Details of Drug Off-Target (DOT)

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

• DOT Name: Pappalysin-2 (PAPPA2)
• Synonyms: EC 3.4.24.-; Pregnancy-associated plasma protein A2; PAPP-A2; Pregnancy-associated plasma protein E1; PAPP-E
• Gene Name: PAPPA2
• Related Disease:
  Precocious puberty
  Advanced cancer
  Classic Hodgkin lymphoma
  Eclampsia
  Fetal growth restriction
  Huntington disease
  Short stature, Dauber-Argente type
  Stroke
  Venous thromboembolism
  Pregnancy disorder
• UniProt ID: PAPP2_HUMAN
• PDB ID: 8SL1
• EC Number: 3.4.24.-
• Pfam ID: PF13385 ; PF05572 ; PF00084
• Sequence:
  MMCLKILRISLAILAGWALCSANSELGWTRKKSLVEREHLNQVLLEGERCWLGAKVRRPR
  ASPQHHLFGVYPSRAGNYLRPYPVGEQEIHHTGRSKPDTEGNAVSLVPPDLTENPAGLRG
  AVEEPAAPWVGDSPIGQSELLGDDDAYLGNQRSKESLGEAGIQKGSAMAATTTTAIFTTL
  NEPKPETQRRGWAKSRQRRQVWKRRAEDGQGDSGISSHFQPWPKHSLKHRVKKSPPEESN
  QNGGEGSYREAETFNSQVGLPILYFSGRRERLLLRPEVLAEIPREAFTVEAWVKPEGGQN
  NPAIIAGVFDNCSHTVSDKGWALGIRSGKDKGKRDARFFFSLCTDRVKKATILISHSRYQ
  PGTWTHVAATYDGRHMALYVDGTQVASSLDQSGPLNSPFMASCRSLLLGGDSSEDGHYFR
  GHLGTLVFWSTALPQSHFQHSSQHSSGEEEATDLVLTASFEPVNTEWVPFRDEKYPRLEV
  LQGFEPEPEILSPLQPPLCGQTVCDNVELISQYNGYWPLRGEKVIRYQVVNICDDEGLNP
  IVSEEQIRLQHEALNEAFSRYNISWQLSVHQVHNSTLRHRVVLVNCEPSKIGNDHCDPEC
  EHPLTGYDGGDCRLQGRCYSWNRRDGLCHVECNNMLNDFDDGDCCDPQVADVRKTCFDPD
  SPKRAYMSVKELKEALQLNSTHFLNIYFASSVREDLAGAATWPWDKDAVTHLGGIVLSPA
  YYGMPGHTDTMIHEVGHVLGLYHVFKGVSERESCNDPCKETVPSMETGDLCADTAPTPKS
  ELCREPEPTSDTCGFTRFPGAPFTNYMSYTDDNCTDNFTPNQVARMHCYLDLVYQQWTES
  RKPTPIPIPPMVIGQTNKSLTIHWLPPISGVVYDRASGSLCGACTEDGTFRQYVHTASSR
  RVCDSSGYWTPEEAVGPPDVDQPCEPSLQAWSPEVHLYHMNMTVPCPTEGCSLELLFQHP
  VQADTLTLWVTSFFMESSQVLFDTEILLENKESVHLGPLDTFCDIPLTIKLHVDGKVSGV
  KVYTFDERIEIDAALLTSQPHSPLCSGCRPVRYQVLRDPPFASGLPVVVTHSHRKFTDVE
  VTPGQMYQYQVLAEAGGELGEASPPLNHIHGAPYCGDGKVSERLGEECDDGDLVSGDGCS
  KVCELEEGFNCVGEPSLCYMYEGDGICEPFERKTSIVDCGIYTPKGYLDQWATRAYSSHE
  DKKKCPVSLVTGEPHSLICTSYHPDLPNHRPLTGWFPCVASENETQDDRSEQPEGSLKKE
  DEVWLKVCFNRPGEARAIFIFLTTDGLVPGEHQQPTVTLYLTDVRGSNHSLGTYGLSCQH
  NPLIINVTHHQNVLFHHTTSVLLNFSSPRVGISAVALRTSSRIGLSAPSNCISEDEGQNH
  QGQSCIHRPCGKQDSCPSLLLDHADVVNCTSIGPGLMKCAITCQRGFALQASSGQYIRPM
  QKEILLTCSSGHWDQNVSCLPVDCGVPDPSLVNYANFSCSEGTKFLKRCSISCVPPAKLQ
  GLSPWLTCLEDGLWSLPEVYCKLECDAPPIILNANLLLPHCLQDNHDVGTICKYECKPGY
  YVAESAEGKVRNKLLKIQCLEGGIWEQGSCIPVVCEPPPPVFEGMYECTNGFSLDSQCVL
  NCNQEREKLPILCTKEGLWTQEFKLCENLQGECPPPPSELNSVEYKCEQGYGIGAVCSPL
  CVIPPSDPVMLPENITADTLEHWMEPVKVQSIVCTGRRQWHPDPVLVHCIQSCEPFQADG
  WCDTINNRAYCHYDGGDCCSSTLSSKKVIPFAADCDLDECTCRDPKAEENQ
• Function: Metalloproteinase which specifically cleaves insulin-like growth factor binding protein (IGFBP)-5 at the '163-Ser-|-Lys-164' bond. Shows limited proteolysis toward IGFBP-3.
• Tissue Specificity: Expressed abundantly in placenta, and non-pregnant mammary gland with low expression in the kidney, fetal brain and pancreas.
• Reactome Pathway: Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) (R-HSA-381426)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Precocious puberty	DISYI2XZ	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[2]
Classic Hodgkin lymphoma	DISV1LU6	Strong	Biomarker	[3]
Eclampsia	DISWPO8U	Strong	Altered Expression	[4]
Fetal growth restriction	DIS5WEJ5	Strong	Altered Expression	[5]
Huntington disease	DISQPLA4	Strong	Biomarker	[3]
Short stature, Dauber-Argente type	DIS0JJA7	Strong	Autosomal recessive	[6]
Stroke	DISX6UHX	moderate	Genetic Variation	[7]
Venous thromboembolism	DISUR7CR	moderate	Genetic Variation	[8]
Pregnancy disorder	DIS5V7J6	Limited	Biomarker	[4]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Pappalysin-2 (PAPPA2) affects the response to substance of Cisplatin.	[16]

