Advances in electrochemical cofactor regeneration: enzymatic and non-enzymatic approaches

Yoo Seok Lee , Rokas Gerulskis and Shelley D Minteer

Abstarct:

Nicotinamide adenine dinucleotide(NAD(P)H) is a metabolically interconnected redox cofactor serving as a hydride source for the majority of oxidoreductases, and consequently constituting a significant cost factor for bioprocessing. Much research has been devoted to the development of efficient, affordable, and sustainable methods for the regeneration of these cofactors through chemical, electrochemical, and photochemical approaches. However, the enzymatic approach using formate dehydrogenase is still the most abundantly employed in industrial applications, even though it suffers from system complexity and product purity issues. In this review, we summarize non-enzymatic and enzymatic electrochemical approaches for cofactor regeneration, then discuss recent phosphorylated form (NADP ) as a cofactor to receive and transfer hydrides between independently catalyzed reactions (Figure 1). Commercial enzymatic redox trans- formations require stoichiometric amounts of NAD(P)H, and the high cost of NADH (>$20/g) [5,6] and NADPH ($500/g) [7 ] has motivated research aimed at their regeneration in both the reduction and oxidation direc- tions. This review provides a compilation of important developments in both enzymatic and non-enzymatic cofactor regeneration systems. Enzymatic systems pre- sented include both electrochemical and non-electro- chemical approaches. The three types of non-enzymatic systems presented employ (1) inorganic reductants (e.g. Rh-catalyst mediated enzyme mutual inactivation, electron- transfer rates, catalyst sustainability, product selectivity and simplifying product purification. Recently reported remedies are discussed, such as heterogeneous metal catalysts generating H as the sole byproduct or high activity and stability redox-polymer immobilized enzymatic systems for sustainable organic synthesis.

Address
Department of Chemistry, University of Utah, 315 S 1400 E, Salt Lake City, UT 84112, USA
Corresponding authors: Lee, Yoo Seok ([email protected]), Minteer, Shelley D ([email protected])
Co-first authors.

Introduction

Enzymatic catalysis systems have widespread use in environmental applications, organic synthesis, and phar- maceutical manufacturing due to the exceptional selectivity and turnover frequencies of enzyme-catalyzed reactions [1,2 ,3 ]. The majority of oxidoreductases, enzymes that catalyze redox reactions [4], employ nicotinamide adenine dinucleotide (NAD ) or its lymers and carbon nitride) [10–12], and/or (3) electroca- talysis (including both direct electrochemical regenera- tion [13,14] and indirect regeneration using homogeneous or heterogeneous inorganic complexes [15,16 ,17–20]).

