Electrochemical Recycling of Adenosine Triphosphate in Biocatalytic Reaction Cascades

Abstract

Adenosine triphosphate (ATP) provides the driving force necessary for critical biological functions in all living organisms. In synthetic biocatalytic reactions, this cofactor is recycled in situ using high-energy stoichiometric reagents, an approach that generates waste and poses challenges with enzyme stability. On the other hand, an electrochemical recycling system would use electrons as a convenient source of energy. We report a method that uses electricity to turn over enzymes for ATP generation in a simplified cellular respiration mimic. The method is simple, robust, and scalable, as well as broadly applicable to complex enzymatic processes including a four-enzyme biocatalytic cascade in the synthesis of the antiviral molnupiravir.

The Evolving Nature of Biocatalysis in Pharmaceutical Research and Development

“…Recently, an alternative electrochemical method for ATP was described under air-free conditions that could be successfully implemented in this cascade to avoid the challenges of oxygen mass transfer. 83 …”

“…The cascade was demonstrated on a 50 g scale starting from ribose 89 to achieve nucleoside 92 in 87% isolated yield which was 70% shorter than the previous chemical route as well as being almost 7-fold higher yielding. Recently, an alternative electrochemical method for ATP was described under air-free conditions that could be successfully implemented in this cascade to avoid the challenges of oxygen mass transfer …”

“…Recently, an alternative electrochemical method for ATP was described under air-free conditions that could be successfully implemented in this cascade to avoid the challenges of oxygen mass transfer. 83 ■ CURRENT STATE-OF-THE-ART Biocatalysis continues to be highly impactful for key synthetic challenges in the pharmaceutical industry. In all the industrial examples highlighted, there have been significant challenges to the implementation of biocatalytic transformations.…”

Phosphorus sustainability: a case for phytic acid as a biorenewable platform

“…We direct readers to an excellent recent article that looks to circumvent this problem electrochemically. 74 Nevertheless, the organophosphorus end-products accessible from ATP are presently limited to organophosphates, and the enzymes mediating this phosphorylation process often operate within a strict set of reaction conditions, which further limits the scope of compatible substrates for ATP-mediated organophosphate production. 75 As such, ATP also fails to meet criterion 3 due to the inefficient processes for harnessing P to manufacture a limited scope of organophosphorus compounds.…”

Accelerated Electrosynthesis Development Enabled by High-Throughput Experimentation

“…Ruccolo et al developed a method to use electricity to regenerate adenosine triphosphate (ATP) for complex enzymatic synthesis processes (Figure 2d). 68 To find the optimal mediator for ATP regeneration, they first used cyclic voltammetry to determine the mechanism of the catalytic pro-Figure 2 High-throughput screening for homogeneous electrocatalysts. (a) Electrochemical co-polymerization for immobilized catalyst preparation and screening.…”