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 Pappalysin-2 (PAPPA2).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Pappalysin-2 (PAPPA2).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Pappalysin-2 (PAPPA2).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Pappalysin-2 (PAPPA2).	[11]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Pappalysin-2 (PAPPA2).	[12]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Pappalysin-2 (PAPPA2).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Pappalysin-2 (PAPPA2).	[15]

References

• [1] Genomic association for sexual precocity in beef heifers using pre-selection of genes and haplotype reconstruction.PLoS One. 2018 Jan 2;13(1):e0190197. doi: 10.1371/journal.pone.0190197. eCollection 2018.
• [2] Identification and characterization of cancer mutations in Japanese lung adenocarcinoma without sequencing of normal tissue counterparts.PLoS One. 2013 Sep 12;8(9):e73484. doi: 10.1371/journal.pone.0073484. eCollection 2013.
• [3] Pregnancy-Associated Plasma Protein A2 in Hemodialysis Patients: Significance for Prognosis.Kidney Blood Press Res. 2017;42(3):509-518. doi: 10.1159/000479847. Epub 2017 Aug 30.
• [4] PAPPA2 is increased in severe early onset pre-eclampsia and upregulated with hypoxia.Reprod Fertil Dev. 2014 Jan;26(2):351-7. doi: 10.1071/RD12384.
• [5] Placental expression of PAPPA, PAPPA-2 and PLAC-1 in pregnacies is associated with FGR.Mol Med Rep. 2018 May;17(5):6435-6440. doi: 10.3892/mmr.2018.8721. Epub 2018 Mar 9.
• [6] Mutations in pregnancy-associated plasma protein A2 cause short stature due to low IGF-I availability. EMBO Mol Med. 2016 Apr 1;8(4):363-74. doi: 10.15252/emmm.201506106.
• [7] Common variants at 6p21.1 are associated with large artery atherosclerotic stroke.Nat Genet. 2012 Oct;44(10):1147-51. doi: 10.1038/ng.2397. Epub 2012 Sep 2.
• [8] A genome-wide search for common SNP x SNP interactions on the risk of venous thrombosis.BMC Med Genet. 2013 Mar 20;14:36. doi: 10.1186/1471-2350-14-36.
• [9] 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.
• [10] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [11] 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.
• [12] Oxidative Stress Alters miRNA and Gene Expression Profiles in Villous First Trimester Trophoblasts. Biomed Res Int. 2015;2015:257090. doi: 10.1155/2015/257090. Epub 2015 Aug 3.
• [13] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [14] 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.
• [15] 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.
• [16] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.