Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7YUSA5)

• DOT Name: Glyceraldehyde-3-phosphate dehydrogenase, testis-specific (GAPDHS)
• Synonyms: EC 1.2.1.12; Spermatogenic cell-specific glyceraldehyde 3-phosphate dehydrogenase 2; GAPDH-2; Spermatogenic glyceraldehyde-3-phosphate dehydrogenase
• Gene Name: GAPDHS
• Related Disease:
  Alzheimer disease
  Familial Alzheimer disease
  Melanoma
  Advanced cancer
  Type-1/2 diabetes
• UniProt ID: G3PT_HUMAN
• PDB ID: 3H9E; 3PFW; 5C7L; 5C7O
• EC Number: 1.2.1.12
• Pfam ID: PF02800 ; PF00044
• Sequence:
  MSKRDIVLTNVTVVQLLRQPCPVTRAPPPPEPKAEVEPQPQPEPTPVREEIKPPPPPLPP
  HPATPPPKMVSVARELTVGINGFGRIGRLVLRACMEKGVKVVAVNDPFIDPEYMVYMFKY
  DSTHGRYKGSVEFRNGQLVVDNHEISVYQCKEPKQIPWRAVGSPYVVESTGVYLSIQAAS
  DHISAGAQRVVISAPSPDAPMFVMGVNENDYNPGSMNIVSNASCTTNCLAPLAKVIHERF
  GIVEGLMTTVHSYTATQKTVDGPSRKAWRDGRGAHQNIIPASTGAAKAVTKVIPELKGKL
  TGMAFRVPTPDVSVVDLTCRLAQPAPYSAIKEAVKAAAKGPMAGILAYTEDEVVSTDFLG
  DTHSSIFDAKAGIALNDNFVKLISWYDNEYGYSHRVVDLLRYMFSRDK
• Function: May play an important role in regulating the switch between different pathways for energy production during spermiogenesis and in the spermatozoon. Required for sperm motility and male fertility.
• Tissue Specificity: Testis specific.
• KEGG Pathway:
  Glycolysis / Gluconeogenesis (hsa00010)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Glycolysis (R-HSA-70171)
  Gluconeogenesis (R-HSA-70263)
  Association of TriC/CCT with target proteins during biosynthesis (R-HSA-390471)
• BioCyc Pathway: MetaCyc:HS02793-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Biomarker	[1]
Familial Alzheimer disease	DISE75U4	Strong	Biomarker	[1]
Melanoma	DIS1RRCY	Strong	Biomarker	[2]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[3]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Glyceraldehyde-3-phosphate dehydrogenase, testis-specific (GAPDHS).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Glyceraldehyde-3-phosphate dehydrogenase, testis-specific (GAPDHS).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Glyceraldehyde-3-phosphate dehydrogenase, testis-specific (GAPDHS).	[6]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Glyceraldehyde-3-phosphate dehydrogenase, testis-specific (GAPDHS).	[8]

References

• [1] Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database.Nat Genet. 2007 Jan;39(1):17-23. doi: 10.1038/ng1934.
• [2] Sperm-specific glyceraldehyde-3-phosphate dehydrogenase is expressed in melanoma cells.Biochem Biophys Res Commun. 2012 Oct 26;427(3):649-53. doi: 10.1016/j.bbrc.2012.09.115. Epub 2012 Sep 28.
• [3] Chemical targeting of GAPDH moonlighting function in cancer cells reveals its role in tubulin regulation.Chem Biol. 2014 Nov 20;21(11):1533-45. doi: 10.1016/j.chembiol.2014.08.017. Epub 2014 Oct 9.
• [4] Oxidation of glyceraldehyde-3-phosphate dehydrogenase decreases sperm motility in diabetes mellitus.Biochem Biophys Res Commun. 2015 Sep 18;465(2):245-8. doi: 10.1016/j.bbrc.2015.08.006. Epub 2015 Aug 5.
• [5] 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.
• [6] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [7] 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.
• [8] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.