Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZD17IM)

• DOT Name: D-glutamate cyclase, mitochondrial (DGLUCY)
• Synonyms: EC 4.2.1.48
• Gene Name: DGLUCY
• Related Disease:
  Advanced cancer
  Cardiac failure
  Congestive heart failure
  Gastric cancer
  Stomach cancer
• UniProt ID: GLUCM_HUMAN
• EC Number: 4.2.1.48
• Pfam ID: PF07286 ; PF14336
• Sequence:
  MPFTLHLRSRLPSAIRSLILQKKPNIRNTSSMAGELRPASLVVLPRSLAPAFERFCQVNT
  GPLPLLGQSEPEKWMLPPQGAISETRMGHPQFWKYEFGACTGSLASLEQYSEQLKDMVAF
  FLGCSFSLEEALEKAGLPRRDPAGHSQTTVPCVTHAGFCCPLVVTMRPIPKDKLEGLVRA
  CCSLGGEQGQPVHMGDPELLGIKELSKPAYGDAMVCPPGEVPVFWPSPLTSLGAVSSCET
  PLAFASIPGCTVMTDLKDAKAPPGCLTPERIPEVHHISQDPLHYSIASVSASQKIRELES
  MIGIDPGNRGIGHLLCKDELLKASLSLSHARSVLITTGFPTHFNHEPPEETDGPPGAVAL
  VAFLQALEKEVAIIVDQRAWNLHQKIVEDAVEQGVLKTQIPILTYQGGSVEAAQAFLCKN
  GDPQTPRFDHLVAIERAGRAADGNYYNARKMNIKHLVDPIDDLFLAAKKIPGISSTGVGD
  GGNELGMGKVKEAVRRHIRHGDVIACDVEADFAVIAGVSNWGGYALACALYILYSCAVHS
  QYLRKAVGPSRAPGDQAWTQALPSVIKEEKMLGILVQHKVRSGVSGIVGMEVDGLPFHNT
  HAEMIQKLVDVTTAQV
• Function: D-glutamate cyclase that converts D-glutamate to 5-oxo-D-proline.
• KEGG Pathway:
  D-Amino acid metabolism (hsa00470)
  Metabolic pathways (hsa01100)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Cardiac failure	DISDC067	Strong	Altered Expression	[2]
Congestive heart failure	DIS32MEA	Strong	Altered Expression	[2]
Gastric cancer	DISXGOUK	Strong	Biomarker	[1]
Stomach cancer	DISKIJSX	Strong	Biomarker	[1]

10 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 D-glutamate cyclase, mitochondrial (DGLUCY).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of D-glutamate cyclase, mitochondrial (DGLUCY).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of D-glutamate cyclase, mitochondrial (DGLUCY).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of D-glutamate cyclase, mitochondrial (DGLUCY).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of D-glutamate cyclase, mitochondrial (DGLUCY).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of D-glutamate cyclase, mitochondrial (DGLUCY).	[8]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of D-glutamate cyclase, mitochondrial (DGLUCY).	[9]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of D-glutamate cyclase, mitochondrial (DGLUCY).	[10]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of D-glutamate cyclase, mitochondrial (DGLUCY).	[12]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of D-glutamate cyclase, mitochondrial (DGLUCY).	[14]

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 D-glutamate cyclase, mitochondrial (DGLUCY).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of D-glutamate cyclase, mitochondrial (DGLUCY).	[13]

References

• [1] C14orf159 suppresses gastric cancer cells' invasion and proliferation by inactivating ERK signaling.Cancer Manag Res. 2019 Feb 19;11:1717-1723. doi: 10.2147/CMAR.S176771. eCollection 2019.
• [2] Structural and enzymatic properties of mammalian d-glutamate cyclase.Arch Biochem Biophys. 2018 Sep 15;654:10-18. doi: 10.1016/j.abb.2018.07.005. Epub 2018 Jul 9.
• [3] Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes. Toxicol Lett. 2018 Jun 1;289:1-13.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [6] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [7] 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.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] 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.
• [12] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [13] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [14] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.