Aldolase Cascade Facilitated by Self-Assembled Nanotubes from Short Peptide Amphiphiles

Article abstract of DOI:10.1002/anie.201914633

Early evolution benefited from a complex network of reactions involving multiple C?C bond forming and breaking events that were critical for primitive metabolism. Nature gradually chose highly evolved and complex enzymes such as lyases to efficiently facilitate C?C bond formation and cleavage with remarkable substrate selectivity. Reported here is a lipidated short peptide which accesses a homogenous nanotubular morphology to efficiently catalyze C?C bond cleavage and formation. This system shows morphology-dependent catalytic rates, suggesting the formation of a binding pocket and registered enhancements in the presence of the hydrogen-bond donor tyrosine, which is exploited by extant aldolases. These assemblies showed excellent substrate selectivity and templated the formation of a specific adduct from a pool of possible adducts. The ability to catalyze metabolically relevant cascade transformations suggests the importance of such systems in early evolution.

Full text of DOI:10.1002/anie.201914633

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Accepted Article
Title: Aldolase Cascade by Self Assembled Nanotubes of Short
Peptide Amphiphile
Authors: Antara Reja, Syed Pavel Afrose, and Dibyendu Das
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201914633
Angew. Chem. 10.1002/ange.201914633
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Aldolase Cascade by Self Assembled Nanotubes of Short Peptide
Amphiphile
Antara Reja, Syed Pavel Afrose and Dibyendu Das*
Abstract: Early evolution benefited from a complex network of
reactions involving multiple cascades of carbon-carbon bond
formation and breaking that were critical for primitive metabolism.
Nature gradually chose highly evolved and complex enzymes such as
lyases featuring binding pockets with precise arrangement of amino
acids to efficiently foster the forward and reverse steps of this C-C
bond cleavage with remarkable selectivity of substrates. We report a
lipidated short peptide which accesses homogenous nanotubular
morphology to efficiently catalyze the C-C bond cleavage and
formation. This system showed morphology-dependent catalytic rates
suggesting the formation of
a binding pocket and registered
enhancements in presence of hydrogen bond donor tyrosine which is
exploited by extant aldolases. Notably, these assemblies showed
excellent selectivity of substrates and templated the formation of a
specific adduct from a pool as a sole product. The ability to catalyze
metabolically relevant cascade transformations argues the
importance of such systems in early evolution.
Present biology uses a number of highly evolved enzymes in
complex chemical networks to achieve the cascade of events
required for anabolic and catabolic pathways.[1,2] The remarkable
catalytic prowess of such modern enzymes arises from complex
three-dimensional structures accessed by long peptide sequence
which folds to create binding sites featuring specific residues.3
Precise arrangement of such residues helps in manipulating
protonation events, inducing a charge-transfer relay network to
polarize and activate nucleophile or electrophile and so forth.
Interestingly, unlike extant enzymes which work on very specific
substrates and usually specialize in only one reaction, the
primitive catalyst had very broad specificities.4 Fewer rudimentary
enzymes showed promiscuity in the primordial conditions as they
were capable of working on multiple substrates, catalyzing
forward and reverse steps for the cascade of reactions required
for early metabolic capabilities and thus contributed greatly
towards enrichment of the chemical inventory.5 Gradual
divergence towards specialized roles of enzymes happened
through duplication, mutation and selection which led to the
existing diversity of biocatalysts and their role towards increased
metabolic efficiency.6 For instance, modern aldolases act as
lyases which use lysine and tyrosine in the binding pockets for
selectively catalyzing the forward and the reverse steps of the
aldol cascade.7 Carbon-carbon bond manipulation is critical for
diverse reactions, from formose reaction to modern metabolic
pathways such as Calvin cycle and glycolysis.8 We asked whether
a
short peptide capable of accessing homogenous
nanostructures would be able to foreshadow the generation of an
enzyme binding pocket and catalyze both the forward and
Figure 1. a) Structures of the peptide amphiphiles. b) Schematic representation
of retro-aldol reaction with A1 in presence of nanotube. c) Cascade reaction
through bond breaking of adduct A1, followed by a selective bond formation in
presence of different ketones acting as nucleophiles. The intermediate Ar-CHO
and final product A3 are shown. d,e) Elaborated view of symbols with structures
of substrates.
