Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTG7N3J7)

DOT Name	Phosphate-regulating neutral endopeptidase PHEX (PHEX)
Synonyms	EC 3.4.24.-; Metalloendopeptidase homolog PEX; Vitamin D-resistant hypophosphatemic rickets protein; X-linked hypophosphatemia protein; HYP
Gene Name	PHEX
Related Disease	Asthma ( ) Disorder of glycogen metabolism ( ) Rheumatoid arthritis ( ) X-linked dominant hypophosphatemic rickets ( ) Autosomal dominant hypophosphatemic rickets ( ) Autosomal recessive hypophosphatemic rickets ( ) Cataract ( ) Colitis ( ) Craniosynostosis ( ) Epilepsy ( ) Head and neck cancer ( ) Head and neck carcinoma ( ) Hepatocellular carcinoma ( ) High blood pressure ( ) Hyperparathyroidism ( ) Inborn error of immunity ( ) Kidney failure ( ) Liver cirrhosis ( ) Multiple sclerosis ( ) Neoplasm ( ) Nephrocalcinosis ( ) Neuralgia ( ) Otitis media ( ) Pituitary dwarfism ( ) Polyneuropathy ( ) Psoriatic arthritis ( ) Pulmonary fibrosis ( ) Relapsing-remitting multiple sclerosis ( ) Transposition of the great arteries ( ) Vitamin D deficiency ( ) X-linked hypophosphatemic rickets ( ) Zellweger spectrum disorders ( ) Alcohol dependence ( ) Bone development disease ( ) Cone-rod dystrophy ( ) Squamous cell carcinoma ( ) Congenital thrombotic thrombocytopenic purpura ( ) Thrombotic thrombocytopenic purpura ( ) Bone osteosarcoma ( ) Glioma ( ) Hypophosphatemia ( ) Hypophosphatemic rickets ( ) Malignant glioma ( ) Metabolic bone disease ( ) Osteosarcoma ( ) Paraneoplastic syndrome ( )
UniProt ID	PHEX_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
EC Number	3.4.24.-
Pfam ID	PF01431 ; PF05649
Sequence	MEAETGSSVETGKKANRGTRIALVVFVGGTLVLGTILFLVSQGLLSLQAKQEYCLKPECI EAAAAILSKVNLSVDPCDNFFRFACDGWISNNPIPEDMPSYGVYPWLRHNVDLKLKELLE KSISRRRDTEAIQKAKILYSSCMNEKAIEKADAKPLLHILRHSPFRWPVLESNIGPEGVW SERKFSLLQTLATFRGQYSNSVFIRLYVSPDDKASNEHILKLDQATLSLAVREDYLDNST EAKSYRDALYKFMVDTAVLLGANSSRAEHDMKSVLRLEIKIAEIMIPHENRTSEAMYNKM NISELSAMIPQFDWLGYIKKVIDTRLYPHLKDISPSENVVVRVPQYFKDLFRILGSERKK TIANYLVWRMVYSRIPNLSRRFQYRWLEFSRVIQGTTTLLPQWDKCVNFIESALPYVVGK MFVDVYFQEDKKEMMEELVEGVRWAFIDMLEKENEWMDAGTKRKAKEKARAVLAKVGYPE FIMNDTHVNEDLKAIKFSEADYFGNVLQTRKYLAQSDFFWLRKAVPKTEWFTNPTTVNAF YSASTNQIRFPAGELQKPFFWGTEYPRSLSYGAIGVIVGHEFTHGFDNNGRKYDKNGNLD PWWSTESEEKFKEKTKCMINQYSNYYWKKAGLNVKGKRTLGENIADNGGLREAFRAYRKW INDRRQGLEEPLLPGITFTNNQLFFLSYAHVRCNSYRPEAAREQVQIGAHSPPQFRVNGA ISNFEEFQKAFNCPPNSTMNRGMDSCRLW
Function	Peptidase that cleaves SIBLING (small integrin-binding ligand, N-linked glycoprotein)-derived ASARM peptides, thus regulating their biological activity. Cleaves ASARM peptides between Ser and Glu or Asp residues. Regulates osteogenic cell differentiation and bone mineralization through the cleavage of the MEPE-derived ASARM peptide. Promotes dentin mineralization and renal phosphate reabsorption by cleaving DMP1- and MEPE-derived ASARM peptides. Inhibits the cleavage of MEPE by CTSB/cathepsin B thus preventing MEPE degradation.
