Communications
doi.org/10.1002/cssc.202100184
ChemSusChem
Very Important Paper
Bioinspired Cooperative Photobiocatalytic Regeneration of
Oxidized Nicotinamide Cofactors for Catalytic Oxidations
Huan-Xin Liao,[a] Hao-Yu Jia,[a] Jian-Rong Dai,[a] Min-Hua Zong,[a] and Ning Li*[a]
oxidations.[7] NAD(P)H oxidases (NOX) represent an elegant
Inspired by water-forming NAD(P)H oxidases, a cooperative
solution for this problem,[8] since they are capable of efficient
photobiocatalytic system has been designed to aerobically
oxidation of NAD(P)H to NAD(P)+ with O2, producing H2O or
regenerate the oxidized nicotinamide cofactors. Photocatalysts
H2O2 as the sole byproduct. H2O2-forming NOX (NOX-1) and
peroxidase (AhpC) constitute alkyl hydroperoxide reductase
(AhpR), but AhpC can not function as NAD(P)H peroxidase
alone. Like water-forming NOX (NOX-2), AhpR enables aerobic
regeneration of NAD(P)+, producing H2O as a byproduct. In the
catalytic pathway of AhpR, NOX-1 depending on flavin adenine
dinucleotide (FAD) catalyze oxidation of NAD(P)H, affording
NAD(P)+ and H2O2; then the resultant H2O2 is used by AhpC to
oxidize NAD(P)H to NAD(P)+, along with H2O.[9] In the case of
NOX-2, Cys42 plus FAD plays a similar catalytic role to AhpC
present in AhpR.[10] In spite of many advantages, NOX are still
associated with shortcomings such as high substrate specificity
toward NADH or NADPH, greatly reduced activities under
neutral and slightly alkaline conditions (the optimal pH range of
most DHs), and limited stability (due to interfacial deactivation
resulting from bubbling aeration and overoxidation of the
preserved Cys42), which may be the major barriers for their
application in organic synthesis.[8,11]
In nature, plants and algae produce a variety of metabolites
by photochemical/enzymatic synthetic systems. Recently, artifi-
cial photobiocatalytic systems have attracted great interest in
synthetic chemistry, because of the combined advantages of
biocatalysis with photocatalysis as well as their good
compatibility.[12] Castagnolo and co-workers described the syn-
thesis of enantiomerically pure 1,3-mercaptoalkanols by a one-
pot photobiocatalytic cascade.[13] Hollmann and co-workers
reported selective activation of sp3 CÀ H bonds using photo-
catalytic oxidation of water/methanol coupled with biocatalytic
oxyfunctionalizations.[14] Zhao, Hartwig, and co-workers pre-
sented a class of cooperative chemoenzymatic reaction that
combines photocatalysts that isomerize alkenes with ene-
reductases that reduce C=C bonds to synthesize enantioen-
riched chemicals.[15] A one-pot photobiocatalytic cascade was
used for the synthesis of chiral alcohols from carboxylic acids
via photocatalytic decarboxylative carbonylation and biocata-
lytic reduction.[16]
enable NAD(P)H oxidation with O2 under visible-light irradiation,
producing H2O2 as a byproduct, which is subsequently used as
an oxidant by the horseradish peroxidase mediator system
(PMS) to oxidize NAD(P)H. The photobiocatalytic system shows
a turnover frequency of 8800 minÀ 1 in the oxidation of NAD(P)
H. Photobiocatalytic NAD(P)H oxidation proceeds smoothly at
pH 6–9. In addition to natural NAD(P)H, synthetic biomimetics
are also good substrates for this regeneration system. Total
turnover numbers of up to 180000 are obtained for the cofactor
when the photobiocatalytic regeneration system is coupled
with dehydrogenase-catalyzed oxidations. It may be a promis-
ing protocol to recycle the oxidized cofactors for catalytic
oxidations.
The oxidations of alcohols, amines, and aldehydes are funda-
mental reactions in synthetic chemistry, which have found wide
applications in chemical, pharmaceutical and food industries.[1]
Biocatalytic oxidation using oxidases and dehydrogenases (DHs)
is a promising alternative to chemical methods,[2] with advan-
tages such as exquisite selectivity, environmental friendliness,
and high catalytic efficiency. DHs oxidize alcohols, amines, and
aldehydes with the oxidized nicotinamide cofactors (NAD(P)+).
From an economical viewpoint, therefore, in situ regeneration
systems of NAD(P)+ are required for DH-catalyzed oxidations.
However, efficient and practical NAD(P)+ regeneration protocols
remain limited, although various chemo-,[3] electro-,[4] photo-,[5]
and biocatalytic methods[6] have been developed, and their
proof-of-concept use for DH-catalyzed oxidations has been
demonstrated. On one hand, in terms of selectivity, biocatalysts
appear to be advantageous over low-molecular-weight chem-
ical counterparts. On the other hand, this feature of enzymes is
a drawback for their catalytic application, given their narrow
substrate scope. Substrate- and enzyme-coupled systems were
well established for enzymatic NAD(P)+ regeneration, with
aldehydes or ketones as terminal electron acceptors.[2a] Utiliza-
tion of sacrificial substrates resulted in the production of
copious waste, impairing the atom economy of biocatalytic
Flavins such as flavin mononucleotide (FMN), a type of
oxidase cofactors, were used as organocatalysts for aerobic
oxidation of NAD(P)H 50 years ago.[17] Although the reaction
rate is improved by two orders of magnitude by photo-
excitation, the turnover frequency (TOF) of FMN remained
low.[18] Inspired by the AhpR system and NOX-2, we constructed
a photobiocatalytic system for regenerating NAD(P)+ and their
biomimetics in this work (Scheme 1), in which photocatalysts
function as NOX-1 and horseradish peroxidase (HRP) functions
as AhpC. The byproduct H2O2 formed by photocatalysis was
[a] H.-X. Liao, H.-Y. Jia, J.-R. Dai, Prof. M.-H. Zong, Prof. N. Li
School of Food Science and Engineering
South China University of Technology
381 Wushan Road, Guangzhou 510640 (P. R. China)
E-mail: lining@scut.edu.cn
Supporting information for this article is available on the WWW under
ChemSusChem 2021, 14, 1687–1691
1687
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