Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTU0BW0Y)

• DOT Name: Phosphomannomutase 1 (PMM1)
• Synonyms: PMM 1; EC 5.4.2.8; PMMH-22
• Gene Name: PMM1
• UniProt ID: PMM1_HUMAN
• PDB ID: 2FUC; 2FUE; 6CFR; 6CFS; 6CFT; 6CFU; 6CFV
• EC Number: 5.4.2.8
• Pfam ID: PF03332
• Sequence:
  MAVTAQAARRKERVLCLFDVDGTLTPARQKIDPEVAAFLQKLRSRVQIGVVGGSDYCKIA
  EQLGDGDEVIEKFDYVFAENGTVQYKHGRLLSKQTIQNHLGEELLQDLINFCLSYMALLR
  LPKKRGTFIEFRNGMLNISPIGRSCTLEERIEFSELDKKEKIREKFVEALKTEFAGKGLR
  FSRGGMISFDVFPEGWDKRYCLDSLDQDSFDTIHFFGNETSPGGNDFEIFADPRTVGHSV
  VSPQDTVQRCREIFFPETAHEA
• Function: Involved in the synthesis of the GDP-mannose and dolichol-phosphate-mannose required for a number of critical mannosyl transfer reactions. In addition, may be responsible for the degradation of glucose-1,6-bisphosphate in ischemic brain.
• Tissue Specificity: Strong expression in liver, heart, brain, and pancreas; lower expression in skeletal muscle.
• 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

9 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 Phosphomannomutase 1 (PMM1).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Phosphomannomutase 1 (PMM1).	[2]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Phosphomannomutase 1 (PMM1).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Phosphomannomutase 1 (PMM1).	[4]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Phosphomannomutase 1 (PMM1).	[5]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Phosphomannomutase 1 (PMM1).	[6]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Phosphomannomutase 1 (PMM1).	[7]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Phosphomannomutase 1 (PMM1).	[8]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Phosphomannomutase 1 (PMM1).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Phosphomannomutase 1 (PMM1).	[9]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [3] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [4] 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.
• [5] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [6] 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.
• [7] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [8] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [9] 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.
• [10] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.