Non-enzymatic electrochemical cofactor
In one of the first methods presented for the non-enzy- matic regeneration of NADH, Wienkamp et al. [16 ] employed the two-electron transfer agent [Rh(bpy)2] generated from [Rh(bpy)3] at a graphite cathode. The use of a [Rh(bpy)3] mediator decreased the over- potential required for NAD reduction by 250 mV when compared to the direct reduction on the electrode surface ( 0.65 V compared to over 0.9 V versus SHE). This decrease minimizes the production of enzymatically inac- tive NAD2 dimers, while avoiding the use of enzymes minimizes productivity losses arising from enzyme inac- tivation. More recently, Zhang et al. [21] demonstrated in a photoelectrochemical system that employing Si nano- wires (SiNW) rather than planar Si at the cathode with dissolved Cp*Rh(bpy) shifts this overpotential yet fur- ther, from 0.35 V (onset versus RHE, peaking at 0.65 V) in Si sheets, to +0.25 V (peaking at 0.05 V) in the SiNW electrode. This corresponded to a catalytic rate of 1.5 mM cm h at 0.5 V (versus SHE) and nearly 100% Faradaic efficiency using the SiNW electrode. To advance this technology, many kinds of metal-based catalysts including iron [22], platinium-gold [23], rhenium [24,25], copper-mercury [26], and iridium [27] have been actively investigated in the past 20 years, while others have focused on the role of Rh-ligand identity [28 ], all with the aim of increasing cofactor conversion kinetics and product yield. Gopalan et al. [29] were the first to utilize core–shell metal nanoparticles as a catalyst for the conversion of NADH to NAD , aiming to make use
(a) NADH is utilized as a cofactor (reducing agents) to donate hydride for oxidoreductase biotransformation; (b) NAD reduction to NADH; (c) formation of enzymatically inactive NAD2 dimer and (d) 1,6-NADH. Reprinted with permission from Ref. [8]. Copyright 2016, American Chemical Society. excellent catalytic and optical [30] properties of this catalyst. Since then, many various core–shell architec- tures have received attention, especially combinations employing a more abundant and cheaper metal core with a noble metal shell. The use of noble metal shells protects the core metal from degradation, but can also improve the catalytic properties due to strain and ligand effects of the core metal on the supported noble metal [31,32].
Ali et al. [33] developed a Pt and Ni nanoparticle-pat- terned electrode with the aim of improving radical pro- tonation kinetics. The undesired production of inactive NAD2 dimers in many direct regeneration systems results from the proximal reduction of multiple NAD molecules at the electrode surface, which dimerize with one another before they can be protonated. The Pt and Ni nano- particles provide ‘active’adsorbed hydrogen at the elec- trode surface to improve radical protonation kinetics and minimize this radical dimerization. The Pt nanoparticle patterned electrode demonstrated a 100% increase in the amount of NADH regenerated with a yield of 65 1.9% compared to the 32 0.02% in the control conversion using a pure electrode. 98% recovery of enzymatically active 1,4-NADH was demonstrated at 1.6 V versus MSE, an impressive selectivity given that direct regener- ation methods typically demonstrate significant loss to NAD reduction side reactions [34,35 ].
Photoinduced cofactor conversion has attracted attention as a cost-effective and sustainable approach by eliminat- ing the need for an external power supply by using available solar energy. Nam et al. [36] utilized proflavine, a photosensitizer with high stability and turnover num- bers under photolysis conditions. Triethanolamine was used as a sacrificial electron donor, and [Cp*Rh(bpy) (H2O)] was applied as an organometallic electron medi- ator to minimize the rate of the dimer and isomer-yielding side-reactions of NAD reduction. This system showed 63.4% maximum yield and an initial turnover frequency (TOF) of 127.8 h for NADH regeneration under Xenon arc lamp and lower TOFs under colored LEDs. Liu et al. [11] proposed an NADH reduction system using a gra- phitic carbon nitride electrode employing [Cp Rh(bpy) H2O] and a frustule structure constructed using sustain- able diatomaceous earth. Again, with triethanolamine as a sacrificial electron donor, the NADH yield reached nearly 100%, with 1,4-NADH as the sole product. This was ascribed to the enhanced light trapping and scattering of the diatom layer promoting high photocatalytic efficiency.

Enzymatic electrochemical cofactor
Regeneration Compared to homogeneous organometallic complexes for catalyzing NADH regeneration, enzyme systems Energy biotechnology typically demonstrate superior regioselectivity, low over- potentials, greener catalytic conditions (temperature, pressure, pH), and higher turnover frequencies [9,37]. For these reasons, enzymatic NADH regeneration is the main regeneration method used by industry. Enzymatic NADH regeneration systems typically employ a dehy- drogenase, which reduces NAD by extracting a hydride from a more affordable substrate, oxidizing it concomitant to NAD reduction. For example, formate dehydrogenase (FDH), which oxidizes formate to CO2, is the most common NADH regenerating dehydrogenase employed at the industrial scale. FDH has been employed to regenerate NADH for the production of several tons per year of L-tert-leucine using leucine dehydrogenase [38]. It was employed to support phenylalanine dehydro- genase mediated manufacture of the antihypertensive drug omapatrilat, (Bristol-Myers Squibb) [39 ], and it is also employed to support the enzymatic conversion of asymmetric ketones to polyols for the production of optically active homogeneous catalysts, although this process is still being developed for use at industrial scales [40]. The TOF of FDH from Candida boidinii is reported as 3900 h , more than three times higher than the TOF of the fastest reported organometallic catalyst (a variant of Cp*Rh(bpy)) [28 ,41]. Other dehydrogenases with high
Figure 2(a) potential for widespread application include [42,43] glu- cose dehydrogenase (oxidizing glucose to gluconolac- tone) and phosphite dehydrogenase (oxidizing phosphite to phosphate). The former shows more versatility in employing NAD or NADP , and higher activity and stability compared to FDH, while the latter reaction does not cause a shift in pH, avoiding the cost of acid/base addition [44]. One of the most significant disadvantages of dehydrogenase-mediated NADH regeneration is the requirement for continual addition of co-substrate (e.g. formate) to the bioreactor, whose often incomplete con- sumption requires downstream purification steps [9,45]. This issue can be resolved electrochemically by employ- ing diaphorase, an enzyme that reduces NAD to NADH. Direct or mediated bioelectrocatalysis can then be used for regeneration without consuming any other co-sub- strates. In spite of this advantage, the potential of diaph- orase to replace existing commercial systems has rarely been investigated.
There are a few enzymes that can directly transfer elec- trons between their cofactors and the electrode surface (direct electron transfer, DET) [46]. However, for elec- tron tunneling rates to be sufficient for physiologically relevant TOFs, direct electrode-enzyme contact (<14 A)
(a) Scheme presenting NADH regeneration using a heterogeneous catalyst (Pt/Al2O3) and H2 coupled with an enzymatic reduction. (b) Variation of NADH yield as a function of time (&) as determined by H NMR ( ). (b) NADH yield validation using enzymatic assay: NADH produced experimentally (&) and from a prepared mixture using commercial NADH and NAD (&). (c) Continuous enzymatic reduction of propanal to propanol coupled with in situ NADH regeneration by Pt/Al

