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Nucleotide Deoxysugars: Essential Tools for the Glycosylation Engineering of Novel Bioactive Compounds

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Abstract:

The irreversible spread of new resistance mechanisms against existing therapeutical antibiotics has led to the development of technologies and strategies for the glycosylation engineering of novel antibiotics. Amino-, C-branched and O-methylated 6-deoxyhexoses play a favourite role in the biosynthesis of clinically important antibiotics like tylosin, erythromycin or oleandomycin and are essential for the antibiotic activity. They are transferred onto the aglycon by glycosyltransferases using dTDP-activated deoxyhexoses. The in vitro biochemical characterization of the biosynthetic enzymes and the glycosyltransferases are, however, hampered due to the poor synthetic access to dTDP-activated deoxysugars and their biosynthetic intermediates. The overcoming of the poor availability of dTDP-activated sugars was the target of several researchers to fulfil their distinct aims with these sugars which were mostly involved in the synthesis of different biological active compounds. Several completely different strategies were used in the past years to improve the availability of dTDP-activated deoxysugars, varying from complete enzymatic synthesis via syntheses using reaction technology for yield optimization to full organic synthesis or shortcuts like the decomposition of commercially available antibiotics and later chemical activation of the sugar moieties. This review gives a survey of the synthesis of dTDP-activated sugars by chemical and chemoenzymatic approaches and discusses the promiscuity of glycosyltransferases to evaluate the chances for applying them for the production of new bioactive compounds. It summarizes the most important enzymes in the field of synthesis using biosynthetic pathway enzymes and describes solutions for occurring challenges during application. Finally, this review will give a survey about the availability of dTDP-activated sugars in sufficient scale and will also point at important sugars which are still bottlenecks and difficult to synthesize and therefore should become a target for enhanced research efforts.

Keywords: chemoenzymatic synthesis; combinatorial biocatalysis; dtdp-deoxyhexoses; enzymatic synthesis; glycosyltransferases; macrolide antibiotics; nucleotide deoxysugars

Document Type: Review Article

DOI: http://dx.doi.org/10.2174/0929867054367167

Affiliations: Department of Biotechnology/Biomaterial Sciences, Helmholtz-Institute for Biomedical Engineering, RWTH Aachen University, Worringer Weg 1, D-52056 Aachen, Germany.

Publication date: July 1, 2005

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  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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