Biocatalytic cascades are driven by enzyme-modified dynamic nucleic acid networks

Published in Chemistry
Biocatalytic cascades are driven by enzyme-modified dynamic nucleic acid networks

      Complex cellular transformations, such as gene expression or cellular metabolic processes, are driven by complex stimuli-responsive network circuitries. Inspired by nature, extensive research efforts are directed to mimic such processes by artificial chemical means.

      Our laboratory has introduced nucleic acid-based constitutional dynamic networks (CDNs), where the constituents exist in equilibrium at compositions dictated by the stabilities of the constituents. By the stabilization of any one of the constituents using an outside trigger, the dynamic network is re-equilibrate to a new composition. During the past few years, we were able to construct constitutional dynamic networks composed of four equilibrated constituents that could be reconfigured to newly adaptive equilibrated compositions by appropriate stabilizing triggers. We were able to duplicate with these artificial nucleic acid network’s features of native networks, such as intercommunication between networks, substitution of networks, feedback-driven networks and cascaded networks.1-3 In the present study (10.1038/s41929-020-00524-7), we were able to enhance the complexities and functionalities of constitutional dynamic networks by conjugating enzymes or enzyme/cofactor units to the components comprising the constituents, thereby controlling biocatalytic cascades driven by the dynamic networks. In one constitutional dynamic network, one of the constituents was functionalized with the spatially proximity positioned two enzymes, glucose oxidase (GOx) and horseradish peroxidase (HRP). The effective transfer of the glucose oxidase-generated hydrogen peroxide product acting as substrate for horseradish peroxidase, activated the bienzyme cascade. The triggered up-regulation of the constituent content in the composition of the network, enhanced the bienzyme cascade, whereas the triggered downregulation of the content of the constituents in the composition of the network inhibited the enzyme cascade. In a second dynamic network system, one of the constituents was substituted at spatially close positions with the NAD+-cofactor-dependent enzyme alcohol dehydrogenase (ADH) and nicotinamide adenine dinucleotide (NAD+) cofactor. The constituent activated the biocatalytic cascade that stimulated the enzyme-cofactor mediated reduction of methylene blue. The triggered up-regulation of the constituent in the equilibrated network composition, enhanced the biocatalytic process, whereas the triggered down-regulation of the constituent in the network composition inhibited, and switched-off the biocatalytic transformation. In addition, the coupling of the two networks and the feedback-driven intercommunication were demonstrated. The ADH/NAD+-modified network generated a fuel strand that stabilized the GOx/HRP-modified constituent in the counter network, resulted in the enhanced GOx/HRP cascade, and the concomitant formation of a fuel-strand that was transferred into the ADH/NAD+-functional network. The transformation stabilized the ADH/ NAD+ constituent and enhanced the ADH/ NAD+ biocatalytic cascade, while affecting the concomitant generation of the fuel-strand for activating the GOx/HRP cascade. This process demonstrated the intercommunication of two networks and the activation of an autonomous feedback-driven control over catalytic cascades in coupled networks.

      The integration of enzymes with nucleic acid-based constitutional dynamic networks represents a major advance in the field of Systems Chemistry by providing innovative means to couple the adaptive and intercommunicating capacities of dynamic networks with the guided control over biocatalytic transformations. We anticipate that the integration of such hybrid systems with cell-like containments could be an important path to mimic cells by artificial protocells.

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  1. Wang, S. et al. Controlling the Catalytic Functions of DNAzymes within Constitutional Dynamic Networks of DNA Nanostructures. J. Am. Chem. Soc. 139, 9662–9671 (2017).
  2. Wang, S. et al. Light-Induced Reversible Reconfiguration of DNA-Based Constitutional Dynamic Networks: Application to Switchable Catalysis. Angew. Chem. Int. Ed. 57, 8105–8109 (2018).
  3. Yue, L. et al. Intercommunication of DNA-Based Constitutional Dynamic Networks.  J. Am. Chem. Soc. 140, 8721–8731 (2018).

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