Abstract
Glucose-1-phosphate uridylyltransferase in conjunction with UDP-glucose pyrophosphorylase was found to catalyse the conversion of a range of 5-substituted UTP derivatives into the corresponding UDP-galactose derivatives in poor yield. Notably the 5-iodo derivative was not converted to UDP-sugar. In contrast, UDP-glucose pyrophosphorylase in conjunction with inorganic pyrophosphatase was particularly effective at converting 5-substituted UTP derivatives, including the iodo compound, into a range of gluco-configured 5-substituted UDP-sugar derivatives in good yields. Attempts to effect 4″-epimerization of these 5-substituted UDP-glucose with UDP-glucose 4″-epimerase from yeast were unsuccessful, while use of the corresponding enzyme from Erwinia amylovora resulted in efficient epimerization of only 5-iodo-UDP-Glc, but not the corresponding 5-aryl derivatives, to give 5-iodo-UDP-Gal. Given the established potential for Pd-mediated cross-coupling of 5-iodo-UDP-sugars, this provides convenient access to the galacto-configured 5-substituted-UDP-sugars from gluco-configured substrates and 5-iodo-UTP.
Highlights
Glycosyltransferases (GTs) are a large class of carbohydrate active enzymes that are involved in numerous important biological processes, with impact in cellular adhesion, carcinogenesis and neurobiology, amongst many others.[1,2,3]
1:10:3.5, the conversion to UDP-Glc (2a) after 30 min was the same as in the absence of 1f, implying that 1f does not compete with UDP-Gal (1a) to bind in the active site of GalPUT. This implies that the formylthienyl substitution of the uracil base prevents the corresponding sugar nucleotides from binding to GalPUT and explains the observed lack of conversion of 2f into 1f in the one-pot General procedure 2 (GalU)-GalPUT protocol
GalU reactions with substituted UTPs The results presented above indicate that GalU possesses a degree of substrate flexibility regarding 5-substitution of UTP, O
Summary
Glycosyltransferases (GTs) are a large class of carbohydrate active enzymes that are involved in numerous important biological processes, with impact in cellular adhesion, carcinogenesis and neurobiology, amongst many others.[1,2,3] As such, GTs have enormous potential as targets for drug discovery. Tel.: +44 1603 450720; fax: +44 1603 450018 (R.A.F.) UDP-sugars with a fluorogenic substituent at position 5 of the uracil base (Fig. 1).[10,11] In a proof of concept study, Wagner et al demonstrated that fluorescence emission by 5-formylthienyl-. Suzuki coupling under aqueous conditions.[6] The aim of the current work was to explore alternative methods for the preparation of 5-substituted UDP-sugars (1–4) using chemo-enzymatic approaches (reviewed in Ref. 13) starting from 5-substituted UTP derivatives 5b–f.12
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