Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTD4VWU6)

DOT Name	Klotho (KL)
Synonyms	EC 3.2.1.31
Gene Name	KL
Related Disease	Cardiomyopathy ( ) Hyperinsulinemia ( ) Melanoma ( ) Breast cancer ( ) Breast carcinoma ( ) Breast neoplasm ( ) Calcinosis ( ) Cardiovascular disease ( ) Chondrocalcinosis ( ) Chronic obstructive pulmonary disease ( ) Cognitive impairment ( ) Colorectal carcinoma ( ) Coronary atherosclerosis ( ) Coronary heart disease ( ) End-stage renal disease ( ) Familial tumoral calcinosis ( ) Hepatocellular carcinoma ( ) High blood pressure ( ) Hypercalcaemia ( ) Infertility ( ) Kidney failure ( ) Lung cancer ( ) Lung carcinoma ( ) Major depressive disorder ( ) Metabolic disorder ( ) Non-insulin dependent diabetes ( ) Osteoarthritis ( ) Osteoporosis ( ) Retinitis pigmentosa ( ) Retinitis pigmentosa 1 ( ) Secondary hyperparathyroidism ( ) Stroke ( ) Tumoral calcinosis, hyperphosphatemic, familial, 1 ( ) Type-1 diabetes ( ) Type-1/2 diabetes ( ) Vascular disease ( ) Multiple sclerosis ( ) Obsolete tumoral calcinosis, hyperphosphatemic, familial, 1 ( ) Skin disease ( ) Chronic renal failure ( ) Diabetic kidney disease ( ) Hyperlipidemia ( ) Hyperlipoproteinemia ( ) Hyperphosphatemia ( ) Renal fibrosis ( ) Rheumatoid arthritis ( ) Tumoral calcinosis, hyperphosphatemic, familial, 3 ( )
UniProt ID	KLOT_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	5W21; 7YSH; 7YSU; 7YSW
EC Number	3.2.1.31
Pfam ID	PF00232
Sequence	MPASAPPRRPRPPPPSLSLLLVLLGLGGRRLRAEPGDGAQTWARFSRPPAPEAAGLFQGT FPDGFLWAVGSAAYQTEGGWQQHGKGASIWDTFTHHPLAPPGDSRNASLPLGAPSPLQPA TGDVASDSYNNVFRDTEALRELGVTHYRFSISWARVLPNGSAGVPNREGLRYYRRLLERL RELGVQPVVTLYHWDLPQRLQDAYGGWANRALADHFRDYAELCFRHFGGQVKYWITIDNP YVVAWHGYATGRLAPGIRGSPRLGYLVAHNLLLAHAKVWHLYNTSFRPTQGGQVSIALSS HWINPRRMTDHSIKECQKSLDFVLGWFAKPVFIDGDYPESMKNNLSSILPDFTESEKKFI KGTADFFALCFGPTLSFQLLDPHMKFRQLESPNLRQLLSWIDLEFNHPQIFIVENGWFVS GTTKRDDAKYMYYLKKFIMETLKAIKLDGVDVIGYTAWSLMDGFEWHRGYSIRRGLFYVD FLSQDKMLLPKSSALFYQKLIEKNGFPPLPENQPLEGTFPCDFAWGVVDNYIQVDTTLSQ FTDLNVYLWDVHHSKRLIKVDGVVTKKRKSYCVDFAAIQPQIALLQEMHVTHFRFSLDWA LILPLGNQSQVNHTILQYYRCMASELVRVNITPVVALWQPMAPNQGLPRLLARQGAWENP YTALAFAEYARLCFQELGHHVKLWITMNEPYTRNMTYSAGHNLLKAHALAWHVYNEKFRH AQNGKISIALQADWIEPACPFSQKDKEVAERVLEFDIGWLAEPIFGSGDYPWVMRDWLNQ RNNFLLPYFTEDEKKLIQGTFDFLALSHYTTILVDSEKEDPIKYNDYLEVQEMTDITWLN SPSQVAVVPWGLRKVLNWLKFKYGDLPMYIISNGIDDGLHAEDDQLRVYYMQNYINEALK AHILDGINLCGYFAYSFNDRTAPRFGLYRYAADQFEPKASMKHYRKIIDSNGFPGPETLE RFCPEEFTVCTECSFFHTRKSLLAFIAFLFFASIISLSLIFYYSKKGRRSYK
Function	May have weak glycosidase activity towards glucuronylated steroids. However, it lacks essential active site Glu residues at positions 239 and 872, suggesting it may be inactive as a glycosidase in vivo. May be involved in the regulation of calcium and phosphorus homeostasis by inhibiting the synthesis of active vitamin D. Essential factor for the specific interaction between FGF23 and FGFR1; The Klotho peptide generated by cleavage of the membrane-bound isoform may be an anti-aging circulating hormone which would extend life span by inhibiting insulin/IGF1 signaling.
