Details of Drug Off-Target (DOT)

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

• DOT Name: All trans-polyprenyl-diphosphate synthase PDSS2 (PDSS2)
• Synonyms: All-trans-decaprenyl-diphosphate synthase subunit 2; EC 2.5.1.91; Candidate tumor suppressor protein; Decaprenyl pyrophosphate synthase subunit 2; Decaprenyl-diphosphate synthase subunit 2; Solanesyl-diphosphate synthase subunit 2
• Gene Name: PDSS2
• Related Disease:
  Coenzyme Q10 deficiency, primary, 3
  Familial prostate carcinoma
  Advanced cancer
  Alzheimer disease
  Cardiac failure
  Chronic obstructive pulmonary disease
  Congestive heart failure
  Ehlers-Danlos syndrome
  Focal segmental glomerulosclerosis
  Gastric cancer
  Hepatocellular carcinoma
  Liver cirrhosis
  Lung cancer
  Lung carcinoma
  Melanoma
  Movement disorder
  Nephropathy
  Nephrotic syndrome
  Non-insulin dependent diabetes
  Parkinson disease
  Sleep disorder
  Stomach cancer
  Leigh syndrome
  Obsolete Leigh syndrome with nephrotic syndrome
  Coenzyme Q10 deficiency
• UniProt ID: DLP1_HUMAN
• EC Number: 2.5.1.91
• Pfam ID: PF00348
• Sequence:
  MNFRQLLLHLPRYLGASGSPRRLWWSPSLDTISSVGSWRGRSSKSPAHWNQVVSEAEKIV
  GYPTSFMSLRCLLSDELSNIAMQVRKLVGTQHPLLTTARGLVHDSWNSLQLRGLVVLLIS
  KAAGPSSVNTSCQNYDMVSGIYSCQRSLAEITELIHIALLVHRGIVNLNELQSSDGPLKD
  MQFGNKIAILSGDFLLANACNGLALLQNTKVVELLASALMDLVQGVYHENSTSKESYITD
  DIGISTWKEQTFLSHGALLAKSCQAAMELAKHDAEVQNMAFQYGKHMAMSHKINSDVQPF
  IKEKTSDSMTFNLNSAPVVLHQEFLGRDLWIKQIGEAQEKGRLDYAKLRERIKAGKGVTS
  AIDLCRYHGNKALEALESFPPSEARSALENIVFAVTRFS
• Function: Heterotetrameric enzyme that catalyzes the condensation of farnesyl diphosphate (FPP), which acts as a primer, and isopentenyl diphosphate (IPP) to produce prenyl diphosphates of varying chain lengths and participates in the determination of the side chain of ubiquinone. Supplies nona and decaprenyl diphosphate, the precursors for the side chain of the isoprenoid quinones ubiquinone-9 (Q9) and ubiquinone-10 (Q10) respectively. The enzyme adds isopentenyl diphosphate molecules sequentially to farnesyl diphosphate with trans stereochemistry. May play a role during cerebellar development. May regulate mitochondrial respiratory chain function.
• KEGG Pathway: Terpenoid backbone biosynthesis (hsa00900)
• Reactome Pathway: Ubiquinol biosynthesis (R-HSA-2142789)
• BioCyc Pathway: MetaCyc:HS15203-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Coenzyme Q10 deficiency, primary, 3	DIS2PUTA	Definitive	Autosomal recessive	[1]
Familial prostate carcinoma	DISL9KNO	Definitive	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[3]
Alzheimer disease	DISF8S70	Strong	Biomarker	[4]
Cardiac failure	DISDC067	Strong	Biomarker	[5]
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Genetic Variation	[6]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[5]
Ehlers-Danlos syndrome	DISSVBRR	Strong	Biomarker	[7]
Focal segmental glomerulosclerosis	DISJNHH0	Strong	Genetic Variation	[8]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[9]
Hepatocellular carcinoma	DIS0J828	Strong	Genetic Variation	[3]
Liver cirrhosis	DIS4G1GX	Strong	Altered Expression	[10]
Lung cancer	DISCM4YA	Strong	Altered Expression	[11]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[11]
Melanoma	DIS1RRCY	Strong	Altered Expression	[12]
Movement disorder	DISOJJ2D	Strong	Biomarker	[13]
Nephropathy	DISXWP4P	Strong	Biomarker	[14]
Nephrotic syndrome	DISSPSC2	Strong	Genetic Variation	[15]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[16]
Parkinson disease	DISQVHKL	Strong	Biomarker	[17]
Sleep disorder	DIS3JP1U	Strong	Biomarker	[18]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[9]
Leigh syndrome	DISWQU45	Moderate	Autosomal recessive	[19]
Obsolete Leigh syndrome with nephrotic syndrome	DIS4M8RK	Supportive	Autosomal recessive	[1]
Coenzyme Q10 deficiency	DIS1HGDF	Disputed	Genetic Variation	[15]