Advances in electrochemical cofactor regeneration Lee, Gerulskis and Minteer 17
is required [47,48], placing an upper limit on catalytic efficiency as a function of electrode surface area. The use of a dissolved redox mediator as an electron transferring agent increases tunneling rates, but this leads to extra product purification steps [49]. Dinh et al. demonstrated a components with byproducts and other components [18,54 ,55,56]. Although the environmental sustainability of proposed regeneration methods is rarely quantified in original literature, a recent work by Saba et al. [57 ] meticulously compared the e-factor (regeneration process diaphorase with surface-conjugation of the mediator ethyl cleanliness as quantified by kg dozens of carboxyethyl viologen (ECV) [50 ], demonstrating 126% improved NAD conversion versus diaphorase in 0.1 mM ECV, after 3 hours electrolysis at 0.85 V versus Ag/AgCl. This performance increase is side-benefit to a regenera- tion system requiring minimal NADH purification result- ing from electrode-conjugation of both catalyst and medi- ator. Unfortunately, redox mediators often suffer from degradation issues mandating frequent replacement or are not commercially available and require complex syn- theses and purifications for use [34,51,52]. Svenja et al. [53] compared different mediators as electron transferring agents in a scalable electrochemical reactor driving NAD (P) regeneration, discussing relative electron transfer efficiencies and required overpotentials.

Recent pioneering developments for cofactor regeneration
All large-scale systems for cofactor regeneration must consider the environmental sustainability of component manufacture, the cost of downstream purification, and the role in system productivity played by the interaction of
Figure 3(a) NAD(P)H regeneration systems. Several recent works demonstrate NAD reduction catalysts producing little byproduct on top of construction without the use of environmentally costly rare metals. Wang et al. [8] pro- posed, for the first time, an in situ NAD conversion to NADH using a heterogeneous Pt/Al2O3 catalyst that uses H2 as its hydride source and generates H as the sole byproduct, as shown in Figure 2. Subsequently, Ali et al. [7 ] improved upon their previous work investigating Ni and Pt NP protonation kinetics by introducing a system employing Ni nanoparticle-dotted multi-walled carbon nanotubes, demonstrating 98% selectivity for functional 1,4-NADH with H as the sole byproduct. These systems exhibit improvements in stability, selectivity, purifica- tion, waste minimization, and sustainability (minimizing the use of rare or toxic metal complexes).
A loss of NAD to side-products is characteristic of direct regeneration systems, which minimize environmental impact through sustainably manufacturable catalysts at the cost of poor selectivity for 1,4-NADH over reduction bipyridyl) (pentamethylcyclopentadienyl)-rhodium complex at the carbon electrode surface (b) Cyclic voltametric response for NAD reduction under gradual addition of NAD . (c) Schematic representation of NADH regeneration mediated by a CF-CNT-Rh electrode. Reprinted with permission from Ref. [60].

Cc-PAA polymer-immobilized DH system capable of NADH production from NAD
Regeneration yield of NADH from NAD over one week for stability test of DH/Cc-PAA. (c) Production of methanol and propanol in the presence of DH and with DH replaced with BSA (control). Reprinted with permission from Ref. [69 ]. Copyright 2019, American Chemical Society. side-products. One approach to overcome this drawback is the employment of renalase [58], an enzyme which catalyzes the oxidation of enzymatically inactive 1,4- NADH and 1,6-NADH (but not NAD2) back to NAD . Recent work [59 ] has made strides in increasing the soluble expression levels and catalytic activity of recombinant renalase, so the future of sustainable direct regeneration systems looks more promising than ever. While NADH-regenerating Rh complexes demonstrate superior stereoselectivity compared to direct regeneration approaches, and often longer lifetimes compared to enzy- matic systems, these catalysts not only have an environ- mental cost resulting from Rh use, but suffer from a well enzymes which leads to mutual inactivation of both catalysts in under 24 hours [18,54 ,55,56]. The last half-decade produced copious studies focused on mini- mizing this interaction through physical barriers. An immobilization procedure proposed by Zhang et al. [60 ] demonstrated porous carbon electrodes with covalently attached [Cp*Rh(bpy)Cl] as shown in Figure 3. When employed with D-sorbitol dehydrogenase and galactitol dehydrogenase, the system showed stable NADH production for over 90 hours. Himiyama et al. instead employed a periodic mesoporous organosilica (PMO) to pack Cp*Rh(bpy), allowing the diffusion of substrates while excluding interactions with large pro-