Tissue Specificity	Specifically expressed in ovary . Expressed at low levels in kidney .

Molecular Interaction Atlas (MIA) of This DOT

46 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Asthma	DISW9QNS	Definitive	Biomarker	[1]
Disorder of glycogen metabolism	DISYGNOB	Definitive	Genetic Variation	[2]
Rheumatoid arthritis	DISTSB4J	Definitive	Biomarker	[3]
X-linked dominant hypophosphatemic rickets	DISU3OP6	Definitive	X-linked	[2]
Autosomal dominant hypophosphatemic rickets	DISG799S	Strong	Genetic Variation	[4]
Autosomal recessive hypophosphatemic rickets	DIS8E3KA	Strong	Genetic Variation	[2]
Cataract	DISUD7SL	Strong	Biomarker	[5]
Colitis	DISAF7DD	Strong	Altered Expression	[6]
Craniosynostosis	DIS6J405	Strong	Genetic Variation	[7]
Epilepsy	DISBB28L	Strong	Biomarker	[8]
Head and neck cancer	DISBPSQZ	Strong	Biomarker	[9]
Head and neck carcinoma	DISOU1DS	Strong	Biomarker	[9]
Hepatocellular carcinoma	DIS0J828	Strong	Genetic Variation	[10]
High blood pressure	DISY2OHH	Strong	Biomarker	[11]
Hyperparathyroidism	DIS4FVAT	Strong	Genetic Variation	[12]
Inborn error of immunity	DISNGCMN	Strong	Biomarker	[13]
Kidney failure	DISOVQ9P	Strong	Biomarker	[14]
Liver cirrhosis	DIS4G1GX	Strong	Genetic Variation	[10]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[15]
Neoplasm	DISZKGEW	Strong	Biomarker	[16]
Nephrocalcinosis	DIS5ZVJP	Strong	Genetic Variation	[17]
Neuralgia	DISWO58J	Strong	Biomarker	[18]
Otitis media	DISGZDUO	Strong	Biomarker	[19]
Pituitary dwarfism	DISI019B	Strong	Biomarker	[13]
Polyneuropathy	DISB9G3W	Strong	Genetic Variation	[20]
Psoriatic arthritis	DISLWTG2	Strong	Genetic Variation	[21]
Pulmonary fibrosis	DISQKVLA	Strong	Biomarker	[22]
Relapsing-remitting multiple sclerosis	DISSXFCF	Strong	Biomarker	[23]
Transposition of the great arteries	DISPXJ8X	Strong	Genetic Variation	[24]
Vitamin D deficiency	DISAWKYI	Strong	Biomarker	[25]
X-linked hypophosphatemic rickets	DISFTLIR	Strong	Genetic Variation	[26]
Zellweger spectrum disorders	DISW52CE	Strong	Genetic Variation	[27]
Alcohol dependence	DIS4ZSCO	moderate	Biomarker	[28]
Bone development disease	DISVKAZS	moderate	Genetic Variation	[29]
Cone-rod dystrophy	DISY9RWN	moderate	Genetic Variation	[30]
Squamous cell carcinoma	DISQVIFL	moderate	Biomarker	[16]
Congenital thrombotic thrombocytopenic purpura	DISC8GS9	Disputed	Biomarker	[31]
Thrombotic thrombocytopenic purpura	DIS3LDOU	Disputed	Biomarker	[31]
Bone osteosarcoma	DIST1004	Limited	Altered Expression	[32]
Glioma	DIS5RPEH	Limited	Biomarker	[33]
Hypophosphatemia	DIS9DZYF	Limited	Genetic Variation	[7]
Hypophosphatemic rickets	DIS7XTW5	Limited	Genetic Variation	[7]
Malignant glioma	DISFXKOV	Limited	Altered Expression	[33]
Metabolic bone disease	DISO7RI8	Limited	Altered Expression	[34]
Osteosarcoma	DISLQ7E2	Limited	Altered Expression	[32]
Paraneoplastic syndrome	DISJUN66	Limited	Altered Expression	[34]
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Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

4 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Phosphate	DMUXQG7	Approved	Phosphate increases the expression of Phosphate-regulating neutral endopeptidase PHEX (PHEX).	[35]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Phosphate-regulating neutral endopeptidase PHEX (PHEX).	[36]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Phosphate-regulating neutral endopeptidase PHEX (PHEX).	[37]
Glycerol-2-Phosphate	DM0J5KF	Investigative	Glycerol-2-Phosphate increases the expression of Phosphate-regulating neutral endopeptidase PHEX (PHEX).	[38]
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References

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3	Hypericin-photodynamic therapy inhibits proliferation and induces apoptosis in human rheumatoid arthritis fibroblast-like synoviocytes cell line MH7A.Iran J Basic Med Sci. 2018 Feb;21(2):130-137. doi: 10.22038/IJBMS.2018.23871.5991.
