Hydrocarbon Synthesis via Photoenzymatic Decarboxylation of Carboxylic Acids

Article abstract of DOI:10.1021/jacs.8b12282

A recently discovered photodecarboxylase from Chlorella variabilis NC64A (CvFAP) bears the promise for the efficient and selective synthesis of hydrocarbons from carboxylic acids. CvFAP, however, exhibits a clear preference for long-chain fatty acids thereby limiting its broad applicability. In this contribution, we demonstrate that the decoy molecule approach enables conversion of a broad range of carboxylic acids by filling up the vacant substrate access channel of the photodecarboxylase. These results not only demonstrate a practical application of a unique, photoactivated enzyme but also pave the way to selective production of short-chain alkanes from waste carboxylic acids under mild reaction conditions.

Full text of DOI:10.1021/jacs.8b12282

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Article
Hydrocarbon synthesis via photoenzymatic
decarboxylation of carboxylic acids
Wuyuan Zhang, Ming Ma, Mieke Huijbers, Georgy A. Filonenko, Evgeny A
Pidko, Morten van Schie, Sabrina de Boer, Bastien Oliver Burek, Jonathan
Bloh, Willem J.H. van Berkel, Prof. Wilson A. Smith, and Frank Hollmann
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 23 Jan 2019
Downloaded from http://pubs.acs.org on January 23, 2019
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Journal of the American Chemical Society
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Hydrocarbon synthesis via photoenzymatic decarboxylation
of carboxylic acids
Wuyuan Zhang†∇, Ming Ma‡∇, Mieke M.E. Huijbers†∇, Georgy A. Filonenko§, Evgeny A. Pidko§,
Morten van Schie†, Sabrina de Boer⊥, Bastien O. Burek⊥, Jonathan Z. Bloh⊥, Willem J. H. van
Berkel∥,Wilson A. Smith‡ and Frank Hollmann†*
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† Biocatalysis Group, Department of Biotechnology, Delft University of Technology, Van der Maasweg 9, 2629 HZ
Delft, The Netherlands.
‡ Materials for Energy Conversion and Storage (MECS), Department of Chemical Engineering, Delft University of
Technology, Van der Maasweg 9, 2629 HZ Delft, The Netherlands.
§ Inorganic Systems Engineering group, Department of Chemical Engineering, Delft University of Technology, Van
der Maasweg 9, 2629 HZ Delft, The Netherlands.
⊥ DECHEMA-Forschungsinstitut, Theodor-Heuss-Allee 25, 60486 Frankfurt am Main, Germany.
∥ Laboratory of Food Chemistry, Wageningen University & Research, P.O. Box 17, 6700 AA Wageningen, The
Netherlands.
Supporting Information Placeholder
reaction conditions and high loadings of precious metal
catalysts. This implies a significant environmental impact of
these reactions and questions their economic feasibility. In
addition, the selectivity of the reported methods mostly is
poor due to the formation of Kolbe- and Hofer–Moest-
byproducts.22,23
ABSTRACT: A recently discovered photodecarboxylase from
Chlorella variabilis NC64A (CvFAP) bears the promise for the
efficient and selective synthesis of hydrocarbons from
carboxylic acids. CvFAP, however, exhibits a clear preference
for long-chain fatty acids thereby limiting its broad
applicability. In this contribution we demonstrate that the
decoy molecule approach enables conversion of a broad range
of carboxylic acids by filling up the vacant substrate access
channel of the photodecarboxylase. These results not only
To overcome some of these drawbacks, enzymes have been
gaining an increasing interest for the direct formation of
hydrocarbons.24-27
Recently,
a
new
fatty
acid
demonstrate
a
practical application of
a
unique,
photodecarboxylase from the unicellular photosynthetic
green microalga Chlorella variabilis NC64A (CvFAP) was
reported by Beisson and coworkers.28 CvFAP mediates the
blue-light driven decarboxylation of various fatty acids to the
corresponding (C1-shortened) alkanes (Fig. 1a). CvFAP,
however, shows a marked preference for long-chain fatty acids
(C16-C17) with its catalytic activity dropping dramatically with
shorter chain carboxylic acids. Presumably, shorter substrates
are less efficiently stabilized in the long, narrow substrate
access channel of the decarboxylase.28
photoactivated enzyme but also pave the way to selective
production of short-chain alkanes from waste carboxylic acids
under mild reaction conditions.
