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 and downstream purification. On the other hand, electrons are a cheap and green source of energy. We report a method that uses electricity to turn over enzymes for ATP generation. 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 ■ 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.…”

The Catalysis Laboratory at Merck: 20 Years of Catalyzing Innovation

“…This process has now also been run on a 1 kg scale (Scheme 22b). 102 With these collective investments in electrochemistry, we are now well-equipped to apply this prospective investment to the company's portfolio when the opportunity arises.…”

“…The Catalysis Laboratory demonstrated that this approach was feasible for the cofactor flavin adenine dinucleotide (FAD) for adenosine triphosphate (ATP) recycle and applied this capability to a biocatalytic cascade process for the glycosylation step in molnupiravir ( 80 ), eliminating the need for dioxygen or catalase. This process has now also been run on a 1 kg scale (Scheme b) . With these collective investments in electrochemistry, we are now well-equipped to apply this prospective investment to the company’s portfolio when the opportunity arises.…”