[a]
Department of Chemical Sciences & Centre for Advanced
Functional Materials, Indian Institute of Science Education and
Research (IISER) Kolkata, Mohanpur, West Bengal, 741246, India
E-mail: dasd@iiserkol.ac.in
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reverse steps of C-C bond cascade transformations.9 Towards
this end, we report self-assembled nanotubes capable of carrying
out two of the most critical transformations in extant biology,
selective carbon-carbon bond breaking/formation, and
importantly directing cascade reactions for specific condensation
product distribution.
predicted model of assembly in Figure S3, SI). Circular dichroism
(CD) spectra showed a negative band at around 220 nm,
indicating β-sheet like secondary structure (Figure 2e).12 The
FTIR spectrum of C10-FFVK peptide amphiphile showed a strong
amide I absorption band at 1613 cm-1 (Figure S4, SI). To
investigate the nature of the surface, the nanotubes were
incubated with negatively charged AuNP. TEM showed ordered
binding of nanoparticles on the nanotubes, indicating the
presence of solvent exposed arrays of positively charged lysines
(Figure 2b). Control done using positively charged AuNP showed
no such specific binding (Figure S5, SI). Further, to check the
ability of the tubes to bind hydrophobic moieties, we used
fluorescent dye coumarin 343 as a model guest. Confocal
microscopy showed fluorescent nanostructures with uniform
binding of the dye on the tubes, underpinning the ability of the
nanotube to bind to small molecules (Figure 2d).
The above experiments suggested the positively charged surface
of nanotubes with dense array of lysines that can be exploited for
catalyzing reactions via formation of imine intermediate.[6c,13] We
investigated whether these nanotubes can catalyze retro-aldol
reactions and importantly, whether these can show selectivity
among substrates. The two substrates used were methodol (A1),
the adduct of acetone and fluorescent 6-methoxy-2-
naphthaldehyde (Ar-CHO) and its more hydrophobic congener
(A2), an adduct of 2-hexanone with the same aldehyde. The
retroaldolase activity was monitored by UV-Vis spectroscopy at
pH 7.45 HEPES buffer (10 mM), (Figure S6, S7, S8 see SI for
details). Interestingly, the peptide nanotubes showed preference
of substrate for the C-C bond cleavage as A1 cleaved with an
order of magnitude higher catalytic activity [kcat = (1.02±0.17)×10-
3
min-1] than A2 [kcat = (0.12±0.016)×10-3 min-1, Figure 2f]. The
reaction progress could also be seen from fluorescence
spectroscopy which showed gradual increment of Ar-CHO at 452
nm (Figure S9, SI). Further, the reaction was monitored from
HPLC analysis. A gradual decrease of peak area of A1 with
simultaneous increase of Ar-CHO was observed (Figure S10, SI).
Control reaction done with only molecular lysine showed more
than 4 order of magnitude lower rates for both the substrates.
Interestingly, retro-aldol reactions done in organic solvent THF
without nanotubes using tertiarybutylammonium hydroxide as
base yielded similar rates for A1 and A2 (Figure 3a) suggesting
the role of the nanotubular surface in selection among substrates.
To find out the reason for the preference of the nanotubes for A1
over A2, we proposed to monitor the binding of the substrates with
fluorescence spectroscopy. To circumvent the problem that would
arise from the cleaved product (Ar-CHO), we mutated lysine with
arginine to create a control sequence C10-FFVR (Figure 1a).
C10-FFVR assembled to form morphologically similar nanotubes
as seen for C10-FFVK (diameter=20± 4 nm, Figure S11). As
predicted, C10-FFVR nanotubes were unable to cleave the
substrates A1 and A2 even after prolonged incubation (Figure 2f).
Figure 2. a) TEM image of nanotube (inset: magnified image of nanotube). b)
TEM image of negatively charged gold nanoparticle bound with nanotube. c)
AFM image of nanotube. d) CLSM image of coumarin 343 dye bound to C10-
FFVK nanotubes (ex=488 nm). e) CD of self-assembled C10-FFVK (nanotube)
before (red) and after (blue) treatment with HFIP (inset: TEM image of HFIP
treated C10-FFVK nanotube) f) Retro-aldol rate of A1 and A2 by the nanotubes
of C10-FFVK (blue bars) and C10-FFVR (grey bars).
