Nucleotide sugar dehydratases: Structure, mechanism, substrate specificity, and application potential

Ulrike Vogel,Koen Beerens,Tom Desmet

doi:10.1016/j.jbc.2022.101809

Abstract

Nucleotide sugar (NS) dehydratases play a central role in the biosynthesis of deoxy and amino sugars, which are involved in a variety of biological functions in all domains of life. Bacteria are true masters of deoxy sugar biosynthesis as they can produce a wide range of highly specialized monosaccharides. Indeed, deoxy and amino sugars play important roles in the virulence of gram-positive and gram-negative pathogenic species and are additionally involved in the biosynthesis of diverse macrolide antibiotics. The biosynthesis of deoxy sugars relies on the activity of NS dehydratases, which can be subdivided into three groups based on their structure and reaction mechanism. The best-characterized NS dehydratases are the 4,6-dehydratases that, together with the 5,6-dehydratases, belong to the NS-short-chain dehydrogenase/reductase superfamily. The other two groups are the less abundant 2,3-dehydratases that belong to the Nudix hydrolase superfamily and 3-dehydratases, which are related to aspartame aminotransferases. 4,6-Dehydratases catalyze the first step in all deoxy sugar biosynthesis pathways, converting nucleoside diphosphate hexoses to nucleoside diphosphate-4-keto-6-deoxy hexoses, which in turn are further deoxygenated by the 2,3- and 3-dehydratases to form dideoxy and trideoxy sugars. In this review, we give an overview of the NS dehydratases focusing on the comparison of their structure and reaction mechanisms, thereby highlighting common features, and investigating differences between closely related members of the same superfamilies.

Highlights

This review aims to give the reader an overview of the different nucleotide sugars (NS) dehydratases
These NS dehydratases are involved in the biosynthesis of deoxy and/or amino sugars [1], which will be further explained in the article
Based on their fold and catalytic mechanisms, the NS active dehydratases can be subdivided into three groups: the NS active short-chain dehydrogenase/reductase (NS-SDR)–like [2, 3], the Nudix hydrolase superfamily–like

Summary

Edited by Chris Whitfield

Nucleotide sugar (NS) dehydratases play a central role in the biosynthesis of deoxy and amino sugars, which are involved in a variety of biological functions in all domains of life. The other dehydratases active on UDP-GlcNAc are the 5-inverting 4,6-dehydratases (performing an additional epimerization at C5) involved in the biosynthesis of Pse acid (in H. pylori and C. jejuni) [38] and the 5,6-dehydratase (TunA in Streptomyces lysosuperificus) that yields UDP-6deoxy-5,6-glycosene as an intermediate in the pathway for biosynthesis of tunicamycins (archetypal nucleoside antibiotics targeting the bacterial peptidoglycan biosynthesis and eukaryotic protein N-glycosylation) [103, 104]. As underlined by the aforementioned examples, dehydratases active on NS are present in all domains of life, where they play a key role in the biosynthetic pathways of bacterial (e.g., LPS, capsule, and other cell surface polysaccharides), mammalian (e.g., ABO antigens), and plant (e.g., cell wall polymers) glycans and saccharides (e.g., human milk oligosaccharide) and for antibiotics and other secondary metabolite synthesis. A detailed description of these different pathways and other enzymes (e.g., reductases, ketoisomerases, aminotransferases, and acetyltransferases) involved in the deoxy and amino sugar biosynthesis, lies outside of the scope of this review

Nucleotide sugar dehydratases and natural evolution

Conclusion