Tissue Specificity	Present in cortical renal tubules (at protein level). Soluble peptide is present in serum and cerebrospinal fluid. Expressed in kidney, placenta, small intestine and prostate. Down-regulated in renal cell carcinomas, hepatocellular carcinomas, and in chronic renal failure kidney.
KEGG Pathway	Pentose and glucuro.te interconversions (hsa00040 ) Ascorbate and aldarate metabolism (hsa00053 ) Metabolic pathways (hsa01100 ) Longevity regulating pathway (hsa04211 ) Parathyroid hormone synthesis, secretion and action (hsa04928 ) Endocrine and other factor-regulated calcium reabsorption (hsa04961 )
Reactome Pathway	PIP3 activates AKT signaling (R-HSA-1257604 ) FGFR1c and Klotho ligand binding and activation (R-HSA-190374 ) Constitutive Signaling by Aberrant PI3K in Cancer (R-HSA-2219530 ) Phospholipase C-mediated cascade (R-HSA-5654219 ) Downstream signaling of activated FGFR1 (R-HSA-5654687 ) SHC-mediated cascade (R-HSA-5654688 ) PI-3K cascade (R-HSA-5654689 ) FRS-mediated FGFR1 signaling (R-HSA-5654693 ) Negative regulation of FGFR1 signaling (R-HSA-5654726 ) 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

47 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Cardiomyopathy	DISUPZRG	Definitive	Altered Expression	[1]
Hyperinsulinemia	DISIDWT6	Definitive	Altered Expression	[2]
Melanoma	DIS1RRCY	Definitive	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[4]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[4]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[5]
Calcinosis	DISQP4OR	Strong	Biomarker	[6]
Cardiovascular disease	DIS2IQDX	Strong	Biomarker	[7]
Chondrocalcinosis	DISP4AHX	Strong	Biomarker	[8]
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Biomarker	[9]
Cognitive impairment	DISH2ERD	Strong	Altered Expression	[10]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[11]
Coronary atherosclerosis	DISKNDYU	Strong	Altered Expression	[12]
Coronary heart disease	DIS5OIP1	Strong	Biomarker	[13]
End-stage renal disease	DISXA7GG	Strong	Altered Expression	[14]
Familial tumoral calcinosis	DISYJZKG	Strong	Genetic Variation	[6]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[15]
High blood pressure	DISY2OHH	Strong	Altered Expression	[16]
Hypercalcaemia	DISKQ2K7	Strong	Altered Expression	[17]
Infertility	DISAMOWP	Strong	Biomarker	[18]
Kidney failure	DISOVQ9P	Strong	Altered Expression	[19]
Lung cancer	DISCM4YA	Strong	Biomarker	[20]
Lung carcinoma	DISTR26C	Strong	Biomarker	[20]
Major depressive disorder	DIS4CL3X	Strong	Altered Expression	[21]
Metabolic disorder	DIS71G5H	Strong	Genetic Variation	[22]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[23]
Osteoarthritis	DIS05URM	Strong	Altered Expression	[24]
Osteoporosis	DISF2JE0	Strong	Biomarker	[25]
Retinitis pigmentosa	DISCGPY8	Strong	Biomarker	[26]
Retinitis pigmentosa 1	DISSLQPP	Strong	Biomarker	[26]
Secondary hyperparathyroidism	DISZX24B	Strong	Altered Expression	[27]
Stroke	DISX6UHX	Strong	Biomarker	[28]
Tumoral calcinosis, hyperphosphatemic, familial, 1	DISL1J2S	Strong	Biomarker	[8]
Type-1 diabetes	DIS7HLUB	Strong	Biomarker	[29]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[30]
Vascular disease	DISVS67S	Strong	Biomarker	[28]
Multiple sclerosis	DISB2WZI	moderate	Biomarker	[31]
