Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGG9KYG)

• DOT Name: Adenosylhomocysteinase 3 (AHCYL2)
• Synonyms: AdoHcyase 3; EC 3.13.2.1; IP(3)Rs binding protein released with IP(3) 2; IRBIT2; Long-IRBIT; S-adenosyl-L-homocysteine hydrolase 3; S-adenosylhomocysteine hydrolase-like protein 2
• Gene Name: AHCYL2
• Related Disease:
  Carcinoma
  Prostate cancer
  Prostate neoplasm
  Acute myelogenous leukaemia
• UniProt ID: SAHH3_HUMAN
• PDB ID: 3GVP
• EC Number: 3.13.2.1
• Pfam ID: PF05221 ; PF00670
• Sequence:
  MSVQVVSAAAAAKVPEVELKDLSPSEAESQLGLSTAAVGAMAPPAGGGDPEAPAPAAERP
  PVPGPGSGPAAALSPAAGKVPQASAMKRSDPHHQHQRHRDGGEALVSPDGTVTEAPRTVK
  KQIQFADQKQEFNKRPTKIGRRSLSRSISQSSTDSYSSAASYTDSSDDETSPRDKQQKNS
  KGSSDFCVKNIKQAEFGRREIEIAEQEMPALMALRKRAQGEKPLAGAKIVGCTHITAQTA
  VLMETLGALGAQCRWAACNIYSTLNEVAAALAESGFPVFAWKGESEDDFWWCIDRCVNVE
  GWQPNMILDDGGDLTHWIYKKYPNMFKKIKGIVEESVTGVHRLYQLSKAGKLCVPAMNVN
  DSVTKQKFDNLYCCRESILDGLKRTTDMMFGGKQVVVCGYGEVGKGCCAALKAMGSIVYV
  TEIDPICALQACMDGFRLVKLNEVIRQVDIVITCTGNKNVVTREHLDRMKNSCIVCNMGH
  SNTEIDVASLRTPELTWERVRSQVDHVIWPDGKRIVLLAEGRLLNLSCSTVPTFVLSITA
  TTQALALIELYNAPEGRYKQDVYLLPKKMDEYVASLHLPTFDAHLTELTDEQAKYLGLNK
  NGPFKPNYYRY
• Function: May regulate the electrogenic sodium/bicarbonate cotransporter SLC4A4 activity and Mg(2+)-sensitivity. On the contrary of its homolog AHCYL1, does not regulate ITPR1 sensitivity to inositol 1,4,5-trisphosphate.
• KEGG Pathway:
  Cysteine and methionine metabolism (hsa00270)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Bicarbonate transporters (R-HSA-425381)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Carcinoma	DISH9F1N	Strong	Biomarker	[1]
Prostate cancer	DISF190Y	Strong	Biomarker	[2]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[2]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[3]

1 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 Adenosylhomocysteinase 3 (AHCYL2).	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Adenosylhomocysteinase 3 (AHCYL2).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Adenosylhomocysteinase 3 (AHCYL2).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Adenosylhomocysteinase 3 (AHCYL2).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Adenosylhomocysteinase 3 (AHCYL2).	[8]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Adenosylhomocysteinase 3 (AHCYL2).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Adenosylhomocysteinase 3 (AHCYL2).	[10]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Adenosylhomocysteinase 3 (AHCYL2).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Adenosylhomocysteinase 3 (AHCYL2).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Adenosylhomocysteinase 3 (AHCYL2).	[13]

References

• [1] New p53 related genes in human tumors: significant downregulation in colon and lung carcinomas.Oncol Rep. 2006 Sep;16(3):603-8. doi: 10.3892/or.16.3.603.
• [2] The bromodomain protein BRD4 regulates the KEAP1/NRF2-dependent oxidative stress response.Cell Death Dis. 2014 Apr 24;5(4):e1195. doi: 10.1038/cddis.2014.157.
• [3] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [4] 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.
• [5] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [6] 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.
• [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] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [11] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [12] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [13] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.