Research review paperPhotocatalyst-enzyme hybrid systems for light-driven biotransformation
Introduction
Enzymatic catalysis has hallmark characteristics of remarkable stereo- and regional-specificity, shorter and more efficient synthetic routes, and environmental friendliness which offers tremendous advantages in the green transformation processes in both the pharmaceutical and fine chemicals industries (Chen and Arnold, 2020; de Carvalho, 2011; Qu et al., 2020; Sheldon and Woodley, 2018; Wu et al., 2021). Redox enzymes are the largest group of enzymes in the Enzyme Commission nomenclature, which account for ~25% of all known enzymes (Monti et al., 2011). These enzymes play an important role in industrially relevant bioreactions (Prier and Kosjek, 2019; Urlacher, 2012), such as asymmetric oxyfunctionalisation (Martínez et al., 2017), CC bond reduction (Toogood and Scrutton, 2018), CO bond reduction (Huisman et al., 2010), Baeyer-Villiger oxidation (Leisch et al., 2011), and nitrogen reduction (Hoffman et al., 2014).
To accomplish catalytic functions, redox enzymes generally require an additional supply of reducing equivalents as electron donors for the redox transformation of a substrate. Natural reducing equivalents, such as nicotinamide adenine dinucleotide cofactor (NADH) and its phosphorylated form (NADPH), are exogenously supplied in the reaction system in a stoichiometric fashion or regenerated in situ by a secondary enzyme (e.g., glucose dehydrogenase, formate dehydrogenase [FDH]) with their associated sacrificial hydride and electron donor (e.g., glucose, formate). However, these two approaches suffer from a high cost of natural cofactors, unsatisfactory catalytic efficiency due to the low regeneration rate of the cofactors, poor sustainability owing to the stoichiometric requirement of electron donors, and the complexity of downstream product purification.
Conversely, the photocatalyst can substitute the secondary enzyme in traditional enzymatic catalysis by providing reducing equivalents, or directly transferring light-energized electrons to redox enzymes to activate redox reactions. Therefore, photocatalysis has become a research-intensive field with wide-ranging applications in past decades (Marzo et al., 2018). Compared to the light-independent alternatives, photocatalysis demonstrates economic feasibility, environmental compatibility, and sustainability owing to its utilisation of renewable solar energy (Du et al., 2014; Knör, 2009; Sun et al., 2017; Wang et al., 2018a; Yoon, 2016). Furthermore, the photocatalyst-enzyme hybrid systems have been successfully utilised for CO2 reduction, N2 fixation, and synthesis of value-added chemicals (Brown et al., 2016a; Litman et al., 2018; Yadav et al., 2012). Compared with traditional enzymatic catalysis, the hybrid systems combine the remarkable catalytic function of enzymes with the merits of photocatalysis— with enhanced catalytic efficiency, energy conversion efficiency, and sustainability (greener chemical processing) (Honda et al., 2016; Ji et al., 2018; Zhang et al., 2020a; Zhang et al., 2017b).
In a typical photocatalyst-enzyme hybrid system, the photocatalyst harvests and converts light to generate photo-induced electrons, which are subsequently converted to reducing equivalents, or directly transferred to the redox enzyme to support the enzymatic catalysis. According to our understanding of electron transfer from photocatalyst to enzyme, the construction schemes of the photocatalyst-enzyme hybrid systems are classified into two modes: the cofactor-mediated mode and the direct contact-based mode (Blue and yellow sectors of Scheme 1, respectively). In cofactor-mediated hybrid systems, cofactors act as reducing equivalents to shuttle electron transfer from the photocatalyst to the enzyme. In the direct-contact mode, the photocatalyst binds to the enzyme to enable direct transfer of photo-induced electrons to the catalytic active sites, or it transfers electrons to the catalytic active sites via redox active cofactors in enzymes. However, the rational design and construction of hybrid systems is still in its infancy and suffers from low overall catalytic efficiency. First, an undesirable charge recombination within the photocatalyst limits the efficiency of photo-induced electron generation. An ideal photocatalyst in the hybrid system should be bio-compatible, stable, and have appropriate band gap to both efficiently oxidize the electron donor and supply sufficient electrons to the enzyme. Second, photocatalytic reactions cause oxidative stress, such as reactive oxygen species (ROS) and photo-induced holes, which damage proteins and significantly decrease enzyme activities. Third, poor interfacial electron transfer from the photocatalyst to the enzyme also limits the overall performance in the hybrid system. These bottlenecks and the corresponding preventative strategies to enable the construction of functionally optimal photocatalyst-enzyme hybrid systems have not been systematically reviewed in recent years (Amao, 2018; Brown and King, 2020; Denard et al., 2013; Evans et al., 2019; Kim and Park, 2019; Kim et al., 2014; Lee et al., 2018a; Lee et al., 2013a; Rudroff et al., 2018; Schmermund et al., 2019; Seel and Gulder, 2019; Utschig et al., 2015; Wang et al., 2017b; Zhang and Hollmann, 2018; Zheng et al., 2020).
