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Abstract
Nucleoside-2′-deoxyribosyl-transferases (NDTs) catalyze a transglycosylation reaction consisting of the exchange of the 2′-deoxyribose moiety between a purine and/or pyrimidine nucleoside and a purine and/or pyrimidine base. Because NDTs are highly specific for 2′-deoxyribonucleosides they generally display poor activity on modified C2′ and C3′ nucleosides and this limitation hampers their applicability as biocatalysts for the synthesis of modified nucleosides. We now report the production and purification of a novel NDT from Archaeoglobus veneficus that is endowed with native ribosyltransferase activity and hence it is more properly classified as an N-ribosyltransferase (AvNRT). Biophysical and biochemical characterization revealed that AvNRT is a homotetramer that displays maximum activity at 80°C and pH 6 and shows remarkably high stability at high temperatures (60–80°C). In addition, the activity of AvNRT was found to increase up to 2-fold in 4 M NaCl aqueous solution and to be retained in the presence of several water-miscible organic solvents. For completeness, and as a proof of concept for possible industrial applications, this thermophilic and halotolerant biocatalyst was successfully employed in the synthesis of different purine ribonucleoside analogs.
Highlights
Nucleoside analogs (NAs) comprise a group of synthetic molecules that mimic natural nucleosides and have been widely used as anticancer agents and to treat some viral and fungal infections since the late 1960’s (De Clercq, 2005; Parker, 2009; Jordheim et al, 2013)
The most commonly used synthetic route for the synthesis of NAs is the transglycosylation reaction catalyzed by nucleoside phosphorylases or 2′-deoxyribosyltransferases (Fresco-Taboada et al, 2013; Lapponi et al, 2016; Del Arco and Fernández-Lucas, 2018; Kamel et al, 2019a; Lewkowicz and Iribarren, 2019; Trelles et al, 2019)
According to their substrate specificity, NDTs are usually classified as: (i) type I NDTs (PDT), which perform this type of transglycosylation reaction between purine bases (Fresco-Taboada et al, 2013; Pérez et al, 2018) and (ii) type II NDTs (NDT), which do not discriminate between purines and pyrimidines (Kaminski, 2002; Fernández-Lucas et al, 2010; Fresco-Taboada et al, 2016)
Summary
Nucleoside analogs (NAs) comprise a group of synthetic molecules that mimic natural nucleosides and have been widely used as anticancer agents and to treat some viral and fungal infections since the late 1960’s (De Clercq, 2005; Parker, 2009; Jordheim et al, 2013). Enzyme-catalyzed synthesis by whole cells or purified proteins offers several advantages, such as one-pot reactions, controlled stereo-, Halotolerant and Thermostable N-Ribosyltransferase regio-, and enantiospecificities, and mild reaction conditions In this regard, the most commonly used synthetic route for the synthesis of NAs is the transglycosylation reaction catalyzed by nucleoside phosphorylases or 2′-deoxyribosyltransferases (Fresco-Taboada et al, 2013; Lapponi et al, 2016; Del Arco and Fernández-Lucas, 2018; Kamel et al, 2019a; Lewkowicz and Iribarren, 2019; Trelles et al, 2019). Several examples of NDT-mediated glycosylation at multiple sites have been recently reported for several sizeexpanded purines (Ye et al, 2014) and azole derivatives (VichierGuerre et al, 2017)
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