Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYLXY4M)

• DOT Name: Neutral alpha-glucosidase AB (GANAB)
• Synonyms: EC 3.2.1.207; Alpha-glucosidase 2; Glucosidase II subunit alpha
• Gene Name: GANAB
• Related Disease:
  Polycystic kidney disease 3 with or without polycystic liver disease
  Autosomal dominant polycystic kidney disease
• UniProt ID: GANAB_HUMAN
• PDB ID: 8D43; 8EMR
• EC Number: 3.2.1.207
• Pfam ID: PF13802 ; PF01055 ; PF21365
• Sequence:
  MAAVAAVAARRRRSWASLVLAFLGVCLGITLAVDRSNFKTCEESSFCKRQRSIRPGLSPY
  RALLDSLQLGPDSLTVHLIHEVTKVLLVLELQGLQKNMTRFRIDELEPRRPRYRVPDVLV
  ADPPIARLSVSGRDENSVELTMAEGPYKIILTARPFRLDLLEDRSLLLSVNARGLLEFEH
  QRAPRVSQGSKDPAEGDGAQPEETPRDGDKPEETQGKAEKDEPGAWEETFKTHSDSKPYG
  PMSVGLDFSLPGMEHVYGIPEHADNLRLKVTEGGEPYRLYNLDVFQYELYNPMALYGSVP
  VLLAHNPHRDLGIFWLNAAETWVDISSNTAGKTLFGKMMDYLQGSGETPQTDVRWMSETG
  IIDVFLLLGPSISDVFRQYASLTGTQALPPLFSLGYHQSRWNYRDEADVLEVDQGFDDHN
  LPCDVIWLDIEHADGKRYFTWDPSRFPQPRTMLERLASKRRKLVAIVDPHIKVDSGYRVH
  EELRNLGLYVKTRDGSDYEGWCWPGSAGYPDFTNPTMRAWWANMFSYDNYEGSAPNLFVW
  NDMNEPSVFNGPEVTMLKDAQHYGGWEHRDVHNIYGLYVHMATADGLRQRSGGMERPFVL
  ARAFFAGSQRFGAVWTGDNTAEWDHLKISIPMCLSLGLVGLSFCGADVGGFFKNPEPELL
  VRWYQMGAYQPFFRAHAHLDTGRREPWLLPSQHNDIIRDALGQRYSLLPFWYTLLYQAHR
  EGIPVMRPLWVQYPQDVTTFNIDDQYLLGDALLVHPVSDSGAHGVQVYLPGQGEVWYDIQ
  SYQKHHGPQTLYLPVTLSSIPVFQRGGTIVPRWMRVRRSSECMKDDPITLFVALSPQGTA
  QGELFLDDGHTFNYQTRQEFLLRRFSFSGNTLVSSSADPEGHFETPIWIERVVIIGAGKP
  AAVVLQTKGSPESRLSFQHDPETSVLVLRKPGINVASDWSIHLR
• Function: Catalytic subunit of glucosidase II that cleaves sequentially the 2 innermost alpha-1,3-linked glucose residues from the Glc(2)Man(9)GlcNAc(2) oligosaccharide precursor of immature glycoproteins. Required for PKD1/Polycystin-1 and PKD2/Polycystin-2 maturation and localization to the cell surface and cilia.
• Tissue Specificity: Detected in placenta . Isoform 1 and isoform 2 are expressed in the kidney and liver .
• KEGG Pathway:
  N-Glycan biosynthesis (hsa00510)
  Metabolic pathways (hsa01100)
  Protein processing in endoplasmic reticulum (hsa04141)
• Reactome Pathway:
  Calnexin/calreticulin cycle (R-HSA-901042)
  Maturation of spike protein (R-HSA-9683686)
  Maturation of spike protein (R-HSA-9694548)
  N-glycan trimming in the ER and Calnexin/Calreticulin cycle (R-HSA-532668)
• BioCyc Pathway: MetaCyc:HS01658-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Polycystic kidney disease 3 with or without polycystic liver disease	DISYK31B	Definitive	Autosomal dominant	[1]
Autosomal dominant polycystic kidney disease	DISBHWUI	Supportive	Autosomal dominant	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Neutral alpha-glucosidase AB (GANAB).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Neutral alpha-glucosidase AB (GANAB).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Neutral alpha-glucosidase AB (GANAB).	[5]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Neutral alpha-glucosidase AB (GANAB).	[6]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Neutral alpha-glucosidase AB (GANAB).	[7]
Selenium	DM25CGV	Approved	Selenium increases the expression of Neutral alpha-glucosidase AB (GANAB).	[8]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Neutral alpha-glucosidase AB (GANAB).	[9]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Neutral alpha-glucosidase AB (GANAB).	[10]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the expression of Neutral alpha-glucosidase AB (GANAB).	[11]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the expression of Neutral alpha-glucosidase AB (GANAB).	[11]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Neutral alpha-glucosidase AB (GANAB).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Neutral alpha-glucosidase AB (GANAB).	[14]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Neutral alpha-glucosidase AB (GANAB).	[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 Neutral alpha-glucosidase AB (GANAB).	[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] Mutations in GANAB, Encoding the Glucosidase II Subunit, Cause Autosomal-Dominant Polycystic Kidney and Liver Disease. Am J Hum Genet. 2016 Jun 2;98(6):1193-1207. doi: 10.1016/j.ajhg.2016.05.004.
• [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] 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.
• [6] Proteomic and functional analyses reveal a dual molecular mechanism underlying arsenic-induced apoptosis in human multiple myeloma cells. J Proteome Res. 2009 Jun;8(6):3006-19.
• [7] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [8] 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.
• [9] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [10] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [11] Comparative proteomics reveals concordant and discordant biochemical effects of caffeine versus epigallocatechin-3-gallate in human endothelial cells. Toxicol Appl Pharmacol. 2019 Sep 1;378:114621. doi: 10.1016/j.taap.2019.114621. Epub 2019 Jun 10.
• [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] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [14] 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.
• [15] 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.