Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8UC40I)

• DOT Name: Adenosylhomocysteinase (AHCY)
• Synonyms: AdoHcyase; EC 3.13.2.1; S-adenosyl-L-homocysteine hydrolase
• Gene Name: AHCY
• Related Disease: Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase
• UniProt ID: SAHH_HUMAN
• PDB ID: 1A7A; 1LI4; 3NJ4; 4PFJ; 4PGF; 4YVF; 5W49; 5W4B
• EC Number: 3.13.2.1
• Pfam ID: PF05221 ; PF00670
• Sequence:
  MSDKLPYKVADIGLAAWGRKALDIAENEMPGLMRMRERYSASKPLKGARIAGCLHMTVET
  AVLIETLVTLGAEVQWSSCNIFSTQDHAAAAIAKAGIPVYAWKGETDEEYLWCIEQTLYF
  KDGPLNMILDDGGDLTNLIHTKYPQLLPGIRGISEETTTGVHNLYKMMANGILKVPAINV
  NDSVTKSKFDNLYGCRESLIDGIKRATDVMIAGKVAVVAGYGDVGKGCAQALRGFGARVI
  ITEIDPINALQAAMEGYEVTTMDEACQEGNIFVTTTGCIDIILGRHFEQMKDDAIVCNIG
  HFDVEIDVKWLNENAVEKVNIKPQVDRYRLKNGRRIILLAEGRLVNLGCAMGHPSFVMSN
  SFTNQVMAQIELWTHPDKYPVGVHFLPKKLDEAVAEAHLGKLNVKLTKLTEKQAQYLGMS
  CDGPFKPDHYRY
• Function: Catalyzes the hydrolysis of S-adenosyl-L-homocysteine to form adenosine and homocysteine. Binds copper ions.
• KEGG Pathway:
  Cysteine and methionine metabolism (hsa00270)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Sulfur amino acid metabolism (R-HSA-1614635)
  Metabolism of ingested SeMet, Sec, MeSec into H2Se (R-HSA-2408508)
  Defective AHCY causes HMAHCHD (R-HSA-5578997)
  Methylation (R-HSA-156581)
• BioCyc Pathway: MetaCyc:HS02273-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase	DISI3RCT	Strong	Autosomal recessive	[1]

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
(L-)-S-adenosyl-L-homocysteine	DMDUN83	Investigative	Adenosylhomocysteinase (AHCY) increases the hydrolysis of (L-)-S-adenosyl-L-homocysteine.	[18]

15 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 Adenosylhomocysteinase (AHCY).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Adenosylhomocysteinase (AHCY).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Adenosylhomocysteinase (AHCY).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Adenosylhomocysteinase (AHCY).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Adenosylhomocysteinase (AHCY).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Adenosylhomocysteinase (AHCY).	[7]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of Adenosylhomocysteinase (AHCY).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Adenosylhomocysteinase (AHCY).	[9]
Resveratrol	DM3RWXL	Phase 3	Resveratrol affects the expression of Adenosylhomocysteinase (AHCY).	[10]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the expression of Adenosylhomocysteinase (AHCY).	[11]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the expression of Adenosylhomocysteinase (AHCY).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Adenosylhomocysteinase (AHCY).	[14]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Adenosylhomocysteinase (AHCY).	[15]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Adenosylhomocysteinase (AHCY).	[16]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Adenosylhomocysteinase (AHCY).	[17]

2 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 Adenosylhomocysteinase (AHCY).	[12]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Adenosylhomocysteinase (AHCY).	[13]

References

• [1] S-adenosylhomocysteine hydrolase deficiency in a human: a genetic disorder of methionine metabolism. Proc Natl Acad Sci U S A. 2004 Mar 23;101(12):4234-9. doi: 10.1073/pnas.0400658101. Epub 2004 Mar 15.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [4] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [5] Multiple pathways are involved in drug resistance to doxorubicin in an osteosarcoma cell line. Anticancer Drugs. 2008 Mar;19(3):257-65.
• [6] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [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] Interplay between cellular methyl metabolism and adaptive efflux during oncogenic transformation from chronic arsenic exposure in human cells. J Biol Chem. 2008 Jul 11;283(28):19342-50.
• [9] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [10] Resveratrol downregulates Akt/GSK and ERK signalling pathways in OVCAR-3 ovarian cancer cells. Mol Biosyst. 2012 Apr;8(4):1078-87. doi: 10.1039/c2mb05486h. Epub 2012 Jan 10.
• [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] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [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] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [16] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [17] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [18] Abnormal Hypermethylation at Imprinting Control Regions in Patients with S-Adenosylhomocysteine Hydrolase (AHCY) Deficiency. PLoS One. 2016 Mar 14;11(3):e0151261. doi: 10.1371/journal.pone.0151261. eCollection 2016.