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Methylation of selenocysteine catalysed by thiopurine S-methyltransferase
Univ Ljubljana, Slovenia.
Slovenian NMR Ctr, Slovenia.
Univ Ljubljana, Slovenia.
Univ Ljubljana, Slovenia.
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2019 (English)In: Biochimica et Biophysica Acta - General Subjects, ISSN 0304-4165, E-ISSN 1872-8006, Vol. 1863, no 1, p. 182-190Article in journal (Refereed) Published
Abstract [en]

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 Se-77 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 Se-77 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.

Place, publisher, year, edition, pages
ELSEVIER SCIENCE BV , 2019. Vol. 1863, no 1, p. 182-190
Keywords [en]
Binding analysis; Enzymatic methylation; NMR spectroscopy; S-adenosylmethionine; Selenocysteine; Thiopurine S-methyltransferase
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:liu:diva-153496DOI: 10.1016/j.bbagen.2018.10.002ISI: 000452343100017PubMedID: 30308221OAI: oai:DiVA.org:liu-153496DiVA, id: diva2:1274654
Note

Funding Agencies|Slovenian Research Agency [J3-6792, P1-0208, MR34512]

Available from: 2019-01-02 Created: 2019-01-02 Last updated: 2019-01-02

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Mårtensson, Lars-Göran
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ChemistryFaculty of Science & Engineering
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