Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTKKFS8)

• DOT Name: Beta-klotho (KLB)
• Synonyms: BKL; BetaKlotho; Klotho beta-like protein
• Gene Name: KLB
• UniProt ID: KLOTB_HUMAN
• PDB ID: 5VAK; 5VAN; 5VAQ; 5WI9; 6NFJ
• Pfam ID: PF00232
• Sequence:
  MKPGCAAGSPGNEWIFFSTDEITTRYRNTMSNGGLQRSVILSALILLRAVTGFSGDGRAI
  WSKNPNFTPVNESQLFLYDTFPKNFFWGIGTGALQVEGSWKKDGKGPSIWDHFIHTHLKN
  VSSTNGSSDSYIFLEKDLSALDFIGVSFYQFSISWPRLFPDGIVTVANAKGLQYYSTLLD
  ALVLRNIEPIVTLYHWDLPLALQEKYGGWKNDTIIDIFNDYATYCFQMFGDRVKYWITIH
  NPYLVAWHGYGTGMHAPGEKGNLAAVYTVGHNLIKAHSKVWHNYNTHFRPHQKGWLSITL
  GSHWIEPNRSENTMDIFKCQQSMVSVLGWFANPIHGDGDYPEGMRKKLFSVLPIFSEAEK
  HEMRGTADFFAFSFGPNNFKPLNTMAKMGQNVSLNLREALNWIKLEYNNPRILIAENGWF
  TDSRVKTEDTTAIYMMKNFLSQVLQAIRLDEIRVFGYTAWSLLDGFEWQDAYTIRRGLFY
  VDFNSKQKERKPKSSAHYYKQIIRENGFSLKESTPDVQGQFPCDFSWGVTESVLKPESVA
  SSPQFSDPHLYVWNATGNRLLHRVEGVRLKTRPAQCTDFVNIKKQLEMLARMKVTHYRFA
  LDWASVLPTGNLSAVNRQALRYYRCVVSEGLKLGISAMVTLYYPTHAHLGLPEPLLHADG
  WLNPSTAEAFQAYAGLCFQELGDLVKLWITINEPNRLSDIYNRSGNDTYGAAHNLLVAHA
  LAWRLYDRQFRPSQRGAVSLSLHADWAEPANPYADSHWRAAERFLQFEIAWFAEPLFKTG
  DYPAAMREYIASKHRRGLSSSALPRLTEAERRLLKGTVDFCALNHFTTRFVMHEQLAGSR
  YDSDRDIQFLQDITRLSSPTRLAVIPWGVRKLLRWVRRNYGDMDIYITASGIDDQALEDD
  RLRKYYLGKYLQEVLKAYLIDKVRIKGYYAFKLAEEKSKPRFGFFTSDFKAKSSIQFYNK
  VISSRGFPFENSSSRCSQTQENTECTVCLFLVQKKPLIFLGCCFFSTLVLLLSIAIFQRQ
  KRRKFWKAKNLQHIPLKKGKRVVS
• Function: Contributes to the transcriptional repression of cholesterol 7-alpha-hydroxylase (CYP7A1), the rate-limiting enzyme in bile acid synthesis. Probably inactive as a glycosidase. Increases the ability of FGFR1 and FGFR4 to bind FGF21.
• KEGG Pathway: Thermogenesis (hsa04714)
• Reactome Pathway:
  (FGFR4)
  PIP3 activates AKT signaling (R-HSA-1257604)
  betaKlotho-mediated ligand binding (R-HSA-1307965)
  Constitutive Signaling by Aberrant PI3K in Cancer (R-HSA-2219530)
  Phospholipase C-mediated cascade (R-HSA-5654228)
  FRS-mediated FGFR4 signaling (R-HSA-5654712)
  SHC-mediated cascade (R-HSA-5654719)
  PI-3K cascade (R-HSA-5654720)
  Negative regulation of FGFR4 signaling (R-HSA-5654733)
  RAF/MAP kinase cascade (R-HSA-5673001)
  PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling (R-HSA-6811558)
  PI3K Cascade (R-HSA-109704)

Molecular Interaction Atlas (MIA) of This DOT

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Beta-klotho (KLB).	[1]

10 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 Beta-klotho (KLB).	[2]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Beta-klotho (KLB).	[3]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Beta-klotho (KLB).	[4]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Beta-klotho (KLB).	[5]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Beta-klotho (KLB).	[6]
Permethrin	DMZ0Q1G	Approved	Permethrin increases the expression of Beta-klotho (KLB).	[7]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Beta-klotho (KLB).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Beta-klotho (KLB).	[9]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Beta-klotho (KLB).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Beta-klotho (KLB).	[11]

References

• [1] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [4] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [5] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [6] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [7] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [8] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [9] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [10] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [11] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.