Enzyme Activity by Design: An Artificial Rhodium Hydroformylase for Linear Aldehydes

Article abstract of DOI:10.1002/anie.201705753

Artificial metalloenzymes (ArMs) are hybrid catalysts that offer a unique opportunity to combine the superior performance of natural protein structures with the unnatural reactivity of transition-metal catalytic centers. Therefore, they provide the prospect of highly selective and active catalytic chemical conversions for which natural enzymes are unavailable. Herein, we show how by rationally combining robust site-specific phosphine bioconjugation methods and a lipid-binding protein (SCP-2L), an artificial rhodium hydroformylase was developed that displays remarkable activities and selectivities for the biphasic production of long-chain linear aldehydes under benign aqueous conditions. Overall, this study demonstrates that judiciously chosen protein-binding scaffolds can be adapted to obtain metalloenzymes that provide the reactivity of the introduced metal center combined with specifically intended product selectivity.

Full text of DOI:10.1002/anie.201705753

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Accepted Article
Title: Enzyme activity by design: an artificial rhodium hydroformylase
for linear aldehydes
Authors: Amanda Jarvis, Lorenz Obrecht, Peter Deuss, Wouter Laan,
Emma Gibson, Peter Wells, and Paul Kamer
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201705753
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Enzyme activity by design: an artificial rhodium hydroformylase
for linear aldehydes
Amanda G. Jarvis,* Lorenz Obrecht, Peter J. Deuss,[a, b] Wouter Laan,[a, g] Emma K. Gibson,[c,d]
[
a]
[a]
Peter P. Wells,[d,e,f] and Paul C. J. Kamer.*[a][h]
Abstract: Artificial metalloenzymes (ArMs) are hybrid catalysts that
offer a unique opportunity to combine the superior performance of
natural protein structures with the unnatural reactivity of transition
metal catalytic centers. Therefore, they provide the prospect of highly
selective and active catalytic chemical conversions for which natural
enzymes are unavailable. Here we show that by rationally combining
robust site-specific phosphine bioconjugation methodology and a
lipid-binding protein (SCP-2L), an artificial rhodium hydroformylase
can be developed that displays remarkable activities and selectivities
for the biphasic production of long chain linear aldehydes under
benign aqueous conditions. Overall, this study demonstrates that
judiciously chosen protein binding scaffolds can be adapted to obtain
metalloenzymes that provide the reactivity of the introduced metal
center combined with specifically intended product selectivity.
The development of substrate and product specific catalytic
processes that operate efficiently at mild reaction temperatures is
a major challenge for the synthetic chemical community.[1]
Enzymes are nature’s main catalysts which catalyse numerous
chemical transformations, typically at benign conditions. However,
many desired chemical reactions are not performed by nature and
therefore suitable natural enzymes are lacking. ArMs provide a
way to bridge that gap between nature and chemical production,
providing enzymes for unnatural reactions.[2] Despite these
successes, most ArMs do not meet the rates and performances
achieved by natural enzymes.[3] In addition, the molecular
recognition and shape selectivity of proteins has typically not been
exploited. The most successful approach to create ArMs has been
the use of non-
Figure 1. A) Conceptual illustration of the use of the apolar tunnel to introduce
regioselectivity into hydroformylation. B) Illustrations of the apolar tunnel in
SCP-2L, showing the position of Triton X-100 in the tunnel in the original crystal
structure pdb: 1IKT[13], the tunnel dimensions and positions of A100 and V83.
covalent anchoring strategies utilizing protein scaffolds with
strong supramolecular recognition motifs e.g. avidin.[4] In these
ArMs the binding site is used to carry the active metal centre or
bind metal-containing cofactors, restricting the possible
applications of a protein’s binding properties. An alternative
[
a]
Dr. A. Jarvis*, Prof. P. C. J. Kamer*, Dr. L. Obrecht, Dr. P. J. Deuss,
Dr. W. Laan.
School of Chemistry, University of St Andrews, North Haugh, St
Andrews, Fife, KY16 9ST.
E-mail: agj2@st-andrews.ac.uk; Paul.Kamer@catalysis.de
Department of Chemical Engineering (ENTEG), University of
Groningen, Nijenborgh 4, 9747 AG Groningen, the Netherlands.
Dr. E. K. Gibson
Department of Chemistry, University College London, 20 Gordon
Street, London WC1H 0AJ, United Kingdom.
