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Issue 43, 2019
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Enzyme-mediated dynamic combinatorial chemistry allows out-of-equilibrium template-directed synthesis of macrocyclic oligosaccharides

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Abstract

We show that the outcome of enzymatic reactions can be manipulated and controlled by using artificial template molecules to direct the self-assembly of specific products in an enzyme-mediated dynamic system. Specifically, we utilize a glycosyltransferase to generate a complex dynamic mixture of interconverting linear and macrocyclic α-1,4-D-glucans (cyclodextrins). We find that the native cyclodextrins (α, β and γ) are formed out-of-equilibrium as part of a kinetically trapped subsystem, that surprisingly operates transiently like a Dynamic Combinatorial Library (DCL) under thermodynamic control. By addition of different templates, we can promote the synthesis of each of the native cyclodextrins with 89–99% selectivity, or alternatively, we can amplify the synthesis of unusual large-ring cyclodextrins (δ and ε) with 9 and 10 glucose units per macrocycle. In the absence of templates, the transient DCL lasts less than a day, and cyclodextrins convert rapidly to short maltooligosaccharides. Templates stabilize the kinetically trapped subsystem enabling robust selective synthesis of cyclodextrins, as demonstrated by the high-yielding sequential interconversion of cyclodextrins in a single reaction vessel. Our results show that given the right balance between thermodynamic and kinetic control, templates can direct out-of-equilibrium self-assembly, and be used to manipulate enzymatic transformations to favor specific and/or alternative products to those selected in Nature.

Graphical abstract: Enzyme-mediated dynamic combinatorial chemistry allows out-of-equilibrium template-directed synthesis of macrocyclic oligosaccharides

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Supplementary files

Article information


Submitted
09 Aug 2019
Accepted
02 Sep 2019
First published
25 Sep 2019

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2019,10, 9981-9987
Article type
Edge Article

Enzyme-mediated dynamic combinatorial chemistry allows out-of-equilibrium template-directed synthesis of macrocyclic oligosaccharides

D. Larsen and S. R. Beeren, Chem. Sci., 2019, 10, 9981
DOI: 10.1039/C9SC03983J

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