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Methylation of selenocysteine catalysed by thiopurine S-methyltransferaseUrbančič, Dunja, farmacevtka ...Background Methylation driven by thiopurine S-methylatransferase (TPMT) is crucial for deactivation of cytostatic and immunosuppressant thiopurines. Despite its remarkable integration into clinical ... practice, the endogenous function of TPMT is unknown. Methods To address the role of TPMT in methylation of selenium compounds, we established the research on saturation transfer difference (STD) and 77Se NMR spectroscopy, fluorescence measurements, as well as computational molecular docking simulations. Results Using STD NMR spectroscopy and fluorescence measurements of tryptophan residues in TPMT, we determined the binding of selenocysteine (Sec) to human recombinant TPMT. By comparing binding characteristics of Sec in the absence and in the presence of methyl donor, we confirmed S-adenosylmethionine (SAM)-induced conformational changes in TPMT. Molecular docking analysis positioned Sec into the active site of TPMT with orientation relevant for methylation reaction. Se-methylselenocysteine (MeSec), produced in the enzymatic reaction, was detected by 77Se NMR spectroscopy. A direct interaction between Sec and SAM in the active site of rTPMT and the formation of both products, MeSec and S-adenosylhomocysteine, was demonstrated using NMR spectroscopy. Conclusions The present study provides evidence on in vitro methylation of Sec by rTPMT in a SAM-dependant manner. General Significance. Our results suggest novel role of TPMT and demonstrate new insights into enzymatic modifications of the 21st amino acid.Source: Biochimica et biophysica acta (G). General subjects. - ISSN 0304-4165 (Vol. 1863, iss. 1, Jan. 2019, str. 182-190)Type of material - article, component partPublish date - 2019Language - englishCOBISS.SI-ID - 4616561
Author
Urbančič, Dunja, farmacevtka |
Kotar, Anita, farmacevtka |
Šmid, Alenka, farmacevtka |
Jukič, Marko |
Gobec, Stanislav, 1970- |
Martensson, Lars |
Plavec, Janez |
Mlinarič-Raščan, Irena
Topics
Jedrska magnetna resonanca |
Binding analysis |
enzymatic methylation |
NMR spectroscopy |
S-adenosylmethionine |
selenocysteine thiopurine |
S-methyltransferase
Author | Urbančič, Dunja, farmacevtka ... |
Title | Methylation of selenocysteine catalysed by thiopurine S-methyltransferase |
Publication date | 2019-01-29 |
COBISS.SI-ID | 4616561 |
Publication version in repository | Publisher's version |
Publication licence | Creative Commons Attribution 4.0 International |
Embargo | Immediate publication for public |
Project(s) from which the publication was funded
Title | Acronym | Project ID | Funder |
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TRANS TIO Translacijske farmakogenomske raziskave tiopurinske terapije | J3-6792-2014 |
Javna agencija za znanstvenoraziskovalno in inovacijsko dejavnost Republike Slovenije |
|
Farmacevtska kemija: načrtovanje, sinteza in vrednotenje učinkovin | P1-0208-2015 |
Javna agencija za znanstvenoraziskovalno in inovacijsko dejavnost Republike Slovenije |
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https://www.sciencedirect.com/science/article/pii/S0304416518303155?via%3Dihub |
https://repozitorij.uni-lj.si/IzpisGradiva.php?id=125358 |
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Links to authors' personal bibliographies | Links to information on researchers in the SICRIS system |
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Urbančič, Dunja, farmacevtka | 34512 |
Kotar, Anita, farmacevtka | 38338 |
Šmid, Alenka, farmacevtka | 29982 |
Jukič, Marko | 32587 |
Gobec, Stanislav, 1970- | 15284 |
Martensson, Lars | |
Plavec, Janez | 10082 |
Mlinarič-Raščan, Irena | 12443 |
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