Dr. E. K. Gibson, Dr. P. P. Wells
UK Catalysis Hub, Research Complex at Harwell, Rutherford
Appleton Laboratory, Harwell Science & Innovation Campus, Didcot,
Oxfordshire, OX11 0FA.
approach
utilizes
site-selective
protein
modification
[
b]
c]
[5]
methodology to incorporate transition metals into a wide range
of protein scaffolds whilst leaving the protein’s innate binding
capabilities largely intact. Any protein scaffold can be used,
allowing the exploitation of the almost unlimited range of highly
specific substrate binding capabilities of proteins. Therefore,
virtually any organometallic non-natural catalytic reaction can be
merged with the sophisticated biological performance of enzymes
and this approach offers significant opportunities for the design of
ArMs aiming at high selectivity via shape selective product
formation. Here we demonstrate the potential of such ArMs by
the development of artificial rhodium enzymes derived from a
protein scaffold that was selected for its apolar substrate binding
properties. These ArMs enable selective aldehyde formation in
the biphasic hydroformylation of long chain linear alkenes, a
reaction for which no natural enzymes are known and which is
[
[d]
[
e]
f]
Dr. P. P. Wells
School of Chemistry, University of Southampton, Southampton,
SO17 1BJ.
Dr P. P. Wells
Diamond Light Source, Harwell Science & Innovation Campus,
Didcot, Oxfordshire, OX11 0DE.
Current Address: Phoreon, Bioincubator I, Gaston Geenslaan 1, B-
[
[
[
g]
h]
3001 Leuven, Belgium.
Bioinspired Homo- & Heterogeneous Catalysis, Leibniz Institute for
Catalysis, Albert-Einstein-Straße 29 a, 18059 Rostock, Germany.
Supporting information for this article is given via a link at the end of
the document.
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challenged in current industrial applications by low solubility of the
substrates in the aqueous phase.[6]
substrates[13] and can be obtained in high yields.[5a] Our
hypothesis was that the apolar tunnel present in SCP-2L (Figure
1b) would be able to facilitate the transport of alkenes to the
aqueous environment and orient the starting alkene along the
tunnel towards the rhodium enabling shape selective production
of the desired linear product (Figure 1a). To introduce the catalytic
rhodium-phosphines, two mutants containing unique cysteines at
either end of the tunnel were prepared (SCP-2L V83C and SCP-
2L A100C, Figure 1b).[5a,14] These two mutants, obtained in
excellent yields, showed little structural permutations and similar
aliphatic substrate binding capabilities as the WT protein (see SI:
Table S3). Both SCP-2L mutants were successfully modified with
aldehyde phosphines P1-P3 through a cysteine modification
strategy (Scheme 1a, characterisation data for SCP-2L V83C-1-
P1-3 see ref 5a and SI for SCP-2L A100C-1-P1-3).
We have previously reported a methodology that enables
such an approach for the synthesis of ArMs containing metal-
binding phosphine ligands (Scheme 1a).[5a,7] Rhodium-phosphine
complexes are known to be highly active and robust
hydroformylation catalysts and thus our strategy provides the
prospect of enzymatic hydroformylation reactions. Rhodium-
protein hybrids tested to date in hydroformylation have utilized
dative protein-rhodium interactions with limited success.[8]
Although, this has led to unprecedented linear selectivities for the
hydroformylation of styrene[9] the exact nature of the active
species, and thus origin of the selectivity is still unclear.[10]
Rhodium-catalyzed hydroformylation is used on a 800,000 tonne
scale to produce butyraldehyde from propene under biphasic
conditions,[ allowing recovery of the expensive rhodium-3,3’,3’’-
phosphanetriyltris(benzenesulfonic acid) trisodium salt catalyst
11]
(
Rh-TPPTS). Long chain aldehydes are desired by industry, as
they are important precursors for the production of detergent and
plasticizers.[ This process is not feasible for long chain alkenes
12]
[
6]
(
>5 carbon atoms) due to their low solubility in water .
Figure 2. Activity (coloured bars) and selectivity (black squares) of the catalytic
hydroformylation: (A) using different artificial metalloenzymes in the
hydroformylation of 1-octene (the values for P1 have been magnified), (B)
Scheme 1. (A) Scheme showing the synthesis of the artificial metalloproteins.
(B) Reaction scheme for the hydroformylation of 1-octene, AA = amino acid.