Introduction
Valorization of biobased feedstock into chemicals1-4 and
fuels5-7 represents one of the pillars of a more sustainable
society. The last few decades have seen an explosion of
synthetic methodologies to transform natural products into
building blocks for the chemical industry.1-4
A similar phenomenon has been observed with the P450
monooxygenase from Bacillus megaterium, which exhibits
(almost) no oxyfunctionalisation activity towards small
substrate molecules. The groups of Reetz29 and Watanabe30
independently proposed to fill up the vacant space left by
small substrate molecules with unreactive, perfluorinated
fatty acids. Inspired by their work we reasoned that a similar
strategy might be applicable to enlarge the substrate scope of
CvFAP (Fig. 1b).
Catalytic methodologies for the conversion of biobased
carboxylic acids, however, are largely limited to esterification
or amidation reactions.8 More recently, chemical9-12 and
biocatalytic13-17 reduction reactions of carboxylic acids have
been developed as well as some approaches for the oxidative
decarboxylation into terminal alkenes.18-21
We propose using simple alkanes as decoy molecules, as co-
catalysts, to accelerate the CvFAP-catalyzed decarboxylation
of short-chain carboxylic acids.
In addition, redox-neutral decarboxylation of carboxylic
acids into the corresponding alkanes represents an attractive
method for the synthesis of alkanes for fuel and synthetic
applications. Conventional methods, however, require harsh
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depended on the concentration of acetic acid (Fig. 2c). In both
Results and Discussion
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cases half-maximal rates were obtained at comparable acetic
acid concentrations (around 50 mM), suggesting that the
decoy molecule did not facilitate the binding of the carboxylic
acid but rather increased the enzyme reaction rate. When
varying the concentration of the decoy molecule (Fig. 2d), a
saturation-type dependency of the reaction rate was observed.
Furthermore, at elevated concentrations of the decoy
molecule an inhibitory effect was observed, which may be
indicative for an ordered mode of binding of substrate and
decoy molecule.
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Figure 1. CvFAP-catalysed photobiocatalytic decarboxylation
reaction. (a) general reaction scheme and reaction conditions;
(b) schematic representation of acetic acid coordinating to the
catalytic flavin group together with tetradecane as decoy
molecule filling up the substrate access channel. CvFAP (PDB:
5NCC) is presented as a green cartoon showing the substrate
channel as transparent grey surface, while FAD (yellow),
acetic acid (blue) and tetradecane (magenta) are represented
as sticks. The distances in angstroms from the carboxylate
oxygen atom of acetic acid to FAD and from the C1-atom of
tetradecane to both carbon atoms of acetic acid are indicated.
First, acetic acid was docked into 5NCC, then tetradecane was
docked into the minimised result of the first docking using
VINA in Yasara (www.yasara.org). The figure was prepared
using PyMol (The PyMOL Molecular Graphics System,
Version 2.0 Schrödinger, LLC).
Figure 2. Photoenzymatic decarboxylation of acetic acid to
methane (A-C). (A) Time course of methane formation
performed with () and without decoy molecule tridecane
(), and in the absence of CvFAP (). Reaction conditions:
[decoy molecule] = 15 mM, [CvFAP] = 6 μM, [acetic acid] = 150
mM, Tris-HCl buffer pH 8.5 (100 mM), 20 % DMSO, 30 °C, blue
light (450 nm). Methane concentration refers to product in
the headspace of the reaction vial (4.0 mL of headspace plus
1.0 mL of liquid). (B) Effect of carbon length of decoy alkane
on the methane formation. Reaction time: 3h. (C) The rate-
dependency of the methane production rate on the acetic acid
concentration with () and without tridecane (). Reaction
time: 3h; (D) Turnover number (TON) of CvFAP in the
production of butane using nonane as decoy molecule. TON =
molbutanemolCvFAP-1. The contribution of reaction without
using nonane was subtracted. Condition: [CvFAP] = 6 μM,
[pentanoic acid] = 150 mM, Tris-HCl buffer pH 8.5 (100 mM),
20 % DMSO, 30 °C, 3h. Error bars indicate the standard
deviation of duplicate experiments (n = 2).