Advances in electrochemical cofactor regeneration Lee, Gerulskis and Minteer 19
decreased the 6 hour conversion % of cyclohexen-1-one by 83% when using free [Cp*Rh(bpy)Cl]Cl as catalyst, this loss of activity was only 9% when employing the PMO-modified catalyst. Morra and Pordea modified an ADH which naturally coordinates Zn to instead encapsu- late a Cp*Rh-based catalyst [57 ]. This method proved to decrease enzyme activity loss after 24 hours from 80% in systems employing traditional Cp*Rh catalysts to less than 20% in those employing the protein conjugate. Zhang et al. investigated a photo-enzymatic system in which Cp*Rh(bpy) receives electrons for NAD reduc- tion from light-activated graphitic carbon nitride (GCN) [62 ], which is also able to inactivate enzymes but through an electron hole-transferring mechanism. These authors employed a Cp*Rh(bpy)-embedded, size-excluding means that the regeneration of these cofactors is critical to the economically feasible enzymatic synthesis of high value-added products. Enzymatic cofactor conversion has historically demonstrated exceptional turnover frequen- cies and product selectivity, but has been held back by product impurity arising from substrate requirements and catalyst mobility. Although performance has not yet crossed traditional systems, diaphorase-based systems, especially with the maturation of redox polymer research, are a promising avenue to address these issues. Molecular catalysts, though demonstrating increasing turnover fre- quencies and product selectivity, still suffer from unde- sired interactions with system components, and are still largely fabricated using unsustainable rare metals. Direct electrochemical regeneration systems, though exceptionally simple and homogenous, have historically also shown ADH activity by 90% in the presence of GCN and 100% in the presence of Cp*Rh(bpy) (interestingly, only 13% without illumination), but only decreased activity by 33% when ADH was protected using the TiO2 layer.
One approach for cofactor regeneration with electron transfer efficiency and purification cost in mind is the use of redox polymers for enzyme immobilization. A redox polymer consists of an insulating polymeric back- bone with covalently bound redox mediators as side chains and serves the function of facilitating rapid elec- tron transfer to the catalyst through self-exchange based conduction. The advantage of redox-polymer mediated enzyme-electrode immobilization lies in the ability to retain enzyme and redox mediating species on the elec- trode when the new reactant solution is replenished, which allows for long-term reuse of electrodes and minimizes purification issues [63–66]. A recent work demonstrated a NAD regeneration system in which a naphthoquinone redox polymer oxidized NADH non- enzymatically [67]. The only redox polymers offering NAD reduction capability are viologen-based, but these have not seen widespread application owing to stability and selectivity issues [50 ]. Quah et al. [68 ] proposed a benzylpropyl-viologen (BPV) redox polymer to support NAD /NADH regeneration with diaphorase. The rela- tively positive potential of BPV ( 0.27 V versus SHE) compared to the cofactor ( 0.32 V versus SHE) makes this polymer more suitable for cofactor oxidation than cofactor reduction. Yuan et al. [69 ] subsequently pro- posed a cobaltocene modified poly(allylamine) polymer (Cc-PAA) immobilized diaphorase system showing super- ior operational stability, Faradaic efficiency (near-100%), durability, turnover frequency, selectivity, and a mild overpotential for bioactive NADH production over one

Conclusion
NAD(P) and NAD(P)H are highly metabolically inter- connected redox cofactors serving the majority of oxido- reductase-catalyzed reactions. This interconnectivity the lowest turnover frequencies and product selectivity. These drawbacks of direct electrochemical regeneration methods are in decline with the advent of novel nano- structured electrodes with performance unprecedented in the category. The unveiling of novel catalyst and system architectures shows rapid performance improvements in all three categories, and the rapid evolution of regenera- tion methods promises exciting developments in the efficiency of regeneration methods and the scope of their parallel biosynthetic pathways.

Acknowledgement
The authors would like to thank the NSF Center for Synthetic Organic Electrochemistry (Grant# 2002158) for funding.

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