Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8OBXKK)

• DOT Name: tRNA-queuosine alpha-mannosyltransferase (GTDC1)
• Synonyms: QTMAN; EC 2.4.1.110; Glycosyltransferase-like domain-containing protein 1; Mannosyltransferase-like protein Xa; Mat-Xa
• Gene Name: GTDC1
• Related Disease:
  Alzheimer disease
  Schizophrenia
  Neurodevelopmental disorder
• UniProt ID: QTMAN_HUMAN
• EC Number: 2.4.1.110
• Pfam ID: PF12038 ; PF00534
• Sequence:
  MSILIIEAFYGGSHKQLVDLLQEELGDCVVYTLPAKKWHWRARTSALYFSQTIPISEHYR
  TLFASSVLNLTELAALRPDLGKLKKILYFHENQLIYPVKKCQERDFQYGYNQILSCLVAD
  VVVFNSVFNMESFLTSMGKFMKLIPDHRPKDLESIIRPKCQVIYFPIRFPDVSRFMPKHK
  TTHLKKMLGLKGNGGAVLSMALPFQPEQRDSEDLLKNFNSECDTHCGLDTARQEYLGNSL
  RQESDLKKSTSSDNSSSHHGENKQNLTVDPCDILGGVDNQQRLLHIVWPHRWEHDKDPES
  FFKVLMHLKDLGLNFHVSVLGETFTDVPDIFSEAKKALGSSVLHWGYLPSKDDYFQVLCM
  ADVVISTAKHEFFGVAMLEAVYCGCYPLCPKDLVYPEIFPAEYLYSTPEQLSKRLQNFCK
  RPDIIRKHLYKGEIAPFSWAALHGKFRSLLTTEPREDL
• Function: Glycosyltransferase that specifically catalyzes mannosylation of cytoplasmic tRNA(Asp) modified with queuosine at position 34 (queuosine(34)). Mannosylates the cyclopentene moiety of queuosine(34) in tRNA(Asp) to form mannosyl-queuosine(34). Mannosylation of queuosine(34) in tRNA(Asp) is required to slow-down elongation at cognate codons, GAC and GAU, thereby regulating protein translation.
• Tissue Specificity: Ubiquitous. Expressed at high levels in the lung, brain, spleen, testis, placenta. ovary, pancreas, spleen and peripheral blood leukocytes. Expressed at low level in the colon, small intestine, kidney, skeletal muscle and thymus. Expressed at high level in colon adenocarcinoma.

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Biomarker	[1]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[2]
Neurodevelopmental disorder	DIS372XH	moderate	Biomarker	[3]

7 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 tRNA-queuosine alpha-mannosyltransferase (GTDC1).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of tRNA-queuosine alpha-mannosyltransferase (GTDC1).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of tRNA-queuosine alpha-mannosyltransferase (GTDC1).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of tRNA-queuosine alpha-mannosyltransferase (GTDC1).	[7]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of tRNA-queuosine alpha-mannosyltransferase (GTDC1).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of tRNA-queuosine alpha-mannosyltransferase (GTDC1).	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of tRNA-queuosine alpha-mannosyltransferase (GTDC1).	[12]

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 tRNA-queuosine alpha-mannosyltransferase (GTDC1).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of tRNA-queuosine alpha-mannosyltransferase (GTDC1).	[11]

References

• [1] MicroRNA-132 promotes neurons cell apoptosis and activates Tau phosphorylation by targeting GTDC-1 in Alzheimer's disease.Eur Rev Med Pharmacol Sci. 2019 Oct;23(19):8523-8532. doi: 10.26355/eurrev_201910_19166.
• [2] Common variants on 8p12 and 1q24.2 confer risk of schizophrenia.Nat Genet. 2011 Oct 30;43(12):1224-7. doi: 10.1038/ng.980.
• [3] Personalized genome sequencing coupled with iPSC technology identifies GTDC1 as a gene involved in neurodevelopmental disorders.Hum Mol Genet. 2017 Jan 15;26(2):367-382. doi: 10.1093/hmg/ddw393.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.