2
across different length alkenes. Standard conditions: 80 bar CO:H (1:1), 35 °C,
Fatty acid transporter proteins contain apolar tunnels and
clefts to bind their hydrophobic cargo. The steroid carrier protein
type 2 like (SCP-2L) domain of the human multifunctional enzyme
(MFE-2) was identified as a suitable linear alkene binding
protein scaffold as it is known to bind a variety of linear aliphatic
625 rpm, 0.5 mL of catalyst solution and 0.5 mL of alkene containing 9% (v/v)
n-heptane and 1% (v/v) diphenyl ether as internal standards. Rh concentrations
were obtained by ICP-MS and used to calculate TON, recorded values between
20 and 100 nmol Rh. Conversions and linear selectivities were obtained by GC
2
using a minimum of 3 runs. Error bars show standard deviation. Further details
available in the SI section 4.
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Table 1: Control reactions for the aqueous hydroformylation of 1-octene.
Entry
Catalyst
TON
% linear aldehyde
78.8 (4.86)
1
ArM: SCP-2L A100C-1-P3-Rh[a]
408.7 (57.79)
Rh(acac)(CO) [
b]
529.7 (53.30)
123.5 (38.19)
2245 (674)
700 (190)
5.4 (3.25)
9.4 (1.01)
55.3 (0.67)
57.8 (0.07)
58.9 (0.41)
56.5 (0.08)
65.9 (8.55)
60.7 (1.48)
67.0 (0.64)
2
3
4
5
6
7
8
2
[
c,d]
Protein scaffold A100C treated with Rh
Rh-TPPTS 1:2[
e]
Rh-TPPTS 1:20[
e]
Rh-TPPTS 1:300[e]
Rh-TPPTS 1:300 + SCP-2L A100C[f]
Rh-TPPTS 1:300 + WT SCP-2L[f]
5.1 (2.48)
Standard conditions: 80 bar syn gas (1:1), 35 °C, stirring 625 rpm, 0.5 mL of catalyst solution and 0.5 mL of 1-octene containing 9% (v/v) n-heptane and 1% (v/v)
diphenyl ether. Rh concentration was obtained by ICP-MS for the ArM entry. Conversions and linear selectivities were obtained by GC using a minimum of 3 runs.
Standard deviation in brackets. a) P:Rh 1.5, 23 nmol Rh, b) 41.25 h, total volumnn 0.4 ml 1-octene, no water 150 nmol Rh, c) Treated with Rh and washed in the
same manner as the metalloproteins. d) 10.0 nmol Rh, e) 30 nmol Rh, f) 2 eq. protein to Rh.
The rhodium proteins (SCP-2L V83C/A100C-1-P1-3-Rh)
were obtained by the addition of Rh(acac)(CO) . Other Rh
precursors did not selectively bind to the phosphine (see Table
S4 for MS and metal loading analysis) Their catalytic activity
the organic phase (Table 1, entries 2, 4 and 5). At the same
concentration as our ArM reactions, over 300 eq of TPPTS ligand
is needed to prevent metal leaching (Table 1, entries 4-6) and
obtain high selectivities. The same effect of rhodium leaching was
2
.
investigated in the hydroformylation of 1-octene at 35 °C and 80
bar synthesis gas (Figure 2, and see SI: Table S5). To minimise
rhodium leaching and therefore false results from ‘free Rh’
observed when the protein was simply mixed with Rh(acac)(CO)
2
(Table 1, entry 3). This, alongside the differences between the two
protein mutants, shows that it is the hybrid catalysts that are
responsible for the hydroformylation results. SCP-2L A100C-1-P3
gave the best performance overall (79% nonanal, 409 TON; Table
1, entry 1). These conversions and selectivities are remarkable as
a benchmark catalyst (Rh-TPPTS) gives negligible conversion
approaching the detection limit (TON  1) when the TPPTS:Rh
ratio is optimised to give similar selectivities to the metalloenzyme
(TPPTS:Rh 30:1 at ~10 times the Rh conc. of the ArM reaction
gives 72% linearity; see SI: Table S7).
Following the successful hydroformylation of 1-octene,
these artificial metalloenzymes were tested in the
hydroformylation of 1-decene, 1-dodecene and 1-octadecene
(Figure 2b).[6] When TPPTS is used a 10-fold rate decrease is
observed on the addition of two carbons to the chain length due
to the reduced water solubility of the alkene.[6] Using the ArM a <
4-fold decrease in activity was observed on going from 1-octene
to 1-decene, and only 10-fold when going to octadecene. Under
selectivity optimised conditions (high ligand concentrations to give
adequate linear selectivity but prevention of Rh-leaching), Rh-
TPPTS displayed no significant activity (Figure 2a, Table 1, entry
6, and SI: Table S7). Control experiments using the Rh-TPPTS
system in the presence of the protein scaffold showed no
significant difference in turnover for 1-octene (Table 1, entry 6 vs.
