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

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 ?-1,4-d-glucans (cyclodextrins). We find that the native cyclodextrins (?, ? and ?) 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 (? and ?) 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.

SUBMITTER: Larsen D

PROVIDER: S-EPMC6979337 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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

Larsen Dennis D Beeren Sophie R SR

Chemical science 20190925 43

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 su ...[more]

PMID: 32055354

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Project description:Examples of using two-dimensional shape-persistent macrocycles, i.e. those having noncollapsible and geometrically well-defined skeletons, for constructing mechanically interlocked molecules are scarce, which contrasts the many applications of these macrocycles in molecular recognition and functional self-assembly. Herein, we report the crucial role played by macrocyclic shape-persistency in enhancing multipoint recognition for the highly efficient template-directed synthesis of rotaxanes. Cyclo[6]aramides, with a near-planar conformation, are found to act as powerful hosts that bind bipyridinium salts with high affinities. This unique recognition module, composed of two macrocyclic molecules with one bipyridinium ion thread through the cavity, is observed both in the solid state and in solution, with unusually high binding constants ranging from ∼1013 M-2 to ∼1015 M-2 in acetone. The high efficacy of this recognition motif is embodied by the formation of compact [3]rotaxanes in excellent yields based on either a "click-capping" (91%) or "facile one-pot" (85%) approach, underscoring the great advantage of using H-bonded aromatic amide macrocycles for the highly efficient template-directed synthesis of mechanically interlocked structures. Furthermore, three cyclo[6]aramides bearing different peripheral chains 1-3 demonstrate high specificity in the synthesis of a [3]rotaxane from 1 and 2, and a [2]rotaxane from 3via a "facile one-pot" approach, in each case as the only isolated product. Analysis of the crystal structure of the [3]rotaxane reveals a highly compact binding mode that would be difficult to access using other macrocycles with a flexible backbone. Leveraging this unique recognition motif, resulting from the shape-persistency of these oligoamide macrocycles, in the template-directed synthesis of compact rotaxanes may open up new opportunities for the development of higher order interlocked molecules and artificial molecular machines.

Dataset Information

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

Publications

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

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