4	Osteocyte regulation of phosphate homeostasis and bone mineralization underlies the pathophysiology of the heritable disorders of rickets and osteomalacia.Bone. 2013 Jun;54(2):213-21. doi: 10.1016/j.bone.2013.01.046. Epub 2013 Feb 9.
5	Late in-the-bag spontaneous IOL dislocation: risk factors and surgical outcomes.Int J Ophthalmol. 2019 Jun 18;12(6):954-960. doi: 10.18240/ijo.2019.06.12. eCollection 2019.
6	Cooperative role of NF-{kappa}B and poly(ADP-ribose) polymerase 1 (PARP-1) in the TNF-induced inhibition of PHEX expression in osteoblasts.J Biol Chem. 2010 Nov 5;285(45):34828-38. doi: 10.1074/jbc.M110.152868. Epub 2010 Sep 3.
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8	Cytogenetic damage by melphalan and hyperthermia in patients with an initial epileptic attack.Mutat Res. 1992 Aug;280(2):143-8. doi: 10.1016/0165-1218(92)90010-w.
9	Monte Carlo radiotherapy simulations of accelerated repopulation and reoxygenation for hypoxic head and neck cancer.Br J Radiol. 2011 Oct;84(1006):903-18. doi: 10.1259/bjr/25012212.
10	Comparison of murine steatohepatitis models identifies a dietary intervention with robust fibrosis, ductular reaction, and rapid progression to cirrhosis and cancer.Am J Physiol Gastrointest Liver Physiol. 2020 Jan 1;318(1):G174-G188. doi: 10.1152/ajpgi.00041.2019. Epub 2019 Oct 21.
11	A brief submaximal isometric exercise test 'unmasks' systolic and diastolic masked hypertension.J Hypertens. 2019 Apr;37(4):710-719. doi: 10.1097/HJH.0000000000001943.
12	The enigma of hyperparathyroidism in hypophosphatemic rickets.Pediatr Nephrol. 2004 May;19(5):473-7. doi: 10.1007/s00467-004-1443-y. Epub 2004 Mar 11.
13	X-linked hypogammaglobulinemia and isolated growth hormone deficiency: an update. Immunol Res. 2008;40(3):262-70. doi: 10.1007/s12026-007-0028-9.
14	Differential regulation of PHEX expression in bone and parathyroid gland by chronic renal insufficiency and 1,25-dihydroxyvitamin D3.Am J Physiol Renal Physiol. 2004 Apr;286(4):F739-48. doi: 10.1152/ajprenal.00321.2003. Epub 2003 Dec 23.
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16	Expression and inactivation of osteopontin-degrading PHEX enzyme in squamous cell carcinoma.Int J Biochem Cell Biol. 2016 Aug;77(Pt A):155-164. doi: 10.1016/j.biocel.2016.05.016. Epub 2016 Jun 4.
17	Hypophosphatemic Rickets.Pediatr Clin North Am. 2019 Feb;66(1):179-207. doi: 10.1016/j.pcl.2018.09.004.
18	HYP-17, a novel voltage-gated sodium channel blocker, relieves inflammatory and neuropathic pain in rats.Pharmacol Biochem Behav. 2017 Feb;153:116-129. doi: 10.1016/j.pbb.2016.12.013. Epub 2016 Dec 24.