7 and 8), providing evidence that the increase in activity for the
ArMs cannot solely be explained by the protein acting as a phase
transfer reagent. We therefore attribute the higher than expected
activity to the presence of the lipid-binding tunnel in the protein
scaffold in direct proximity of the Rh center.
(
leading to low selectivity (~55% linearity) and high TON’s (>500)
Table 1, entry 2), a slight excess of protein (2 eq.) was used. Even
though these reactions were performed at a relatively low
temperature (typically industrial conditions are 125 °C), significant
hydroformylation activity was detected over 48 h for several of the
rhodium-phosphine ArMs (Figure 2a). Reactions over time
showed that the enzyme was active across the whole 48 h (see
SI: Table S6). Control reactions with the ArM phosphine selenide
or ArM phosphine gold complex showed that the rhodium was
required for the hydroformylation reaction to occur (see SI: Table
S5).
The structure of the phosphine cofactor was found to have
a large effect on the turnover number, with the activity increasing
as the phosphine moved from the ortho (P1) to meta position (P2),
and the ortho (P1) to para position (P3) by 30 fold and 70 fold,
respectively for SCP-2L V83C. The protein scaffold also
influenced the reactivity, with a marked improvement in turnover
found when using SCP-2L A100C-1-P3, achieving TONs of >400,
versus 75 for SCP-2L V83C-1-P3. The selectivity of the reaction
was also found to vary depending on the combination of protein
scaffold and phosphine cofactor applied. It ranged between 69
and 79% for the linear product (nonanal), matching typical
selectivities for double phosphine ligated rhodium catalyzed
hydroformylation.[15] Selectivities of 80% are rarely seen with
monoligated P-Rh systems. Control reactions with P1-3 or
Rh(acac)(CO)(PPh
3
)
in neat alkene show that with
monophosphine’s in the organic phase of our reaction selectivities
up to 74% can be achieved (refer to SI Table S8-9). Catalyst
degradation and leaching of the phosphine and rhodium to the
organic phase was not responsible for the observed selectivities
as only minimal rhodium leaching and degradation were observed
Overall, the selectivities for the linear hydroformylation
products were remarkably high for monophosphine-ligated
rhodium in water indicating that the protein scaffold counter
balances the lack of phosphine ligands. In addition, both the
phosphine-cofactor and protein mutant affect the activity of the
reaction. To better understand the observed selectivity of our
hydroformylase we investigated the local environment of the Rh
in the protein scaffold. Both the X-ray absorption near edge
(
see SI: Table S11 and Figs S12 and S13). It should be noted that
our ArM system has a low P:Rh ratio, which, when using a
benchmark biphasic Rh-TPPTS catalytic system only gives
activity and selectivities that correspond to rhodium leaching into
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structure (XANES) and extended X-ray absorption fine structure
To probe the possibility of a near-by methionine to the Rh
center, the selenomethionine derivative of the protein scaffold
were expressed and purified. Rhodium complexation of the
(
EXAFS) of SCP-2L A100C-1-P3-Rh at the Rh K edge were
assessed. Comparing the XANES of SCP-2L A100C-1-P3-Rh to
model Rh complexes (see SI: Figure S10) suggested the loss of
2
phosphine modified SeMet protein using Rh(acac)(CO) gave
carbonyl functionalities from the Rh(acac)(CO)
2
precursor. This
similar results as for SCP-2L A100C-1-P3, exhibiting the RhCO
adducts in the mass spectrometry, and also showed a small shift
in the 77Se NMR upon Rh addition (see SI: Figure S11). There
was a profound change in the Rh K edge EXAFS data of SeMet-
A100C-1-P3-Rh compared to SCP-2L A100C-1-P3-Rh (Figure
was further supported by the lack of CO stretches in the IR and
fitting the EXAFS data of SCP-2L A100C-1-P3-Rh (see SI: Table
S1).
3c). The differences observed can be rationalised by the
coordination to a neighbour of higher atomic number with a larger
backscattering amplitude; between the analogous systems Rh-S
interactions have been replaced by Rh-Se. The EXAFS analysis
supports our hypothesis that there is monophosphine
coordination, coupled with further interaction with S from a
methionine residue. Moreover, through observation of this Rh-
S/Se interaction we have direct evidence of the coordination of
the protein scaffold with the Rh centre.
