Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTD5VJ9A)

• DOT Name: Lysosomal thioesterase PPT2 (PPT2)
• Synonyms: PPT-2; EC 3.1.2.-; S-thioesterase G14
• Gene Name: PPT2
• Related Disease:
  Neoplasm
  Advanced cancer
  Lysosomal storage disease
  Membranous glomerulonephritis
  Multiple sclerosis
  Neuroblastoma
  Neuronal ceroid lipofuscinosis
  Plasma cell myeloma
  Prostate neoplasm
  Pulmonary emphysema
  Rheumatoid arthritis
  Type-1 diabetes
  Vitiligo
  Cerebellar ataxia
• UniProt ID: PPT2_HUMAN
• PDB ID: 1PJA
• EC Number: 3.1.2.-
• Pfam ID: PF02089
• Sequence:
  MLGLCGQRLPAAWVLLLLPFLPLLLLAAPAPHRASYKPVIVVHGLFDSSYSFRHLLEYIN
  ETHPGTVVTVLDLFDGRESLRPLWEQVQGFREAVVPIMAKAPQGVHLICYSQGGLVCRAL
  LSVMDDHNVDSFISLSSPQMGQYGDTDYLKWLFPTSMRSNLYRICYSPWGQEFSICNYWH
  DPHHDDLYLNASSFLALINGERDHPNATVWRKNFLRVGHLVLIGGPDDGVITPWQSSFFG
  FYDANETVLEMEEQLVYLRDSFGLKTLLARGAIVRCPMAGISHTAWHSNRTLYETCIEPW
  LS
• Function: Removes thioester-linked fatty acyl groups from various substrates including S-palmitoyl-CoA. Has the highest S-thioesterase activity for the acyl groups palmitic and myristic acid followed by other short- and long-chain acyl substrates. However, because of structural constraints, is unable to remove palmitate from peptides or proteins.
• Tissue Specificity: Broadly expressed, with highest levels in skeletal muscle.
• KEGG Pathway:
  Fatty acid elongation (hsa00062)
  Metabolic pathways (hsa01100)
  Fatty acid metabolism (hsa01212)
  Lysosome (hsa04142)
• Reactome Pathway: Fatty acyl-CoA biosynthesis (R-HSA-75105)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Lysosomal storage disease	DIS6QM6U	Strong	Biomarker	[3]
Membranous glomerulonephritis	DISFSUKQ	Strong	Genetic Variation	[4]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[5]
Neuroblastoma	DISVZBI4	Strong	Altered Expression	[6]
Neuronal ceroid lipofuscinosis	DIS9A4K4	Strong	Biomarker	[7]
Plasma cell myeloma	DIS0DFZ0	Strong	Genetic Variation	[8]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[2]
Pulmonary emphysema	DIS5M7HZ	Strong	Genetic Variation	[9]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[10]
Type-1 diabetes	DIS7HLUB	Strong	Genetic Variation	[11]
Vitiligo	DISR05SL	Strong	Genetic Variation	[12]
Cerebellar ataxia	DIS9IRAV	Limited	Biomarker	[3]

6 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 Lysosomal thioesterase PPT2 (PPT2).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Lysosomal thioesterase PPT2 (PPT2).	[14]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Lysosomal thioesterase PPT2 (PPT2).	[15]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Lysosomal thioesterase PPT2 (PPT2).	[17]
Mifepristone	DMGZQEF	Approved	Mifepristone increases the expression of Lysosomal thioesterase PPT2 (PPT2).	[18]
Acocantherin	DM7JT24	Approved	Acocantherin decreases the expression of Lysosomal thioesterase PPT2 (PPT2).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Lysosomal thioesterase PPT2 (PPT2).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Lysosomal thioesterase PPT2 (PPT2).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Lysosomal thioesterase PPT2 (PPT2).	[21]

References

• [1] Prostate cancer stem cell-targeted efficacy of a new-generation taxoid, SBT-1214 and novel polyenolic zinc-binding curcuminoid, CMC2.24.PLoS One. 2013 Sep 24;8(9):e69884. doi: 10.1371/journal.pone.0069884. eCollection 2013.
• [2] Biodistribution and Pharmacokinetic Evaluations of a Novel Taxoid DHA-SBT-1214 in an Oil-in-Water Nanoemulsion Formulation in Nave and Tumor-Bearing Mice.Pharm Res. 2018 Mar 8;35(4):91. doi: 10.1007/s11095-018-2349-x.
• [3] Disruption of PPT2 in mice causes an unusual lysosomal storage disorder with neurovisceral features.Proc Natl Acad Sci U S A. 2003 Oct 14;100(21):12325-30. doi: 10.1073/pnas.2033229100. Epub 2003 Oct 3.
• [4] Risk HLA-DQA1 and PLA(2)R1 alleles in idiopathic membranous nephropathy.N Engl J Med. 2011 Feb 17;364(7):616-26. doi: 10.1056/NEJMoa1009742.
• [5] Evidence for VAV2 and ZNF433 as susceptibility genes for multiple sclerosis.J Neuroimmunol. 2010 Oct 8;227(1-2):162-6. doi: 10.1016/j.jneuroim.2010.06.003. Epub 2010 Jul 2.
• [6] Neurokinin-immunoreactivity in human neuroblastomas. Evidence for selective expression of the preprotachykinin (PPT) II gene.FEBS Lett. 1990 Dec 17;277(1-2):83-7. doi: 10.1016/0014-5793(90)80814-y.
• [7] Correlations between genotype, ultrastructural morphology and clinical phenotype in the neuronal ceroid lipofuscinoses.Neurogenetics. 2005 Sep;6(3):107-26. doi: 10.1007/s10048-005-0218-3. Epub 2005 Sep 28.
• [8] Common variation at 3q26.2, 6p21.33, 17p11.2 and 22q13.1 influences multiple myeloma risk.Nat Genet. 2013 Oct;45(10):1221-1225. doi: 10.1038/ng.2733. Epub 2013 Aug 18.
• [9] Genome-wide study of percent emphysema on computed tomography in the general population. The Multi-Ethnic Study of Atherosclerosis Lung/SNP Health Association Resource Study.Am J Respir Crit Care Med. 2014 Feb 15;189(4):408-18. doi: 10.1164/rccm.201306-1061OC.
• [10] A genome-wide association study suggests contrasting associations in ACPA-positive versus ACPA-negative rheumatoid arthritis.Ann Rheum Dis. 2011 Feb;70(2):259-65. doi: 10.1136/ard.2009.126821. Epub 2010 Dec 14.
• [11] A genome-wide association study identifies KIAA0350 as a type 1 diabetes gene.Nature. 2007 Aug 2;448(7153):591-4. doi: 10.1038/nature06010. Epub 2007 Jul 15.
• [12] Genome-wide association study for vitiligo identifies susceptibility loci at 6q27 and the MHC.Nat Genet. 2010 Jul;42(7):614-8. doi: 10.1038/ng.603. Epub 2010 Jun 6.
• [13] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [14] Gamma-irradiation and doxorubicin treatment of normal human cells cause cell cycle arrest via different pathways. Mol Cells. 2005 Dec 31;20(3):331-8.
• [15] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [16] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [17] 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.
• [18] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [19] Ouabain at pathological concentrations might induce damage in human vascular endothelial cells. Acta Pharmacol Sin. 2006 Feb;27(2):165-72. doi: 10.1111/j.1745-7254.2006.00244.x.
• [20] 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.
• [21] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.