Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTP9COQT)

• DOT Name: Phosphatidylserine decarboxylase proenzyme, mitochondrial (PISD)
• Synonyms: EC 4.1.1.65
• Gene Name: PISD
• Related Disease:
  Advanced cancer
  Liberfarb syndrome
  Neoplasm
  Spondyloepimetaphyseal dysplasia
  Clear cell renal carcinoma
  Cataract
  Human papillomavirus infection
  Intellectual disability
  Isolated congenital microcephaly
  Osteochondrodysplasia
  Skeletal dysplasia
• UniProt ID: PISD_HUMAN
• EC Number: 4.1.1.65
• Pfam ID: PF02666
• Sequence:
  MATSVGHRCLGLLHGVAPWRSSLHPCEITALSQSLQPLRKLPFRAFRTDARKIHTAPART
  MFLLRPLPILLVTGGGYAGYRQYEKYRERELEKLGLEIPPKLAGHWEVALYKSVPTRLLS
  RAWGRLNQVELPHWLRRPVYSLYIWTFGVNMKEAAVEDLHHYRNLSEFFRRKLKPQARPV
  CGLHSVISPSDGRILNFGQVKNCEVEQVKGVTYSLESFLGPRMCTEDLPFPPAASCDSFK
  NQLVTREGNELYHCVIYLAPGDYHCFHSPTDWTVSHRRHFPGSLMSVNPGMARWIKELFC
  HNERVVLTGDWKHGFFSLTAVGATNVGSIRIYFDRDLHTNSPRHSKGSYNDFSFVTHTNR
  EGVPMRKGEHLGEFNLGSTIVLIFEAPKDFNFQLKTGQKIRFGEALGSL
• Function: Catalyzes the formation of phosphatidylethanolamine (PtdEtn) from phosphatidylserine (PtdSer). Plays a central role in phospholipid metabolism and in the interorganelle trafficking of phosphatidylserine. May be involved in lipid droplet biogenesis at the endoplasmic reticulum membrane.
• KEGG Pathway:
  Glycerophospholipid metabolism (hsa00564)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Synthesis of PE (R-HSA-1483213)
• BioCyc Pathway: MetaCyc:HS01985-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Liberfarb syndrome	DISGD13Z	Strong	Autosomal recessive	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Spondyloepimetaphyseal dysplasia	DISO4L5A	Strong	Genetic Variation	[2]
Clear cell renal carcinoma	DISBXRFJ	moderate	Biomarker	[3]
Cataract	DISUD7SL	Limited	Biomarker	[4]
Human papillomavirus infection	DISX61LX	Limited	Genetic Variation	[5]
Intellectual disability	DISMBNXP	Limited	Biomarker	[4]
Isolated congenital microcephaly	DISUXHZ6	Limited	Biomarker	[4]
Osteochondrodysplasia	DIS9SPWW	Limited	Biomarker	[4]
Skeletal dysplasia	DIS5Z8U6	Limited	Biomarker	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	Phosphatidylserine decarboxylase proenzyme, mitochondrial (PISD) affects the response to substance of Fluorouracil.	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Phosphatidylserine decarboxylase proenzyme, mitochondrial (PISD).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Phosphatidylserine decarboxylase proenzyme, mitochondrial (PISD).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Phosphatidylserine decarboxylase proenzyme, mitochondrial (PISD).	[8]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Phosphatidylserine decarboxylase proenzyme, mitochondrial (PISD).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Phosphatidylserine decarboxylase proenzyme, mitochondrial (PISD).	[10]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Phosphatidylserine decarboxylase proenzyme, mitochondrial (PISD).	[11]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Phosphatidylserine decarboxylase proenzyme, mitochondrial (PISD).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Phosphatidylserine decarboxylase proenzyme, mitochondrial (PISD).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Phosphatidylserine decarboxylase proenzyme, mitochondrial (PISD).	[14]

References

• [1] Functional Isolation of Tumor-Initiating Cells using Microfluidic-Based Migration Identifies Phosphatidylserine Decarboxylase as a Key Regulator.Sci Rep. 2018 Jan 10;8(1):244. doi: 10.1038/s41598-017-18610-5.
• [2] The homozygous variant c.797G>A/p.(Cys266Tyr) in PISD is associated with a Spondyloepimetaphyseal dysplasia with large epiphyses and disturbed mitochondrial function. Hum Mutat. 2019 Mar;40(3):299-309. doi: 10.1002/humu.23693. Epub 2018 Dec 21.
• [3] Forkhead-box series expression network is associated with outcome of clear-cell renal cell carcinoma.Oncol Lett. 2018 Jun;15(6):8669-8680. doi: 10.3892/ol.2018.8405. Epub 2018 Apr 2.
• [4] PISD is a mitochondrial disease gene causing skeletal dysplasia, cataracts, and white matter changes.Life Sci Alliance. 2019 Mar 11;2(2):e201900353. doi: 10.26508/lsa.201900353. Print 2019 Apr.
• [5] The retinoblastoma protein/p16 INK4A pathway but not p53 is disrupted by human papillomavirus in penile squamous cell carcinoma.Histopathology. 2011 Feb;58(3):433-9. doi: 10.1111/j.1365-2559.2011.03762.x. Epub 2011 Feb 16.
• [6] Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes. Toxicol Lett. 2018 Jun 1;289:1-13.
• [7] 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.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [10] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [11] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [12] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [13] 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.
• [14] 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.
• [15] Mechanistic and predictive profiling of 5-Fluorouracil resistance in human cancer cells. Cancer Res. 2004 Nov 15;64(22):8167-76. doi: 10.1158/0008-5472.CAN-04-0970.