We were intrigued if the methionine coordination would
have an effect on the catalytic performance of the ArM, or if the
methionine would just decoordinate under the reaction conditions
to give the same active catalyst, and thus same catalytic results
in all cases. To probe this further 4 mutants of SCP-2L A100C
were prepared in which each Met residue was replaced by alanine,
and the proteins then modified as above. The initial catalytic
results are ambiguous, the activity of SCP-2L A100C M105A-1-
P3 was on average higher than A100C or the other mutants (TON
=
112,(±33) and TON 60-86 for the others, see SI: Table S10)
which could indicate that M105 is indeed involved in rhodium
coordination. However, this can also be due to other factors like
structural changes or decreased protein stability. More detailed
studies are required before firm conclusions can be drawn on the
role of the methionines in the hydroformylation by these ArMs.
In summary, we show that rhodium phosphine modified
SCP-2Ls are linear-selective catalysts in the hydroformylation of
long chain alkenes. SCP-2L A100C-1-P3-Rh showed a rate-
enhancement of at least 103 compared to the traditional
Rh/TPPTS system in the biphasic hydroformylation of 1-octene
and 1-decene. This demonstrates that a protein chosen for its
specific binding properties can be converted into an enzyme in
which these properties are used to transmit product selectivity.
Combining this technology with the recent advances in chemical
biology will allow us to rapidly engineer highly selective catalysts
that operate under benign conditions. Moving forward we believe
this approach has the potential to be used for a whole range of
reactions, which traditionally use phosphines as ligands and
convert these into biocatalytic processes. In the long term, as
chemogenetic optimisation is used to improve activity, this could
open the door to a new era of biocatalytic chemical production.
Figure 3. (A) Cartoon of the hypothesised metal environment. (B) Model of
A100C (Swiss model) with 1-P3 docked using Gold to illustrate the reach of this
added cofactor. Methionines within range are highlighted in yellow. (C) k3
weighted Rh K edge EXAFS data (black lines) and associated fit (dashed red
line) for A100C-1-P3-Rh and SeMet-A100C-1-P3-Rh.
The fitting model applied used characteristic scattering paths from
both acac and PPh Ar ligands, with a derived Rh-P coordination
2
number of two. EXAFS is unable to distinguish between scattering
neighbours of like atomic number, especially where Z = ± 1. The
prospect of two phosphorous atoms coordinated to the rhodium
appeared unlikely due to the resulting steric congestion of placing
two protein scaffolds around the metal. Thus, we postulated the
possibility of one of the observed Rh-P neighbours arising from a
Rh-S interaction (Figure 3b); the protein scaffold contains
functionalised sulfur in the forms of methionine, at the N-terminus
and on the flexible alpha helices, and the introduced cysteine
Acknowledgements
This work was supported by the EU through NEST Adventure
STREP Project Artizymes (contract no. FP6-2003-NEST-B3
15471); Marie Curie Excellence Grants, Artizyme Catalysis,
(
Figure 3a).
(
contract no. MEXT-2004-014320), and through a Marie Curie
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Individual Fellowship project ArtOxiZymes to AGJ (contract no.
H2020-MSCA-IF-2014-657755). The authors thank the EPSRC
for funding through EPSRC Critical mass grant ‘Clean catalysis
for sustainable development’ (EP/J018139/1) and Sasol (CASE
studentship to P.J.D.). The UK Catalysis Hub is kindly thanked for
resources and support provided via our membership of the UK
Catalysis Hub Consortium and funded by EPSRC (grants
EP/K014706/2, EP/K014668/1, EP/K014854/1, EP/K014714/1
and EP/M013219/1). We acknowledge Diamond Light Source for
beamtime through award SP10306, and thank the beamline
scientists Dr Diego Gianolio and Dr Giannantonio Cibin. We thank
Dr Sally Shirran and Dr Catherine Botting for advice on mass
spectrometry, and Dr Thomas Lebl for help with 77Se NMR. We
also thank Dr T. Glumoff (University of Oulu, Finland) for providing
plasmids. A.G.J thanks Dr Irshad Baig for assistance with WT
SCP-2L protein production. P.J.D thanks Yiteng Zhang for
assistance.
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Keywords: Artificial metalloenzymes • Catalyst design •
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
Artificial
metalloenzymes for
the linear
hydroformylation of
long chain alkenes
have been prepared
which show enzyme
like rate
A. G. Jarvis,* L.
Obrecht, P. J.
Deuss, W. Laan, E.
K. Gibson, P. P.
Wells, and P. C. J.
Kamer.*
XX-XX
enhancements.
Enzyme activity by
design: an artificial
rhodium
hydroformylase for
linear aldehydes
Layout 2:
COMMUNICATION
Author(s), Corresponding Author(s)*
Page No. – Page No.
Title
Text for Table of Contents
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