Details of Drug Off-Target (DOT)

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

• DOT Name: 6-pyruvoyl tetrahydrobiopterin synthase (PTS)
• Synonyms: PTP synthase; PTPS; EC 4.2.3.12
• Gene Name: PTS
• Related Disease:
  BH4-deficient hyperphenylalaninemia A
  Primary hyperoxaluria
  Alzheimer disease type 1
  Amyotrophic lateral sclerosis type 1
  Aromatic L-amino acid decarboxylase deficiency
  Colitis
  Dihydropteridine reductase deficiency
  Dopa-responsive dystonia due to sepiapterin reductase deficiency
  Familial Alzheimer disease
  Familial amyotrophic lateral sclerosis
  Hepatocellular carcinoma
  Hyperphenylalaninemia
  Intellectual disability
  Metabolic disorder
  Mixed anxiety and depressive disorder
  Phenylketonuria
  Bipolar disorder
  Colorectal carcinoma
  Neoplasm
  Classic phenylketonuria
  Dystonia
  Post-traumatic stress disorder
  Venous thromboembolism
• UniProt ID: PTPS_HUMAN
• PDB ID: 3I2B
• EC Number: 4.2.3.12
• Pfam ID: PF01242
• Sequence:
  MSTEGGGRRCQAQVSRRISFSASHRLYSKFLSDEENLKLFGKCNNPNGHGHNYKVVVTVH
  GEIDPATGMVMNLADLKKYMEEAIMQPLDHKNLDMDVPYFADVVSTTENVAVYIWDNLQK
  VLPVGVLYKVKVYETDNNIVVYKGE
• Function: Involved in the biosynthesis of tetrahydrobiopterin, an essential cofactor of aromatic amino acid hydroxylases. Catalyzes the transformation of 7,8-dihydroneopterin triphosphate into 6-pyruvoyl tetrahydropterin.
• KEGG Pathway:
  Folate biosynthesis (hsa00790)
  Metabolic pathways (hsa01100)
  Biosynthesis of cofactors (hsa01240)
• Reactome Pathway: Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation (R-HSA-1474151)
• BioCyc Pathway: MetaCyc:HS07692-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
BH4-deficient hyperphenylalaninemia A	DISYYKL5	Definitive	Autosomal recessive	[1]
Primary hyperoxaluria	DIS0L16N	Definitive	Biomarker	[2]
Alzheimer disease type 1	DIS1ILLO	Strong	Biomarker	[3]
Amyotrophic lateral sclerosis type 1	DIS5A2M0	Strong	Genetic Variation	[3]
Aromatic L-amino acid decarboxylase deficiency	DIS3C407	Strong	Genetic Variation	[4]
Colitis	DISAF7DD	Strong	Genetic Variation	[5]
Dihydropteridine reductase deficiency	DIS1IC3E	Strong	Biomarker	[4]
Dopa-responsive dystonia due to sepiapterin reductase deficiency	DISZ8S4R	Strong	Genetic Variation	[4]
Familial Alzheimer disease	DISE75U4	Strong	Genetic Variation	[3]
Familial amyotrophic lateral sclerosis	DISWZ9CJ	Strong	Genetic Variation	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Genetic Variation	[6]
Hyperphenylalaninemia	DISCQU4G	Strong	Biomarker	[7]
Intellectual disability	DISMBNXP	Strong	Biomarker	[8]
Metabolic disorder	DIS71G5H	Strong	Biomarker	[9]
Mixed anxiety and depressive disorder	DISV809X	Strong	Biomarker	[10]
Phenylketonuria	DISCU56J	Strong	Biomarker	[11]
Bipolar disorder	DISAM7J2	moderate	Genetic Variation	[12]
Colorectal carcinoma	DIS5PYL0	moderate	Altered Expression	[13]
Neoplasm	DISZKGEW	moderate	Biomarker	[13]
Classic phenylketonuria	DISLU64N	Disputed	Biomarker	[3]
Dystonia	DISJLFGW	Limited	Biomarker	[14]
Post-traumatic stress disorder	DISHL1EY	Limited	Biomarker	[15]
Venous thromboembolism	DISUR7CR	Limited	Biomarker	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of 6-pyruvoyl tetrahydrobiopterin synthase (PTS).	[17]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of 6-pyruvoyl tetrahydrobiopterin synthase (PTS).	[18]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of 6-pyruvoyl tetrahydrobiopterin synthase (PTS).	[19]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of 6-pyruvoyl tetrahydrobiopterin synthase (PTS).	[20]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of 6-pyruvoyl tetrahydrobiopterin synthase (PTS).	[21]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of 6-pyruvoyl tetrahydrobiopterin synthase (PTS).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of 6-pyruvoyl tetrahydrobiopterin synthase (PTS).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of 6-pyruvoyl tetrahydrobiopterin synthase (PTS).	[24]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of 6-pyruvoyl tetrahydrobiopterin synthase (PTS).	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of 6-pyruvoyl tetrahydrobiopterin synthase (PTS).	[26]

