Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLABE56)

• DOT Name: Kelch-like protein 41 (KLHL41)
• Synonyms: Kel-like protein 23; Kelch repeat and BTB domain-containing protein 10; Kelch-related protein 1; Sarcosin
• Gene Name: KLHL41
• Related Disease:
  Cryptococcosis
  Nemaline myopathy 9
  Childhood-onset nemaline myopathy
  Intermediate nemaline myopathy
  Severe congenital nemaline myopathy
  Typical nemaline myopathy
  Nemaline myopathy
• UniProt ID: KLH41_HUMAN
• Pfam ID: PF07707 ; PF00651 ; PF01344
• Sequence:
  MDSQRELAEELRLYQSTLLQDGLKDLLDEKKFIDCTLKAGDKSLPCHRLILSACSPYFRE
  YFLSEIDEAKKKEVVLDNVDPAILDLIIKYLYSASIDLNDGNVQDIFALASRFQIPSVFT
  VCVSYLQKRLAPGNCLAILRLGLLLDCPRLAISAREFVSDRFVQICKEEDFMQLSPQELI
  SVISNDSLNVEKEEAVFEAVMKWVRTDKENRVKNLSEVFDCIRFRLMTEKYFKDHVEKDD
  IIKSNPDLQKKIKVLKDAFAGKLPEPSKNAAKTGAGEVNGDVGDEDLLPGYLNDIPRHGM
  FVKDLILLVNDTAAVAYDPTENECYLTALAEQIPRNHSSIVTQQNQIYVVGGLYVDEENK
  DQPLQSYFFQLDSIASEWVGLPPLPSARCLFGLGEVDDKIYVVAGKDLQTEASLDSVLCY
  DPVAAKWNEVKKLPIKVYGHNVISHKGMIYCLGGKTDDKKCTNRVFIFNPKKGDWKDLAP
  MKIPRSMFGVAVHKGKIVIAGGVTEDGLSASVEAFDLTTNKWDVMTEFPQERSSISLVSL
  AGSLYAIGGFAMIQLESKEFAPTEVNDIWKYEDDKKEWAGMLKEIRYASGASCLATRLNL
  FKLSKL
• Function: Involved in skeletal muscle development and differentiation. Regulates proliferation and differentiation of myoblasts and plays a role in myofibril assembly by promoting lateral fusion of adjacent thin fibrils into mature, wide myofibrils. Required for pseudopod elongation in transformed cells.
• Tissue Specificity: Sarcomeric muscle.
• 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
Cryptococcosis	DISDYDTK	Strong	Biomarker	[1]
Nemaline myopathy 9	DIS4WFUM	Strong	Autosomal recessive	[2]
Childhood-onset nemaline myopathy	DIST7MSL	Supportive	Autosomal dominant	[2]
Intermediate nemaline myopathy	DISMJ4LI	Supportive	Autosomal dominant	[2]
Severe congenital nemaline myopathy	DISJR7WP	Supportive	Autosomal recessive	[2]
Typical nemaline myopathy	DISY1645	Supportive	Autosomal dominant	[2]
Nemaline myopathy	DIS5IYLY	Limited	Biomarker	[3]

9 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 41 (KLHL41).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Kelch-like protein 41 (KLHL41).	[5]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Kelch-like protein 41 (KLHL41).	[6]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Kelch-like protein 41 (KLHL41).	[7]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Kelch-like protein 41 (KLHL41).	[8]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Kelch-like protein 41 (KLHL41).	[9]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Kelch-like protein 41 (KLHL41).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Kelch-like protein 41 (KLHL41).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Kelch-like protein 41 (KLHL41).	[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 increases the methylation of Kelch-like protein 41 (KLHL41).	[10]

References

• [1] A Predicted Mannoprotein Participates in Cryptococcus gattii Capsular Structure.mSphere. 2018 Apr 25;3(2):e00023-18. doi: 10.1128/mSphere.00023-18. Print 2018 Apr 25.
• [2] Identification of KLHL41 Mutations Implicates BTB-Kelch-Mediated Ubiquitination as an Alternate Pathway to Myofibrillar Disruption in Nemaline Myopathy. Am J Hum Genet. 2013 Dec 5;93(6):1108-17. doi: 10.1016/j.ajhg.2013.10.020. Epub 2013 Nov 21.
• [3] Dysregulation of NRAP degradation by KLHL41 contributes to pathophysiology in nemaline myopathy.Hum Mol Genet. 2019 Aug 1;28(15):2549-2560. doi: 10.1093/hmg/ddz078.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] 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.
• [6] 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.
• [7] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [8] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] 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.
• [11] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [12] 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.
• [13] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.