Obsolete tumoral calcinosis, hyperphosphatemic, familial, 1	DISP6X5E	Supportive	Autosomal recessive	[6]
Skin disease	DISDW8R6	Disputed	Biomarker	[32]
Chronic renal failure	DISGG7K6	Limited	Genetic Variation	[22]
Diabetic kidney disease	DISJMWEY	Limited	Biomarker	[33]
Hyperlipidemia	DIS61J3S	Limited	Biomarker	[34]
Hyperlipoproteinemia	DISVBLBO	Limited	Biomarker	[34]
Hyperphosphatemia	DISHW3R3	Limited	Genetic Variation	[35]
Renal fibrosis	DISMHI3I	Limited	Biomarker	[36]
Rheumatoid arthritis	DISTSB4J	Limited	Biomarker	[7]
Tumoral calcinosis, hyperphosphatemic, familial, 3	DIS31PO5	Limited	Autosomal recessive	[37]
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Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Klotho (KL).	[38]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Klotho (KL).	[45]
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11 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 Klotho (KL).	[39]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Klotho (KL).	[40]
Phenobarbital	DMXZOCG	Approved	Phenobarbital decreases the expression of Klotho (KL).	[41]
Cocaine	DMSOX7I	Approved	Cocaine increases the expression of Klotho (KL).	[42]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Klotho (KL).	[43]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Klotho (KL).	[44]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the expression of Klotho (KL).	[44]
Guaiacol	DMN4E7T	Phase 3	Guaiacol decreases the expression of Klotho (KL).	[44]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Klotho (KL).	[44]
Puerarin	DMJIMXH	Phase 2	Puerarin decreases the expression of Klotho (KL).	[44]
Pyrrolidine dithiocarbamate	DM5ZAS6	Investigative	Pyrrolidine dithiocarbamate increases the expression of Klotho (KL).	[46]
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⏷ Show the Full List of 11 Drug(s)

References

1	Klotho is upregulated in human cardiomyopathy independently of circulating Klotho levels.Sci Rep. 2018 May 30;8(1):8429. doi: 10.1038/s41598-018-26539-6.
2	Age-Related Expression of Human AT1R Variants and Associated Renal Dysfunction in Transgenic Mice.Am J Hypertens. 2018 Oct 15;31(11):1234-1242. doi: 10.1093/ajh/hpy121.
3	Inhibition of Age-Related Therapy Resistance in Melanoma by Rosiglitazone-Mediated Induction of Klotho.Clin Cancer Res. 2017 Jun 15;23(12):3181-3190. doi: 10.1158/1078-0432.CCR-17-0201. Epub 2017 Feb 23.
4	The Hormone KL1: A Regulator of Breast Cancer Cell Metabolism.Isr Med Assoc J. 2019 Jul;21(7):504.
5	Discovery of Klotho peptide antagonists against Wnt3 and Wnt3a target proteins using combination of protein engineering, protein-protein docking, peptide docking and molecular dynamics simulations.J Enzyme Inhib Med Chem. 2017 Dec;32(1):84-98. doi: 10.1080/14756366.2016.1235569. Epub 2016 Oct 21.
6	A homozygous missense mutation in human KLOTHO causes severe tumoral calcinosis. J Clin Invest. 2007 Sep;117(9):2684-91. doi: 10.1172/JCI31330.
7	FGF23-Klotho axis in patients with rheumatoid arthritis.Clin Exp Rheumatol. 2020 Jan-Feb;38(1):50-57. Epub 2019 Apr 16.
8	N-ethyl-N-Nitrosourea (ENU) induced mutations within the klotho gene lead to ectopic calcification and reduced lifespan in mouse models.PLoS One. 2015 Apr 10;10(4):e0122650. doi: 10.1371/journal.pone.0122650. eCollection 2015.