We firstly evaluated CvFAP as a photobiocatalyst for the
decarboxylation of acetic acid to methane in the presence of
various decoy alkanes (Fig. 2). For this the enzyme was
overproduced in Escherichia coli BL21 (DE3). A typical time
course of the reaction is shown in Fig. 2a. No methane could
be detected in the absence of CvFAP and only minor amounts
were formed in the absence of active illumination (possibly
due to the incomplete light-insulation of the reaction vessel).
Moreover, no background activity was found in crude extracts
prepared from E. coli cells containing an empty vector. 13CH3-
CO2H was converted into 13CH4 (Fig. S6). Most interestingly,
the rate of methane accumulation was almost doubled in the
presence of tridecane as decoy molecule, while also the
robustness of the reaction increased significantly leading to
more than a three-fold increase of methane yield. The highest
acceleration of methane production was achieved in the
presence of tetradecane (Fig 2b). Both in the absence and
presence of a decoy molecule, the enzyme reaction rate
The rate of the photobiocatalytic decarboxylation reaction
was linearly dependent on both the enzyme concentration
(Fig. S7) and the light intensity (Fig. S8). The rate of the
reaction in D2O was approximately 1.5-times faster than the
same reaction in H2O (Fig. S9). This inverse kinetic isotope
effect most probably is due to an increased lifetime of the
photoexcited flavin cofactor of CvFAP in D2O, as well
documented previously for other flavoproteins.31-33 We
interpret these findings with the lifetime of the photoexcited
flavin of CvFAP being overall rate-limiting.
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Encouraged by these promising results, we further
significant rates. Decarboxylation of acrylic acid and propionic
acid was only possible with the assistance of decoy molecules.
Notably, hydrogen gas was formed from the decarboxylation
of formic acid. It also becomes clear from
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evaluated the decarboxylation of a broader range of short-
chain carboxylic acids (Table 1). The substrate scope of CvFAP
was not limited to straight-chain carboxylic acids as also some
branched and unsaturated carboxylic acids were converted at
5
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Table 1. Substrate scope of the photobiocatalytic decarboxylation of short-chain carboxylic acids[a]
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8
9
[Product]
with
decoy
(M)
[Product]
without
decoy (M)
Best
Decoy
molecule
Accelerat TON
Selectivity
(%)[b]
Entry Substrate
Product
ion
(- (CvFAP) with
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fold)
decoy
O
291.7
14.2
±
1
C15
C14
C13
C12
C9
48.8 ± 5.6
2.7 ± 0.2
6.0
2.5
3.4
2.9
2.8
194
100
H
H
H
OH
O
CH4
2
3
4
5
7.5 ± 0.5
5.0
100
H3C
H3C
OH
O
347,1
12.7
±
±
±
99.6[c]
99.96[c]
99.99[c]
H3C CH3
103 ± 7.9
289
OH
O
1090.5
28.9
382.2 ± 9.9
860.7 ± 42.5
908.6
2034
H3C
H3C
CH3
H3C
H3C
OH
O
2440
62.4
CH3
OH
O
1007
57.3
±
H3C
H3C
6
C13
305.15 ± 36.1
3.3
839
99.8[c]
H3C
CH3
OH
O
CH3
CH3
CH3
CH3
940.2
29
±
±
7
C9
268.6 ± 19.4
1601.3 ± 40.1
3.5
1.2
783.6
1656
99.95[c]
100
OH
H3C
H3C
O
1987.3
28.7
8[d]
C14
CH3
H3C
H2C
OH
O
H2C CH2
9
C13
C12
C10
0
2.1 ± 0.3
7,9 ± 0.7
162 ± 11.3
-
1.6
n.d.
100
100
100
OH
O
CH3
10
11
1.08 ± 0.1
24.27 ± 1.7
188.3 ±1 5.2
7.3
6.8
2.7
6.9
134.5
418
H2C
H2C
OH
O
H2C
H2C
CH3
OH
O
502.7
10.9
±
12
CH3 C9
H2C
OH
H2C
HC
O
13
C14
0
9.3 ± 1.2
-
7.1
100
HC CH
OH
[a] Reaction conditions: [decoy molecule] = 7.5 mM, [CvFAP] = 6 M, [substrate] = 150 mM, Tris-HCl pH 8.5 (100 mM), 20 %
DMSO, 30 °C, 3h, blue light (450 nm), photon flux 13.8 µE/Ls. The standard deviation is based on duplicate experiments (n = 2).
