Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTADC03N)

• DOT Name: Mannose-1-phosphate guanyltransferase alpha (GMPPA)
• Synonyms: GDP-mannose pyrophosphorylase A; GMPP-alpha; GTP-mannose-1-phosphate guanylyltransferase alpha
• Gene Name: GMPPA
• Related Disease:
  Alacrima, achalasia, and intellectual disability syndrome
  Triple-A syndrome
  Intellectual disability
• UniProt ID: GMPPA_HUMAN
• PDB ID: 7D72; 7D73; 7D74
• Pfam ID: PF00132 ; PF00483
• Sequence:
  MLKAVILIGGPQKGTRFRPLSFEVPKPLFPVAGVPMIQHHIEACAQVPGMQEILLIGFYQ
  PDEPLTQFLEAAQQEFNLPVRYLQEFAPLGTGGGLYHFRDQILAGSPEAFFVLNADVCSD
  FPLSAMLEAHRRQRHPFLLLGTTANRTQSLNYGCIVENPQTHEVLHYVEKPSTFISDIIN
  CGIYLFSPEALKPLRDVFQRNQQDGQLEDSPGLWPGAGTIRLEQDVFSALAGQGQIYVHL
  TDGIWSQIKSAGSALYASRLYLSRYQDTHPERLAKHTPGGPWIRGNVYIHPTAKVAPSAV
  LGPNVSIGKGVTVGEGVRLRESIVLHGATLQEHTCVLHSIVGWGSTVGRWARVEGTPSDP
  NPNDPRARMDSESLFKDGKLLPAITILGCRVRIPAEVLILNSIVLPHKELSRSFTNQIIL
• Function: May serve as a regulatory subunit and allow allosteric feedback inhibition of GMPPB by GDP-mannose.
• Tissue Specificity: Expressed in fibroblasts (at protein level).
• KEGG Pathway:
  Fructose and mannose metabolism (hsa00051)
  Amino sugar and nucleotide sugar metabolism (hsa00520)
  Metabolic pathways (hsa01100)
  Biosynthesis of cofactors (hsa01240)
  Biosynthesis of nucleotide sugars (hsa01250)
• Reactome Pathway: Synthesis of GDP-mannose (R-HSA-446205)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alacrima, achalasia, and intellectual disability syndrome	DIS5JRV9	Definitive	Autosomal recessive	[1]
Triple-A syndrome	DISCOH2J	Supportive	Autosomal recessive	[2]
Intellectual disability	DISMBNXP	Limited	Biomarker	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Mannose-1-phosphate guanyltransferase alpha (GMPPA) decreases the response to substance of Cisplatin.	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Mannose-1-phosphate guanyltransferase alpha (GMPPA).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Mannose-1-phosphate guanyltransferase alpha (GMPPA).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Mannose-1-phosphate guanyltransferase alpha (GMPPA).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Mannose-1-phosphate guanyltransferase alpha (GMPPA).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Mannose-1-phosphate guanyltransferase alpha (GMPPA).	[8]
Selenium	DM25CGV	Approved	Selenium increases the expression of Mannose-1-phosphate guanyltransferase alpha (GMPPA).	[9]
Mifepristone	DMGZQEF	Approved	Mifepristone decreases the expression of Mannose-1-phosphate guanyltransferase alpha (GMPPA).	[10]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Mannose-1-phosphate guanyltransferase alpha (GMPPA).	[11]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Mannose-1-phosphate guanyltransferase alpha (GMPPA).	[12]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Mannose-1-phosphate guanyltransferase alpha (GMPPA).	[9]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Mannose-1-phosphate guanyltransferase alpha (GMPPA).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Mannose-1-phosphate guanyltransferase alpha (GMPPA).	[15]

1 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 affects the methylation of Mannose-1-phosphate guanyltransferase alpha (GMPPA).	[13]

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] Mutations in GMPPA cause a glycosylation disorder characterized by intellectual disability and autonomic dysfunction. Am J Hum Genet. 2013 Oct 3;93(4):727-34. doi: 10.1016/j.ajhg.2013.08.002. Epub 2013 Sep 12.
• [3] Early menopause in women with Down's syndrome.J Intellect Disabil Res. 1997 Jun;41 ( Pt 3):264-7. doi: 10.1111/j.1365-2788.1997.tb00706.x.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] 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.
• [6] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] 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.
• [9] 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.
• [10] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [11] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [12] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [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] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [15] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [16] Gene expression analysis using human cancer xenografts to identify novel predictive marker genes for the efficacy of 5-fluorouracil-based drugs. Cancer Sci. 2006 Jun;97(6):510-22. doi: 10.1111/j.1349-7006.2006.00204.x.