Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBXEB91)

• DOT Name: Phosphomannomutase 2 (PMM2)
• Synonyms: PMM 2; EC 5.4.2.8
• Gene Name: PMM2
• Related Disease:
  Congenital disorder of glycosylation type I
  PMM2-congenital disorder of glycosylation
  SRD5A3-congenital disorder of glycosylation
• UniProt ID: PMM2_HUMAN
• PDB ID: 2AMY; 2Q4R; 7O0C; 7O1B; 7O4G; 7O58; 7O5Z
• EC Number: 5.4.2.8
• Pfam ID: PF03332
• Sequence:
  MAAPGPALCLFDVDGTLTAPRQKITKEMDDFLQKLRQKIKIGVVGGSDFEKVQEQLGNDV
  VEKYDYVFPENGLVAYKDGKLLCRQNIQSHLGEALIQDLINYCLSYIAKIKLPKKRGTFI
  EFRNGMLNVSPIGRSCSQEERIEFYELDKKENIRQKFVADLRKEFAGKGLTFSIGGQISF
  DVFPDGWDKRYCLRHVENDGYKTIYFFGDKTMPGGNDHEIFTDPRTMGYSVTAPEDTRRI
  CELLFS
• Function: Involved in the synthesis of the GDP-mannose and dolichol-phosphate-mannose required for a number of critical mannosyl transfer reactions.
• 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)
  Defective PMM2 causes PMM2-CDG (R-HSA-4043911)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congenital disorder of glycosylation type I	DISBHHT1	Definitive	Autosomal recessive	[1]
PMM2-congenital disorder of glycosylation	DISZRBCA	Definitive	Autosomal recessive	[1]
SRD5A3-congenital disorder of glycosylation	DISGHPPC	Definitive	Autosomal recessive	[2]

11 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 2 (PMM2).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Phosphomannomutase 2 (PMM2).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Phosphomannomutase 2 (PMM2).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Phosphomannomutase 2 (PMM2).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Phosphomannomutase 2 (PMM2).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Phosphomannomutase 2 (PMM2).	[8]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Phosphomannomutase 2 (PMM2).	[9]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Phosphomannomutase 2 (PMM2).	[10]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Phosphomannomutase 2 (PMM2).	[11]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Phosphomannomutase 2 (PMM2).	[13]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Phosphomannomutase 2 (PMM2).	[14]

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 increases the methylation of Phosphomannomutase 2 (PMM2).	[12]

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] Hyperinsulinaemic hypoglycaemia--leading symptom in a patient with congenital disorder of glycosylation Ia (phosphomannomutase deficiency). J Inherit Metab Dis. 2001 Dec;24(8):858-62. doi: 10.1023/a:1013944308881.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] 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.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [12] 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.
• [13] Targeting Myc in KSHV-associated primary effusion lymphoma with BET bromodomain inhibitors. Oncogene. 2014 May 29;33(22):2928-37. doi: 10.1038/onc.2013.242. Epub 2013 Jun 24.
• [14] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.