We started with residue 18 to 20 (18VF20F) of the core of A 1-42
sequence which is associated with the protein deposits seen in
Alzheimer’s disease.10 To impart colloidal stability, we installed
lysine at the C-terminal while the N-terminal was coupled to
decanoic acid, yielding the amphiphile C10-FFVK (Figure 1a,
Figure S1, SI). Transmission electron microscopy (TEM) images
of the assemblies showed different morphologies depending on
the incubation time. Assemblies aged up to 7-15 days showed
mostly nanofiber like structures (Figure S2, SI). Interestingly, on
aging for up to 30 days and more, the peptide assemblies
accessed homogenous nanotubular structures having a diameter
of 23 ± 2 nm with well-defined walls (Figure 2a, S2, SI).11 Atomic
force microscopy done with the 30 days incubated samples also
revealed homogenous nanotubular morphologies with heights of
18 ± 2 nm, suggesting a wall thickness of 9 ± 1 nm (Figure 2c,
Notably, A1 showed
a
significant enhancement of the
fluorescence compared to A2 (ex=290 nm, Figure S12),
indicating more binding for A1 resulting in higher rates.
We further found that the morphology of the assembled peptide
had a remarkable role on the activity. Fiber like morphology
accessed after ca. 15 days of assembly showed ca. 50 % lower
activity compared to the activity seen in case of the matured
nanotubes assembled for 30 days (Table S1, SI).[11d, 14] To probe
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this, the binding capabilities of C10-FFVK based on their states of
assembly
were
investigated.
Fluorophore
8-Anilino-1-
naphthalenesulfonic acid (ANS), known to report the
hydrophobicity of the binding sites of the self-assembled systems,
showed significant increase in intensity along with a substantial
blue shift in the emission maxima when incubated with the C10-
FFVK nanotubes (em=485 nm, em(in buffer)=516 nm).15 However,
for fibers, ANS showed substantially lower fluorescence intensity
with lesser extent of blue shift (em=489 nm, Figure S13, SI). This
suggested stronger binding capability of the nanotubes in
comparison to the fibers. Intrinsic fluorescence of A1 showed a
similar trend with the assemblies of the control sequence C10-
FFVR (Figure S12).
Notably, the fibers had lesser selectivity between the substrates
A1 and A2 when the ratio of retroaldolase activities was
compared with the nanotubes (Figure 3a). This again highlighted
the role of a binding surface on the nanotubes which resulted in
higher activity with more selectivity. To further investigate the
importance of the self-assembled nanotubes and the binding
surface generated upon assembly, we treated the nanotubes by
hexafluoroisopropanol (HFIP) to disassemble the nanostructures
completely and checked the activity within ca. 2 min (See SI for
details). The disassembly was confirmed from the loss of CD
signal and through TEM (Figure 2e, SI for details). The
disassembled peptide amphiphile showed ca. 28 times lower
activity with no selectivity when compared to the assembled
nanotubes, thus underpinning the role of binding surface for
catalysis and selectivity (Figure 3a, Table S1, SI). To probe the
binding surface further, we used ANS fluorescence which
suggested poor binding of the fluorophore to the disassembled
peptides of C10-FFVK (Figure S13, SI). Congo Red (CR) binding
studies with UV Vis spectroscopy also suggested stronger binding
to the nanotubes than fibers and disassembled peptides (Figure
S14).12a
Extant aldolases elegantly use the H-bond donor capabilities of a
proximal tyrosine in the active site to facilitate the C-C bond
cleavage. The phenolic –OH group of tyrosine critically assists by
proton transfer thus increasing the electrophilicity of the carbonyl
group of the substrate prior to formation of the imine. Mutant
proteins with phenyl alanine in place of tyrosine results in sharp
decline of activity despite the presence of lysine.[13c,d] We asked
whether our designed catalytic nanotubes having lysine arrays
can show higher activity in presence of tyrosine on its surface. For
this purpose, we used Fmoc-Y (Figure 3b) which can bind via the
hydrophobic interactions, in a similar fashion as seen for coumarin
343. The fluorescence of Fmoc-Y in presence of peptide
nanotubes showed red shift along with quenching of fluorescence
intensity of the fluorenyl moiety and thus suggested binding
(Figure S15, SI). Notably, we found a significant enhancement in
the reaction rate with A1 in presence of Fmoc-Y which was
almost 4.9 times higher [kcat = (4.93±0.48) ×10-3 min-1] than the
nanotubes without tyrosine (Figure 3b, S6, S16, Table S1, SI).
Figure 3. a) Ratio of retro-aldol rates of A1 vs A2 catalyzed by 1) fiber 2)
nanotube 3) nanotube + Fmoc-Y 4) HFIP treated nanotube in buffer and 5)
tetrabutylammonium hydroxide in THF. b) Retro-aldol rates of A1 catalyzed by
1) nanotube and nanotube along with 2) Fmoc-Y 3) Fmoc-F 4) