Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1LMRTG)

• DOT Name: D-3-phosphoglycerate dehydrogenase (PHGDH)
• Synonyms: 3-PGDH; EC 1.1.1.95; 2-oxoglutarate reductase; EC 1.1.1.399; Malate dehydrogenase; EC 1.1.1.37
• Gene Name: PHGDH
• Related Disease:
  Neurometabolic disorder due to serine deficiency
  PHGDH deficiency
  Neu-Laxova syndrome
• UniProt ID: SERA_HUMAN
• PDB ID: 2G76; 5N53; 5N6C; 5NZO; 5NZP; 5NZQ; 5OFM; 5OFV; 5OFW; 6CWA; 6PLF; 6PLG; 6RIH; 6RJ2; 6RJ3; 6RJ5; 6RJ6; 7CVP; 7DKM; 7EWH; 7VA1
• EC Number: 1.1.1.37; 1.1.1.399; 1.1.1.95
• Pfam ID: PF00389 ; PF02826 ; PF19304
• Sequence:
  MAFANLRKVLISDSLDPCCRKILQDGGLQVVEKQNLSKEELIAELQDCEGLIVRSATKVT
  ADVINAAEKLQVVGRAGTGVDNVDLEAATRKGILVMNTPNGNSLSAAELTCGMIMCLARQ
  IPQATASMKDGKWERKKFMGTELNGKTLGILGLGRIGREVATRMQSFGMKTIGYDPIISP
  EVSASFGVQQLPLEEIWPLCDFITVHTPLLPSTTGLLNDNTFAQCKKGVRVVNCARGGIV
  DEGALLRALQSGQCAGAALDVFTEEPPRDRALVDHENVISCPHLGASTKEAQSRCGEEIA
  VQFVDMVKGKSLTGVVNAQALTSAFSPHTKPWIGLAEALGTLMRAWAGSPKGTIQVITQG
  TSLKNAGNCLSPAVIVGLLKEASKQADVNLVNAKLLVKEAGLNVTTSHSPAAPGEQGFGE
  CLLAVALAGAPYQAVGLVQGTTPVLQGLNGAVFRPEVPLRRDLPLLLFRTQTSDPAMLPT
  MIGLLAEAGVRLLSYQTSLVSDGETWHVMGISSLLPSLEAWKQHVTEAFQFHF
• Function: Catalyzes the reversible oxidation of 3-phospho-D-glycerate to 3-phosphonooxypyruvate, the first step of the phosphorylated L-serine biosynthesis pathway. Also catalyzes the reversible oxidation of 2-hydroxyglutarate to 2-oxoglutarate and the reversible oxidation of (S)-malate to oxaloacetate.
• KEGG Pathway:
  Glycine, serine and threonine metabolism (hsa00260)
  Cysteine and methionine metabolism (hsa00270)
  Metabolic pathways (hsa01100)
  Carbon metabolism (hsa01200)
  Biosynthesis of amino acids (hsa01230)
• Reactome Pathway: Serine biosynthesis (R-HSA-977347)
• BioCyc Pathway: MetaCyc:HS01776-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neurometabolic disorder due to serine deficiency	DISCF5UM	Definitive	Autosomal recessive	[1]
PHGDH deficiency	DIS958K3	Definitive	Autosomal recessive	[2]
Neu-Laxova syndrome	DISKU3GJ	Supportive	Autosomal recessive	[2]

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Etoposide	DMNH3PG	Approved	D-3-phosphoglycerate dehydrogenase (PHGDH) affects the response to substance of Etoposide.	[38]
Mitoxantrone	DMM39BF	Approved	D-3-phosphoglycerate dehydrogenase (PHGDH) affects the response to substance of Mitoxantrone.	[38]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	D-3-phosphoglycerate dehydrogenase (PHGDH) affects the binding of 4-hydroxy-2-nonenal.	[39]

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 D-3-phosphoglycerate dehydrogenase (PHGDH).	[3]
Arsenic	DMTL2Y1	Approved	Arsenic increases the ubiquitination of D-3-phosphoglycerate dehydrogenase (PHGDH).	[12]

40 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 D-3-phosphoglycerate dehydrogenase (PHGDH).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of D-3-phosphoglycerate dehydrogenase (PHGDH).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of D-3-phosphoglycerate dehydrogenase (PHGDH).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of D-3-phosphoglycerate dehydrogenase (PHGDH).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of D-3-phosphoglycerate dehydrogenase (PHGDH).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of D-3-phosphoglycerate dehydrogenase (PHGDH).	[9]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of D-3-phosphoglycerate dehydrogenase (PHGDH).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of D-3-phosphoglycerate dehydrogenase (PHGDH).	[11]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of D-3-phosphoglycerate dehydrogenase (PHGDH).	[13]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of D-3-phosphoglycerate dehydrogenase (PHGDH).	[14]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of D-3-phosphoglycerate dehydrogenase (PHGDH).	[15]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of D-3-phosphoglycerate dehydrogenase (PHGDH).	[16]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of D-3-phosphoglycerate dehydrogenase (PHGDH).	[17]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of D-3-phosphoglycerate dehydrogenase (PHGDH).	[18]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of D-3-phosphoglycerate dehydrogenase (PHGDH).	[19]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of D-3-phosphoglycerate dehydrogenase (PHGDH).	[20]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of D-3-phosphoglycerate dehydrogenase (PHGDH).	[16]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of D-3-phosphoglycerate dehydrogenase (PHGDH).	[21]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of D-3-phosphoglycerate dehydrogenase (PHGDH).	[22]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of D-3-phosphoglycerate dehydrogenase (PHGDH).	[23]
Cidofovir	DMA13GD	Approved	Cidofovir affects the expression of D-3-phosphoglycerate dehydrogenase (PHGDH).	[24]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of D-3-phosphoglycerate dehydrogenase (PHGDH).	[24]
Ifosfamide	DMCT3I8	Approved	Ifosfamide increases the expression of D-3-phosphoglycerate dehydrogenase (PHGDH).	[24]
Clodronate	DM9Y6X7	Approved	Clodronate decreases the expression of D-3-phosphoglycerate dehydrogenase (PHGDH).	[24]
Lucanthone	DMZLBUO	Approved	Lucanthone decreases the expression of D-3-phosphoglycerate dehydrogenase (PHGDH).	[25]
Benzatropine	DMF7EXL	Approved	Benzatropine decreases the expression of D-3-phosphoglycerate dehydrogenase (PHGDH).	[26]
Prednisolone	DMQ8FR2	Approved	Prednisolone decreases the expression of D-3-phosphoglycerate dehydrogenase (PHGDH).	[16]
Vitamin C	DMXJ7O8	Approved	Vitamin C decreases the expression of D-3-phosphoglycerate dehydrogenase (PHGDH).	[27]
Methylprednisolone	DM4BDON	Approved	Methylprednisolone decreases the expression of D-3-phosphoglycerate dehydrogenase (PHGDH).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of D-3-phosphoglycerate dehydrogenase (PHGDH).	[4]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of D-3-phosphoglycerate dehydrogenase (PHGDH).	[28]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of D-3-phosphoglycerate dehydrogenase (PHGDH).	[29]
UNC0379	DMD1E4J	Preclinical	UNC0379 decreases the expression of D-3-phosphoglycerate dehydrogenase (PHGDH).	[30]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of D-3-phosphoglycerate dehydrogenase (PHGDH).	[31]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of D-3-phosphoglycerate dehydrogenase (PHGDH).	[32]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of D-3-phosphoglycerate dehydrogenase (PHGDH).	[33]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of D-3-phosphoglycerate dehydrogenase (PHGDH).	[34]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of D-3-phosphoglycerate dehydrogenase (PHGDH).	[35]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of D-3-phosphoglycerate dehydrogenase (PHGDH).	[36]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone decreases the expression of D-3-phosphoglycerate dehydrogenase (PHGDH).	[37]

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] Neu-Laxova syndrome, an inborn error of serine metabolism, is caused by mutations in PHGDH. Am J Hum Genet. 2014 Jun 5;94(6):898-904. doi: 10.1016/j.ajhg.2014.04.015. Epub 2014 May 15.
• [3] 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.
• [4] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [5] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [6] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [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] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [10] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [11] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [12] Quantitative Assessment of Arsenite-Induced Perturbation of Ubiquitinated Proteome. Chem Res Toxicol. 2022 Sep 19;35(9):1589-1597. doi: 10.1021/acs.chemrestox.2c00197. Epub 2022 Aug 22.
• [13] 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.
• [14] 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.
• [15] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [16] Antirheumatic drug response signatures in human chondrocytes: potential molecular targets to stimulate cartilage regeneration. Arthritis Res Ther. 2009;11(1):R15.
• [17] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [18] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [19] 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.
• [20] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [21] Effects of acute ethanol treatment on NCCIT cells and NCCIT cell-derived embryoid bodies (EBs). Toxicol In Vitro. 2010 Sep;24(6):1696-704. doi: 10.1016/j.tiv.2010.05.017. Epub 2010 May 26.
• [22] Characterizing the genetic basis for nicotine induced cancer development: a transcriptome sequencing study. PLoS One. 2013 Jun 18;8(6):e67252.
• [23] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [24] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [25] Lucanthone is a novel inhibitor of autophagy that induces cathepsin D-mediated apoptosis. J Biol Chem. 2011 Feb 25;286(8):6602-13.
• [26] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [27] Antiproliferative effect of ascorbic acid is associated with the inhibition of genes necessary to cell cycle progression. PLoS One. 2009;4(2):e4409.
• [28] 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.
• [29] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [30] Epigenetic siRNA and chemical screens identify SETD8 inhibition as a therapeutic strategy for p53 activation in high-risk neuroblastoma. Cancer Cell. 2017 Jan 9;31(1):50-63.
• [31] Epigenetic influences of low-dose bisphenol A in primary human breast epithelial cells. Toxicol Appl Pharmacol. 2010 Oct 15;248(2):111-21.
• [32] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [33] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [34] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [35] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [36] Persistence of epigenomic effects after recovery from repeated treatment with two nephrocarcinogens. Front Genet. 2018 Dec 3;9:558.
• [37] Evaluation of an in vitro model of androgen ablation and identification of the androgen responsive proteome in LNCaP cells. Proteomics. 2007 Jan;7(1):47-63.
• [38] 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.
• [39] Site-specific protein adducts of 4-hydroxy-2(E)-nonenal in human THP-1 monocytic cells: protein carbonylation is diminished by ascorbic acid. Chem Res Toxicol. 2010 Jan;23(1):37-47. doi: 10.1021/tx9002462.