9	Notch promotes DNMT-mediated hypermethylation of Klotho leads to COPD-related inflammation.Exp Lung Res. 2018 Sep;44(7):368-377. doi: 10.1080/01902148.2018.1556749. Epub 2019 Jan 26.
10	Lentiviral vector-mediated overexpression of Klotho in the brain improves Alzheimer's disease-like pathology and cognitive deficits in mice.Neurobiol Aging. 2019 Jun;78:18-28. doi: 10.1016/j.neurobiolaging.2019.02.003. Epub 2019 Feb 13.
11	Klotho suppresses colorectal cancer through modulation of the unfolded protein response.Oncogene. 2019 Feb;38(6):794-807. doi: 10.1038/s41388-018-0489-4. Epub 2018 Sep 19.
12	Klotho, fibroblast growth factor-23, and the renin-angiotensin system - an analysis from the PEACE trial.Eur J Heart Fail. 2019 Apr;21(4):462-470. doi: 10.1002/ejhf.1424. Epub 2019 Feb 18.
13	The Biological Role of Klotho Protein in the Development of Cardiovascular Diseases.Biomed Res Int. 2018 Dec 24;2018:5171945. doi: 10.1155/2018/5171945. eCollection 2018.
14	Relationship between cFGF23/Klotho ratio and phosphate levels in patients with chronic kidney disease.Int Urol Nephrol. 2019 Mar;51(3):503-507. doi: 10.1007/s11255-019-02079-4. Epub 2019 Jan 28.
15	Klotho: a tumor suppressor and modulator of the Wnt/-catenin pathway in human hepatocellular carcinoma.Lab Invest. 2016 Feb;96(2):197-205. doi: 10.1038/labinvest.2015.86. Epub 2015 Aug 3.
16	Placental and serum levels of human Klotho in severe preeclampsia: A potential sensitive biomarker.Placenta. 2019 Sep 15;85:49-55. doi: 10.1016/j.placenta.2019.08.084. Epub 2019 Aug 19.
17	Impact of Altered Mineral Metabolism on Pathological Cardiac Remodeling in Elevated Fibroblast Growth Factor 23.Front Endocrinol (Lausanne). 2018 Jun 21;9:333. doi: 10.3389/fendo.2018.00333. eCollection 2018.
18	Mutation of the mouse klotho gene leads to a syndrome resembling ageing.Nature. 1997 Nov 6;390(6655):45-51. doi: 10.1038/36285.
19	Role of Klotho in bone and implication for CKD.Curr Opin Nephrol Hypertens. 2018 Jul;27(4):298-304. doi: 10.1097/MNH.0000000000000423.
20	Overexpression of Klotho Inhibits HELF Fibroblasts SASP-related Protumoral Effects on Non-small Cell Lung Cancer Cells.J Cancer. 2018 Mar 14;9(7):1248-1258. doi: 10.7150/jca.23967. eCollection 2018.
21	Differences in the immune-inflammatory profiles of unipolar and bipolar depression.J Affect Disord. 2020 Feb 1;262:8-15. doi: 10.1016/j.jad.2019.10.037. Epub 2019 Oct 30.
22	Association of klotho gene polymorphism and the regulation of calcium-phosphate metabolism disorders in patients with end-stage renal disease.Nephrology (Carlton). 2019 Oct;24(10):1001-1008. doi: 10.1111/nep.13547. Epub 2019 May 2.
23	FGF23 and Klotho Levels are Independently Associated with Diabetic Foot Syndrome in Type 2 Diabetes Mellitus.J Clin Med. 2019 Apr 3;8(4):448. doi: 10.3390/jcm8040448.
24	Secreted -Klotho maintains cartilage tissue homeostasis by repressing NOS2 and ZIP8-MMP13 catabolic axis.Aging (Albany NY). 2018 Jun 19;10(6):1442-1453. doi: 10.18632/aging.101481.
25	Regulation of -Klotho Expression by Dietary Phosphate During Growth Periods.Calcif Tissue Int. 2019 Jun;104(6):667-678. doi: 10.1007/s00223-019-00525-0. Epub 2019 Jan 23.