The concentration refers to product in the headspace of the reaction vial (4.0 mL of headspace plus 1.0 mL of liquid). [b] Selectivity
% = [target product]/([target product]+[other product])100, calculation based on GC; [c] 0.4% propane, 0.038% ethane, 0.01%
ethane, 0.2% isopentane and 0.05% propane were observed from Entries 3-7, accordingly; [d] reaction was performed at 40 °C.
Table 1 (and Fig. S11-19) that the most suited decoy molecule
depends on the carboxylic acid used. In general the number of
carbon atoms of substrate and decoy molecule should sum up
to 16, which is in line with the previously reported optimal
fatty acid chain length.28 It is also interesting to note that the
accelerating effect of the decoy molecule decreased with the
chain length of the substrate carboxylic acids.
The quantum efficiency of the photobiocatalytic
decarboxylation reactions was determined. Using acetic acid,
butyric acid, pentanoic acid and hexanoic acid, the quantum
efficiency (at photon flux 13.8 µE L-1s-1) was 0.008%, 1.3%, 3.2%
and 2.7%, respectively (Fig. S10). It should be noted that a
direct comparison with the numbers reported in the initial
report is difficult due to the lack of all necessary data.
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A further insight into the decarboxylation mechanism was
ASSOCIATED CONTENT
Supporting Information
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obtained in the framework of the density functional theory
(DFT) and time-dependent (TD-DFT) density functional
theory (PBE1PBE+D3(BJ)/6-311+G(d,p)+PCM(water)) analysis.
These calculations were carried out on a representative model
system mimicking the reactive complex of the flavin active site
of the FDA and acetate anion as the representative substrate.
Our calculations reveal the crucial role of the pre-
arrangement of acetate in the vicinity of the N(5) site of the
FAD (CH3COO‒ ··· FAD, Fig. S32). This van der Waals complex
closely resembles the configuration found from the crystal
structure analysis shown in Figure 1. Importantly, in the
absence of the confinement caused by the protein residues of
CvFAP, an alternative coordination mode dominated by H-
bonding between the acetate anion and the N-H moiety of
FAD is favoured by ca. 20 kJ/mol. However, we were not able
to identify a favourable decarboxylation path initiated from
this structure, which is in agreement with the lack of
decarboxylation activity of the free flavin (Fig. S33) .
Experimental details including the preparation of the cell free
extracts, photoenzymatic reactions, length of decoy molecule
on decarboxylation activity, GC chromatogram and DFC
calculations (PDF)
AUTHOR INFORMATION
Corresponding Author
9
f.hollmann@tudelft.nl
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Author Contributions
∇ W.Z, M.M and M.M.E.H contributed equally.
Notes
The authors declare no competing financial interest.
When acetate substrate prearrangement is effective, the
decarboxylation path starts from the CH3COO‒···FAD van der
Waals complex an absorption maximum at 467 nm.33 Analysis
of the respective frontier orbitals (HOMO, LUMO, Fig. S32a)
shows that photoexcitation of this molecular complex yields a
CH3COO· ··· FAD· radical pair, from which the decarboxylation
of the CH3COO· proceeds rapidly via a highly favourable and
low-barrier non-catalytic process. Computational studies
propose that the generated CH3 radical further binds the
anionic flavin semiquinone resulting in the relaxation of the
excited state to the original S0 and the formation of a covalent
dearomatized methylquinone flavin adduct. The overall
decarboxylation reaction is slightly thermodynamically
favourable (ΔGo=-5 kJ·mol-1) allowing thus for a smooth
continuation of the catalytic cycle. The flavin adduct
intermediate (CH3-FAD-) is then protonated to release the
alkane product and regenerate the oxidized FAD closing the
catalytic cycle (Fig. S32b). Such a reaction pathway is also in
agreement with the observed excellent selectivity of the
photobiocatalytic decarboxylation reactions with all
substrates used. This high selectivity makes the occurrence of
free, C-centered radicals (at least for a prolonged period)
highly unlikely.
ACKNOWLEDGMENT
The Netherlands Organisation for Scientific Research is
gratefully acknowledged for financial support through a VICI
grant (no. 724.014.003). We thank Dr. Linda G. Otten and Dr.
Fabio Tonin for support with the modelling.
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acids using the fatty acid photodecarboxylase from Chlorella
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