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Review of NAD(P)H-Dependent Oxidoreductases: Properties, Engineering T and Application ⁎ Lara Sellés Vidal, Ciarán L

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Review of NAD(P)H-Dependent Oxidoreductases: Properties, Engineering T and Application ⁎ Lara Sellés Vidal, Ciarán L BBA - Proteins and Proteomics 1866 (2018) 327–347 Contents lists available at ScienceDirect BBA - Proteins and Proteomics journal homepage: www.elsevier.com/locate/bbapap Review Review of NAD(P)H-dependent oxidoreductases: Properties, engineering T and application ⁎ Lara Sellés Vidal, Ciarán L. Kelly, Paweł M. Mordaka, John T. Heap Centre for Synthetic Biology and Innovation, Department of Life Sciences, Imperial College London, South Kensington Campus, London SW7 2AZ, United Kingdom ARTICLE INFO ABSTRACT Keywords: NAD(P)H-dependent oxidoreductases catalyze the reduction or oxidation of a substrate coupled to the oxidation NAD(P)H-dependent oxidoreductases or reduction, respectively, of a nicotinamide adenine dinucleotide cofactor NAD(P)H or NAD(P)+. NAD(P)H- Metabolic engineering dependent oxidoreductases catalyze a large variety of reactions and play a pivotal role in many central metabolic Protein engineering pathways. Due to the high activity, regiospecificity and stereospecificity with which they catalyze redox reac- Directed evolution tions, they have been used as key components in a wide range of applications, including substrate utilization, the Enzyme promiscuity synthesis of chemicals, biodegradation and detoxification. There is great interest in tailoring NAD(P)H-depen- Substrate specificity dent oxidoreductases to make them more suitable for particular applications. Here, we review the main prop- erties and classes of NAD(P)H-dependent oxidoreductases, the types of reactions they catalyze, some of the main protein engineering techniques used to modify their properties and some interesting examples of their mod- ification and application. 1. Introduction electron transport capability as it is located far from the electron transfer region (Fig. 2). However, the phosphate group modifies the Oxidoreductases (Enzyme Commission [EC] primary class 1) cata- structure of the cofactor, which allows different enzymes to have dif- lyze the oxidation of one chemical species (a reducing agent or electron ferent specificities for NADH/NAD+ and NADPH/NADP+, thereby al- donor) with the concurrent reduction of another (an oxidizing agent or lowing these to act as two equivalent but independent redox systems. − − electron acceptor) in the form A +B→ A+B and comprise almost This has a physiological function, allowing different a redox poise one third of all enzymatic activities registered in the BRaunschweig (degree of reduction of the cofactor pool) to be maintained in the two ENzyme Database, BRENDA (Fig. 1). Oxidoreductases can act on a wide systems, and independent fluxes. Typically, at least in heterotrophs, range of both organic substrates including alcohols, amines and ketones enzymes of catabolic pathways use NADH/NAD+, while NADPH/ and inorganic substrates including small anions such as sulfite, and NADP+ is the preferred cofactor for anabolism [3,4]. The redox poise of metals such as mercury. the NADH/NAD+ pool depends upon the availability and redox state of NAD(P)H-dependent oxidoreductases are able to oxidize a substrate external electron acceptors and of substrates. This variation in redox − by transferring a hydride (H ) group to a nicotinamide adenine dinu- poise can be observed for example in Escherichia coli growing via cleotide cofactor (either NAD+ or NADP+), resulting in the reduced aerobic respiration, anaerobic respiration, or anaerobic fermentation, form NADH or NADPH (Fig. 2), and make up over 50% of all oxidor- where factors such as the oxygen availability when growing aerobically, eductase activities registered in the BRENDA (Fig. 1). There are over or the redox potential of other electron acceptors used when growing 150,000 different sequences annotated as or predicted to be NAD(P)H- anaerobically, affect the steady-state NADH/NAD+ ratio [5]. In con- dependent oxidoreductases [1]. trast, the poise of the NADPH/NADP+ pool is maintained in a more NADH/NAD+ and NADPH/NADP+ serve as pools of redox cofactors reduced state in order to more effectively provide reducing power for for the cell. The nicotinamide ring of NADH/NAD+ or NADPH/NADP+ biosynthesis [6]. Accordingly, NADH-dependence is more prevalent is the part of the cofactor directly involved in the transfer of electrons among oxidoreductases acting on smaller molecules, which include during the reactions catalyzed by NAD(P)H-dependent oxidoreductases, most substrates and products of catabolism (Fig. 3). Interestingly, while the C4 carbon atom of the nicotinamide ring acts as the acceptor/ substrates of low molecular weight can be metabolized by a higher donor of a proton [2]. The