14 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 All trans-polyprenyl-diphosphate synthase PDSS2 (PDSS2).	[20]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of All trans-polyprenyl-diphosphate synthase PDSS2 (PDSS2).	[21]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of All trans-polyprenyl-diphosphate synthase PDSS2 (PDSS2).	[22]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of All trans-polyprenyl-diphosphate synthase PDSS2 (PDSS2).	[23]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of All trans-polyprenyl-diphosphate synthase PDSS2 (PDSS2).	[24]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of All trans-polyprenyl-diphosphate synthase PDSS2 (PDSS2).	[25]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of All trans-polyprenyl-diphosphate synthase PDSS2 (PDSS2).	[26]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of All trans-polyprenyl-diphosphate synthase PDSS2 (PDSS2).	[27]
Selenium	DM25CGV	Approved	Selenium decreases the expression of All trans-polyprenyl-diphosphate synthase PDSS2 (PDSS2).	[28]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of All trans-polyprenyl-diphosphate synthase PDSS2 (PDSS2).	[29]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of All trans-polyprenyl-diphosphate synthase PDSS2 (PDSS2).	[30]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of All trans-polyprenyl-diphosphate synthase PDSS2 (PDSS2).	[31]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of All trans-polyprenyl-diphosphate synthase PDSS2 (PDSS2).	[32]
Arachidonic acid	DMUOQZD	Investigative	Arachidonic acid decreases the expression of All trans-polyprenyl-diphosphate synthase PDSS2 (PDSS2).	[33]