References

• [1] 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.
• [2] Molecular recognition of PTS-1 cargo proteins by Pex5p: implications for protein mistargeting in primary hyperoxaluria.Biomolecules. 2015 Feb 13;5(1):121-41. doi: 10.3390/biom5010121.
• [3] Chromosome-wide assessment of replication timing for human chromosomes 11q and 21q: disease-related genes in timing-switch regions.Hum Mol Genet. 2002 Jan 1;11(1):13-21. doi: 10.1093/hmg/11.1.13.
• [4] Urinary sulphatoxymelatonin as a biomarker of serotonin status in biogenic amine-deficient patients.Sci Rep. 2017 Nov 7;7(1):14675. doi: 10.1038/s41598-017-15063-8.
• [5] Enterococcus faecalis Gluconate Phosphotransferase System Accelerates Experimental Colitis and Bacterial Killing by Macrophages.Infect Immun. 2019 Jun 20;87(7):e00080-19. doi: 10.1128/IAI.00080-19. Print 2019 Jul.
• [6] Identification of mutations causing 6-pyruvoyl-tetrahydropterin synthase deficiency in four Italian families.Hum Mutat. 1997;10(1):25-35. doi: 10.1002/(SICI)1098-1004(1997)10:1<25::AID-HUMU4>3.0.CO;2-L.
• [7] Diagnosis, treatment and follow-up of patients with tetrahydrobiopterin deficiency in Shandong province, China.Brain Dev. 2015 Jun;37(6):592-8. doi: 10.1016/j.braindev.2014.09.008. Epub 2014 Oct 7.
• [8] Advantages and pitfalls of an extended gene panel for investigating complex neurometabolic phenotypes.Brain. 2016 Nov 1;139(11):2844-2854. doi: 10.1093/brain/aww221.
• [9] 6-Pyruvoyltetrahydropterin Synthase Deficiency: Review and Report of 28 Arab Subjects.Pediatr Neurol. 2019 Jul;96:40-47. doi: 10.1016/j.pediatrneurol.2019.02.008. Epub 2019 Feb 18.
• [10] Risk Factors Associated with Alcohol Use in Early Adolescence among American Inner-City Youth: A Longitudinal Study.Subst Use Misuse. 2020;55(3):358-366. doi: 10.1080/10826084.2019.1671867. Epub 2019 Nov 5.
• [11] Mutation spectrum of six genes in Chinese phenylketonuria patients obtained through next-generation sequencing.PLoS One. 2014 Apr 4;9(4):e94100. doi: 10.1371/journal.pone.0094100. eCollection 2014.
• [12] Genome-wide association study identifies SESTD1 as a novel risk gene for lithium-responsive bipolar disorder.Mol Psychiatry. 2016 Sep;21(9):1290-7. doi: 10.1038/mp.2015.165. Epub 2015 Oct 27.
• [13] PTPS Facilitates Compartmentalized LTBP1 S-Nitrosylation and Promotes Tumor Growth under Hypoxia.Mol Cell. 2020 Jan 2;77(1):95-107.e5. doi: 10.1016/j.molcel.2019.09.018. Epub 2019 Oct 15.
• [14] Genetics of Phenylketonuria: Then and Now.Hum Mutat. 2016 Jun;37(6):508-15. doi: 10.1002/humu.22980. Epub 2016 Mar 18.
• [15] Network models of posttraumatic stress symptoms across trauma types.J Anxiety Disord. 2018 Aug;58:70-77. doi: 10.1016/j.janxdis.2018.07.004. Epub 2018 Jul 21.
• [16] Post thrombotic syndrome following deep vein thrombosis in paediatric patients.Phlebology. 2018 Apr;33(3):185-194. doi: 10.1177/0268355516686597. Epub 2017 Jan 25.
• [17] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [18] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [19] 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.
• [20] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [21] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [22] Differentially expressed genes in the prostate cancer cell line LNCaP after exposure to androgen and anti-androgen. Cancer Genet Cytogenet. 2006 Apr 15;166(2):130-8. doi: 10.1016/j.cancergencyto.2005.09.012.
• [23] 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.
• [24] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [25] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [26] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.