19	A mouse model with postnatal endolymphatic hydrops and hearing loss.Hear Res. 2008 Mar;237(1-2):90-105. doi: 10.1016/j.heares.2008.01.002. Epub 2008 Jan 15.
20	Variant analysis of PEX11B gene from a family with peroxisome biogenesis disorder 14B by whole exome sequencing.Mol Genet Genomic Med. 2020 Jan;8(1):10.1002/mgg3.1042. doi: 10.1002/mgg3.1042. Epub 2019 Nov 13.
21	PHEX 3'-UTR c.*231A>G near the polyadenylation signal is a relatively common, mild, American mutation that masquerades as sporadic or X-linked recessive hypophosphatemic rickets.J Bone Miner Res. 2015 Jan;30(1):137-43. doi: 10.1002/jbmr.2307.
22	Costunolide inhibits pulmonary fibrosis via regulating NF-kB and TGF-(1)/Smad(2)/Nrf(2)-NOX(4) signaling pathways.Biochem Biophys Res Commun. 2019 Mar 5;510(2):329-333. doi: 10.1016/j.bbrc.2019.01.104. Epub 2019 Jan 29.
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24	Effect of GH replacement therapy in two male siblings with combined X-linked hypophosphatemia and partial GH deficiency.Eur J Endocrinol. 2003 Oct;149(4):317-21. doi: 10.1530/eje.0.1490317.
25	The rachitic tooth.Endocr Rev. 2014 Feb;35(1):1-34. doi: 10.1210/er.2013-1009. Epub 2013 Dec 4.
26	'Isolated' germline mosaicism in the phenotypically normal father of a girl with X-linked hypophosphatemic rickets.Eur J Endocrinol. 2020 Jan;182(1):K1-K6. doi: 10.1530/EJE-19-0472.
27	Biochemical and clinical profiles of 52 Tunisian patients affected by Zellweger syndrome.Pediatr Neonatol. 2017 Dec;58(6):484-489. doi: 10.1016/j.pedneo.2016.08.011. Epub 2017 Feb 17.
28	Genetic and environmental influences on externalizing behavior and alcohol problems in adolescence: a female twin study.Pharmacol Biochem Behav. 2009 Sep;93(3):313-21. doi: 10.1016/j.pbb.2009.03.011. Epub 2009 Mar 31.
29	A pilot study of gene testing of genetic bone dysplasia using targeted next-generation sequencing.J Hum Genet. 2015 Dec;60(12):769-76. doi: 10.1038/jhg.2015.112. Epub 2015 Sep 17.
30	An Xp22.1-p22.2 YAC contig encompassing the disease loci for RS, KFSD, CLS, HYP and RP15: refined localization of RS.Eur J Hum Genet. 1996;4(2):101-4. doi: 10.1159/000472177.
31	Management of thrombotic thrombocytopenic purpura without plasma exchange: the Jehovah's Witness experience.Blood Adv. 2017 Oct 30;1(24):2161-2165. doi: 10.1182/bloodadvances.2017012351. eCollection 2017 Nov 14.
32	Significance of NF-kappaB signaling and PARP1 activity in the TNF-induced inhibition of PHEX gene expression in human osteoblasts.Acta Biochim Pol. 2018 Nov 15;65(4):573-571. doi: 10.18388/abp.2018_2633.
33	PEX-producing human neural stem cells inhibit tumor growth in a mouse glioma model.Clin Cancer Res. 2005 Aug 15;11(16):5965-70. doi: 10.1158/1078-0432.CCR-05-0371.
34	Cloning of human PEX cDNA. Expression, subcellular localization, and endopeptidase activity.J Biol Chem. 1998 May 29;273(22):13729-37. doi: 10.1074/jbc.273.22.13729.
35	Bone as a source of FGF23: regulation by phosphate?. Bone. 2004 Nov;35(5):1192-9. doi: 10.1016/j.bone.2004.06.014.
36	Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
37	BET bromodomain protein inhibition is a therapeutic option for medulloblastoma. Oncotarget. 2013 Nov;4(11):2080-95.
38	The role of tissue-nonspecific alkaline phosphatase in the phosphate-induced activation of alkaline phosphatase and mineralization in SaOS-2 human osteoblast-like cells. Mol Cell Biochem. 2008 Aug;315(1-2):51-60.