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2
New Trends in the In Situ Enzymatic Recycling of NAD(P)(H)
Cofactors

Erica Elisa Ferrandi, Daniela Monti, and Sergio Riva

2.1
Introduction

The large-scale industrial exploitation of cofactor-dependent enzymes has been
considered an issue for a long time due to both the increased process complexity
and the cost of the coenzymes to be added to the reaction mixture when they are
not covalently bound to the biocatalyst.
This is the case with NAD(P)H-dependent dehydrogenases, where enzymes find
applications in several synthetic processes (comprising the reduction of aldehydes,
ketones, carboxylic acids, double, and triple carbon–carbon bonds), aimed at the
preparation of chiral enantiopure bioactive compounds and of building blocks for
fine chemicals and pharmaceutical products. Moreover, dehydrogenase-catalyzed
oxidation reactions are gaining increasing interest as an environmentally friendly
alternative to chemical oxidation processes, especially in those cases where a
defined selectivity (either stereo-, regio-, or chemoselectivity) is required as well [1].
In recent years, these facts have significantly prompted the research toward
the development of new and more efficient in situ regeneration systems of the
NAD(P)(H) cofactors [2, 3], which allow their use in catalytic instead of stoichio-
metric amounts, thus making the dehydrogenase-catalyzed processes acceptable
from an economical point of view. Moreover, the recycling reactions can be also
used to shift the equilibrium of thermodynamically unfavorable transformations
toward product formation.
Among the several ways through which the regeneration of the NAD(P)(H)
cofactors can be accomplished, this chapter will focus on the enzymatic processes,
which represent the most convenient strategies at the moment. In fact, they show
+
high regioselectivity in the reduction of NAD(P) to the active 1,4-dihydropyridine
form, thus avoiding the formation of the enzymatically inactive 1,6-dihydropyridine
isomer.
Only in the case of alcohol dehydrogenase (ADH)-catalyzed reactions, a substrate-
coupled system can be applied, in which the enzyme that transforms the substrate
of interest also regenerates the cofactor at the expense of a co-substrate to be used
in at least stoichiometric amounts with respect to the substrate.

Cascade Biocatalysis: Integrating Stereoselective and Environmentally Friendly Reactions, First Edition.
Edited by Sergio Riva and Wolf-Dieter Fessner.
c 2014 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2014 by Wiley-VCH Verlag GmbH & Co. KGaA.