addition of the phosphate to the 2′-OH group number of enzymatic activities, indicating that smaller substrates have of the adenine ribose ring in NADPH/NADP+ does not modify the a role as central hubs of redox metabolic networks (Fig. 3b). There is ⁎ Corresponding author. E-mail address: [email protected] (J.T. Heap). https://doi.org/10.1016/j.bbapap.2017.11.005 Received 16 August 2017; Received in revised form 27 October 2017; Accepted 8 November 2017 Available online 10 November 2017 1570-9639/ Crown Copyright © 2017 Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/BY/4.0/). L. Sellés Vidal et al. BBA - Proteins and Proteomics 1866 (2018) 327–347 NAD(P)H-dependent oxidoreductases also another, smaller increase of both the absolute number of oxidor- NADPH-dependent oxidoreductases eductase activities (Fig. 3a) and the number of oxidoreductase activities per substrate for substrates of molecular weight between 700 and NADH-dependent oxidoreductases 1100 Da, which is partially due to substrates that need to be activated Other oxidoreductases by binding to coenzyme A (CoA) before the corresponding oxidor- eductase can act on them (Fig. 3). Canonically the differing redox states of the two systems (NADH and NADPH) is achieved in heterotrophs using NAD+-dependent glycolysis and the NADP+-dependent pentose phosphate pathway, but there are several variations and alternatives [7], and photoautotrophs generate NADPH using the light-dependent reactions of photosynthesis. The independence of the NADH/NAD+ and NADPH/NADP+ pools also allows different enzymes with different redox cofactors to catalyze key steps of opposite pathways helping to prevent futile cycles [8]. NAD(P)H-dependent oxidoreductases are of great interest from an industrial point of view as they perform the critical steps in the pro- duction of many hard-to-synthesize compounds, under mild conditions. For example, even though several chemical methods have been devel- oped to perform the oxidation of primary alcohols, they are usually laborious and can lead to the formation of toxic products [9], which can be avoided through enzymatic catalysis. Additionally, NAD(P)H-de- Fig. 1. Distribution of enzymatic activities registered in BRENDA. Oxidoreductases con- pendent oxidoreductases possess other properties which make them stitute approximately 30% of all the BRENDA enzymatic activities, among which around + + very attractive alternatives to organic chemical synthesis, such as ste- 50% use NADH/NAD and/or NADPH/NADP as a cofactor. The number of enzymatic fi fi activities of each EC class, as well as the number of NADH, NADPH and NAD(P)H-de- reospeci city, regiospeci city and the possibility to tailor them to have pendent oxidoreductases, were obtained from BRENDA by means of manual queries and the appropriate kinetic parameters and the desired substrate specificity plotted with R and the ggplot2 package. [10]. For these reasons, NAD(P)H-dependent oxidoreductases have been used extensively in metabolic engineering for the production of Fig. 2. Molecular formula of NAD(P)H and NAD(P)+. The NADH molecule contains adenine and nicotinamide nucleosides linked by a pyrophosphate linkage. The nicotinamide ring is the acceptor/donor of the electrons and the C4 (red) of the nicotinamide ring is the acceptor/donor of the proton. NADPH differs from NADH in the substituent at the C2 position of the adenosine moiety, indicated as ‘R’ in the figure, which is a hydroxy in NADH and a phosphate in NADPH. This phosphate group does not alter the ability of the co- factor to transfer electrons. NAD+ is the oxidized form of NADH, and NADP+ is the oxidized form of NADPH. 328 L. Sellés Vidal et al. BBA - Proteins and Proteomics 1866 (2018) 327–347 Fig. 3. a. Number of oxidoreductase activities versus molecular/ atomic weight of the substrates. Substrates are grouped in in- a NAD(P)H-dependent oxidoreductases tervals of 100 Da. Some substrate examples are labelled. A list of NADPH-dependent oxidoreductases enzymes was extracted from the KEGG database using R with NADH-dependent oxidoreductases the KEGGREST package by imposing the condition that either + Other oxidoreductases NAD(P) or NAD(P)H were involved in the reaction as substrate or product. Results were plotted with R and the ggplot2 package. b. Number of oxidoreductase activities per substrate versus molecular/atomic weight of the substrates. Data were obtained and plotted in the same way as for Fig. 3a, but the number of oxidoreductase activities in each range of molecular/ atomic weight was divided by the total number of substrates in that interval. b low, mid and high value products [11]. a variety of different reactions other than hydrolysis of esters in non- NAD(P)H-dependent oxidoreductases are too numerous and diverse aqueous media, such as transesterification alcoholysis or acidolysis to review exhaustively. Therefore, the reader
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