEFDLIDHSDLHILDFSPSLKTLCKLAVIQYNLDQSCLPHDI
  RWELNAMTTNSNISRPIVSSHG
• Function: Substrate-recognition component of a Cul2-RING (CRL2) E3 ubiquitin-protein ligase complex of the DesCEND (destruction via C-end degrons) pathway, which recognizes a C-degron located at the extreme C terminus of target proteins, leading to their ubiquitination and degradation. The C-degron recognized by the DesCEND pathway is usually a motif of less than ten residues and can be present in full-length proteins, truncated proteins or proteolytically cleaved forms. The CRL2(KLHDC3) complex specifically recognizes proteins with a glycine (Gly) at the C-terminus, leading to their ubiquitination and degradation: recognizes the C-terminal -Arg-(Xaa)n-Arg-Gly, -Arg-(Xaa)n-Lys-Gly, and -Arg-(Xaa)n-Gln-Gly degrons. The CRL2(KLHDC3) complex mediates ubiquitination and degradation of truncated SELENOV and SEPHS2 selenoproteins produced by failed UGA/Sec decoding, which end with a glycine. May be involved in meiotic recombination process.
• Reactome Pathway: XBP1(S) activates chaperone genes (R-HSA-381038)

Molecular Interaction Atlas (MIA) of This DOT

5 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 Kelch domain-containing protein 3 (KLHDC3).	[1]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Kelch domain-containing protein 3 (KLHDC3).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Kelch domain-containing protein 3 (KLHDC3).	[3]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Kelch domain-containing protein 3 (KLHDC3).	[4]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Kelch domain-containing protein 3 (KLHDC3).	[6]

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 domain-containing protein 3 (KLHDC3).	[5]

References

• [1] 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.
• [2] 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.
• [3] 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.
• [4] 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.
• [5] 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.
• [6] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.