In this review, we focus on recent advances and strategies in the construction and optimisation of the catalytic efficiency and performance of photocatalyst-enzyme hybrid systems. We also discuss the pros and cons of various photocatalysts used in hybrid systems. In particular, the progress in modifying materials to suppress electron-hole recombination and promote electrons output are reviewed. In addition, we focus on the delicate design strategies in enhancing electron transfer efficiency across the interfaces between photocatalysts and enzymes, such as integrating an electron mediator with the photocatalyst, or creating a ‘hardwire’ between the photocatalyst and the distal iron-sulphur cluster to shorten electron transfer distance. Moreover, we review the strategies used to address the incompatibility between biotic and abiotic components, which is necessary to preserve high enzymatic activity and to prevent enzymes from being damaged by the photocatalysis. Besides discussing the cofactor-mediated and direct contact-based modes, a novel reaction cascade mode (depicted in the pink sector of Scheme 1) is reviewed. Compared to the first two modes that involve different electron transfer pathways, reaction cascades demonstrate a means to integrate photocatalysis with enzymatic catalysis by using an intermediate. In this regard, the chemical product of the first photocatalytic step is used as a substrate (or co-substrate) in the subsequent biocatalytic step to enable the ultimate chemical conversions, forming ‘cascade reactions’ that are unachievable using a single catalysis step. Notably, researchers recently discovered a photo-induced enzyme catalytic promiscuity, which serve as an underlying mechanism of how the radical intermediate supplied by photocatalysis is stereo-selectively quenched at the active sites within the enzyme. These studies unlock non-native new catalytic functions of enzymes and expand the repertoire of enzymatic reactions.
Section snippets
Mechanisms underlying cofactor-mediated hybrid systems
For most redox enzymes, the catalytic active site is usually buried deeply beneath the surface of the enzyme molecule, thus shielded from direct electron transfer with a photocatalyst. By drawing lessons learned from natural photosynthesis, researchers developed strategies to utilise cofactors as electron carriers to transfer electrons between a photocatalyst and enzyme.
In natural photosynthesis, photosystem I and II on thylakoid membrane harness sunlight to extract electrons from water before
Direct contact-based photocatalyst-enzyme hybrid systems
In Section 2, we discussed the cofactor-mediated photocatalyst-enzyme hybrid systems, in which cofactors are indispensable for boosting turnover in the systems. Even though various endeavours have been made to improve cofactor regeneration, efficiency losses caused by multi-electron transfer processes are inevitable (Kim et al., 2014). In Section 3, we review the direct contact combination of photocatalysts and enzymes, which implies that enzymes could accept electrons directly from the
Reaction cascade of photocatalysis and enzymatic catalysis
In the former two Sections, we reviewed the nature-inspired photocatalyst-enzyme hybrid systems in which photocatalysis either directly feeds electrons to enzymes or indirectly provides stoichiometric reducing equivalents (cofactors) for driving the enzymatic catalysis. In this Section, we introduce an emerging hybrid mode between photocatalytic and biocatalytic reactions, namely the concurrent reaction cascade of photocatalysis and biocatalysis, which realizes inconceivable conversions in a
Summary and outlook
Although natural photosynthesis has evolved with perfect biological fitness, it suffers from sluggish efficiency in biomass production. Reactions that utilise isolated enzymes can exclude futile metabolic pathways to form non-target biomass. Furthermore, the catalytic process of a specific enzyme is easier to be investigate, elucidate, and regulate—tasks which are more challenging in organisms. The photocatalyst-enzyme hybrid systems provide possibilities to utilise solar energy for achieving
Declaration of Competing Interest
All authors declare that there is not any actual or potential conflict of interest including any financial, personal, or other relationships with other people or organizations within five years of beginning the submitted work.
Acknowledgements
The authors are grateful for the financial support from the National Key Research and Development Program of China (2018YFA0901300), and the National Natural Science Foundation of China (32071411, 21621004).
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