About this Research Topic

Background

Biocatalytic reactions and microbial transformations have emerged as a sustainable approach for the synthesis of valuable chemicals. A recent, very promising trend is the application of enzymes for the utilization of bio-based resources. The tremendous progress in molecular biology has greatly facilitated the discovery of new enzymes and their improvement by protein engineering, which has in turn greatly widened the catalytic scope of enzymatic processes. In this context, oxidoreductases offer a wide diversity of highly chemo-, regio- and enantioselective transformations. With often outstanding selectivities, monooxygenases, alcohol dehydrogenases, ene reductases and the recently discovered imine reductases have emerged as widely applied biocatalysts. A current limitation for a more widespread use of these versatile enzymes is their need for electrons from cofactors, which in turn require a stoichiometric supply of sacrificial co-substrates for regeneration. This common feature of enzymatic redox reactions is a severe limitation for electron transfer and atom efficiency, which consequently leads to significant cost issues.

In whole-cell biotransformations, the synthesis of redox cofactors in living cells avoids the need for the external addition of costly cofactors. However, side reactions from cellular metabolism limit the yield of the utilization of sacrificial co-substrate. In living cells, the generation of NADH from carbohydrates is straightforward, whereas, in most bacteria and yeast, the intracellular recycling of NADPH is more challenging, and usually requires the co-expression of additional enzymes such as glucose-6-phosphate dehydrogenase, so called ‘designer cells’. In both cases, respiration and cell growth consume a large part of the carbon source.

New concepts in the recycling of cofactors improve the supply or increase the efficiency of cofactor use. For example, metabolic engineering reduces side reactions and greatly improves the efficiency of intracellular cofactor regeneration. Protein engineering allows molecular strategies such as a switch of cofactor dependency from NADPH to NADH (or vice versa) or the generation of fusion proteins that increase the local concentration of reduced cofactors and thus improve their utilization. Recently developed processes using sacrificial co-substrates, such as the complete oxidation of methanol or even the use of molecular hydrogen, have expanded the possibilities to drive redox reactions. NAD(P)H-independent oxidoreductases, such as alpha-ketoglutarate dependent hydroxylases, and peroxygenases, circumvent the use of NAD(P)H and NAD(P)H-dependent enzymes. Another strategy is the use of inexpensive cofactor-analogues accepted by certain oxidoreductases. Finally, radical concepts such as light-catalyzed water splitting, electro-biocatalysis or convergent redox neutral enzyme cascades allow selective redox reactions without the need to add sacrificial co-substrates, thus greatly increasing the atom-efficiency of the process. In addition to the widely used regeneration of nicotinamide cofactors, the supply of different cofactors such as S-adenosylmethionine and ATP have seen considerable progress and may soon be economically feasible in vitro, thus avoiding the cost and effort of whole-cell biotransformations.

This Research Topic provides recent advances and strategies in the supply of redox cofactors. The topic presents new approaches and their successful application with synthetically attractive examples to showcase the importance of tackling the cofactor issue in terms of electron transfer efficiency. The aim is to design economically attractive redox reactions and extend the catalytic scope of oxidoreductases from the production of high-value compounds to the synthesis of low-price, high-volume products. The latter is an important requirement for the application of biocatalysis for the utilization of renewable resources and the production of tomorrow’s chemicals.

Keywords: oxidoreductase, nicotinamide cofactor, NADH, NADPH, cofactor regeneration, S-adenosylmethionine

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