26	Retinitis Pigmentosa: over-expression of anti-ageing protein Klotho in degenerating photoreceptors.J Neurochem. 2013 Dec;127(6):868-79. doi: 10.1111/jnc.12353. Epub 2013 Jul 22.
27	Changes in serum FGF23 and Klotho levels and calcification scores of the abdominal aorta after parathyroidectomy for secondary hyperparathyroidism.Am J Surg. 2019 Sep;218(3):609-612. doi: 10.1016/j.amjsurg.2018.12.026. Epub 2018 Dec 18.
28	Plasma Klotho concentrations predict functional outcome at three months after acute ischemic stroke patients.Ann Med. 2019 May-Jun;51(3-4):262-269. doi: 10.1080/07853890.2019.1617434. Epub 2019 Jun 5.
29	The KL-VS polymorphism of KLOTHO gene is protective against retinopathy incidence in patients with type 1 diabetes.Biochim Biophys Acta Mol Basis Dis. 2018 Mar;1864(3):758-763. doi: 10.1016/j.bbadis.2017.12.015. Epub 2017 Dec 13.
30	Soluble Klotho is associated with mortality and cardiovascular events in hemodialysis.BMC Nephrol. 2019 Jun 11;20(1):217. doi: 10.1186/s12882-019-1391-1.
31	Differential Expression of Klotho in the Brain and Spinal Cord is Associated with Total Antioxidant Capacity in Mice with Experimental Autoimmune Encephalomyelitis.J Mol Neurosci. 2018 Apr;64(4):543-550. doi: 10.1007/s12031-018-1058-6. Epub 2018 Mar 14.
32	Klotho Protein Protects Human Keratinocytes from UVB-Induced Damage Possibly by Reducing Expression and Nuclear Translocation of NF-B.Med Sci Monit. 2018 Nov 27;24:8583-8591. doi: 10.12659/MSM.910687.
33	Klotho attenuates diabetic nephropathy in db/db mice and ameliorates high glucose-induced injury of human renal glomerular endothelial cells.Cell Cycle. 2019 Mar-Apr;18(6-7):696-707. doi: 10.1080/15384101.2019.1580495. Epub 2019 Mar 17.
34	Endothelial dysfunction in the klotho mouse and downregulation of klotho gene expression in various animal models of vascular and metabolic diseases.Cell Mol Life Sci. 2000 May;57(5):738-46. doi: 10.1007/s000180050038.
35	A Novel Heterozygous Deletion Variant in KLOTHO Gene Leading to Haploinsufficiency and Impairment of Fibroblast Growth Factor 23 Signaling Pathway.J Clin Med. 2019 Apr 12;8(4):500. doi: 10.3390/jcm8040500.
36	Klotho recovery by genistein via promoter histone acetylation and DNA demethylation mitigates renal fibrosis in mice.J Mol Med (Berl). 2019 Apr;97(4):541-552. doi: 10.1007/s00109-019-01759-z. Epub 2019 Feb 26.
37	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.
38	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.
39	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.
40	Gene expression profile induced by arsenic trioxide in chronic lymphocytic leukemia cells reveals a central role for heme oxygenase-1 in apoptosis and regulation of matrix metalloproteinase-9. Oncotarget. 2016 Dec 13;7(50):83359-83377.
41	Dose- and time-dependent effects of phenobarbital on gene expression profiling in human hepatoma HepaRG cells. Toxicol Appl Pharmacol. 2009 Feb 1;234(3):345-60.
42	Gene expression profile of the nucleus accumbens of human cocaine abusers: evidence for dysregulation of myelin. J Neurochem. 2004 Mar;88(5):1211-9. doi: 10.1046/j.1471-4159.2003.02247.x.
43	LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
44	Examining the genomic influence of skin antioxidants in vitro. Mediators Inflamm. 2010;2010.
45	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.
46	Indoxyl sulfate downregulates renal expression of Klotho through production of ROS and activation of nuclear factor-?B. Am J Nephrol. 2011;33(4):319-24. doi: 10.1159/000324885. Epub 2011 Mar 9.