References

• [1] Leigh syndrome with nephropathy and CoQ10 deficiency due to decaprenyl diphosphate synthase subunit 2 (PDSS2) mutations. Am J Hum Genet. 2006 Dec;79(6):1125-9. doi: 10.1086/510023. Epub 2006 Oct 27.
• [2] Arg462Gln sequence variation in the prostate-cancer-susceptibility gene RNASEL and age of onset of hereditary non-polyposis colorectal cancer: a case-control study.Lancet Oncol. 2005 Aug;6(8):566-72. doi: 10.1016/S1470-2045(05)70253-9.
• [3] PDSS2 Deficiency Induces Hepatocarcinogenesis by Decreasing Mitochondrial Respiration and Reprogramming Glucose Metabolism.Cancer Res. 2018 Aug 15;78(16):4471-4481. doi: 10.1158/0008-5472.CAN-17-2172. Epub 2018 Jul 2.
• [4] Dynamin-like protein 1 cleavage by calpain in Alzheimer's disease.Aging Cell. 2019 Jun;18(3):e12912. doi: 10.1111/acel.12912. Epub 2019 Feb 14.
• [5] Adrenergic Regulation of Drp1-Driven Mitochondrial Fission in Cardiac Physio-Pathology.Antioxidants (Basel). 2018 Dec 18;7(12):195. doi: 10.3390/antiox7120195.
• [6] Genome-Wide Association Study Identification of Novel Loci Associated with Airway Responsiveness in Chronic Obstructive Pulmonary Disease.Am J Respir Cell Mol Biol. 2015 Aug;53(2):226-34. doi: 10.1165/rcmb.2014-0198OC.
• [7] Association between Sleep Disturbances and Daytime Somnolence in Parkinson's Disease.Eur Neurol. 2018;80(5-6):268-276. doi: 10.1159/000496937. Epub 2019 Feb 7.
• [8] Focal segmental glomerulosclerosis is associated with a PDSS2 haplotype and, independently, with a decreased content of coenzyme Q10.Am J Physiol Renal Physiol. 2013 Oct 15;305(8):F1228-38. doi: 10.1152/ajprenal.00143.2013. Epub 2013 Aug 7.
• [9] Decreased expression of prenyl diphosphate synthase subunit 2 correlates with reduced survival of patients with gastric cancer.J Exp Clin Cancer Res. 2014 Oct 22;33(1):88. doi: 10.1186/s13046-014-0088-3.
• [10] Clinical utility of PDSS2 expression to stratify patients at risk for recurrence of hepatocellular carcinoma.Int J Oncol. 2014 Nov;45(5):2005-12. doi: 10.3892/ijo.2014.2637. Epub 2014 Sep 3.
• [11] Sp1 Mediates the Constitutive Expression and Repression of the PDSS2 Gene in Lung Cancer Cells.Genes (Basel). 2019 Nov 27;10(12):977. doi: 10.3390/genes10120977.
• [12] Identification and characterization of a novel melanoma tumor suppressor gene on human chromosome 6q21.Clin Cancer Res. 2009 Feb 1;15(3):797-803. doi: 10.1158/1078-0432.CCR-08-1472.
• [13] Impact of sleep-related symptoms on clinical motor subtypes and disability in Parkinson's disease: a multicentre cross-sectional study.J Neurol Neurosurg Psychiatry. 2017 Nov;88(11):953-959. doi: 10.1136/jnnp-2017-316136. Epub 2017 Aug 28.
• [14] Inhibiting cytosolic translation and autophagy improves health in mitochondrial disease.Hum Mol Genet. 2015 Sep 1;24(17):4829-47. doi: 10.1093/hmg/ddv207. Epub 2015 Jun 3.
• [15] Diffuse mesangial sclerosis in a PDSS2 mutation-induced coenzyme Q10 deficiency.Pediatr Nephrol. 2018 Mar;33(3):439-446. doi: 10.1007/s00467-017-3814-1. Epub 2017 Oct 14.
• [16] Genome-wide association study of coronary artery calcified atherosclerotic plaque in African Americans with type 2 diabetes.BMC Genet. 2017 Dec 8;18(1):105. doi: 10.1186/s12863-017-0572-9.
• [17] Rapid eye movement behavior disorder in drug-nave patients with Parkinson's disease.J Clin Neurosci. 2019 Jan;59:254-258. doi: 10.1016/j.jocn.2018.07.007. Epub 2018 Oct 9.
• [18] Mandibular advancement device in Parkinson's disease: a pilot study on efficacy and usability.Sleep Med. 2020 Feb;66:78-81. doi: 10.1016/j.sleep.2019.08.010. Epub 2019 Aug 30.
• [19] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [20] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [21] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [22] Toxicogenomics-based prediction of acetaminophen-induced liver injury using human hepatic cell systems. Toxicol Lett. 2016 Jan 5;240(1):50-9.
• [23] 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.
• [24] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [25] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [26] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [27] Effect of mitochondrial dysfunction and oxidative stress on endogenous levels of coenzyme Q(10) in human cells. J Biochem Mol Toxicol. 2011 Sep-Oct;25(5):280-9. doi: 10.1002/jbt.20387. Epub 2011 Feb 9.
• [28] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [29] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [30] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [31] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [32] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [33] Arachidonic acid-induced gene expression in colon cancer cells. Carcinogenesis. 2006 Oct;27(10):1950-60.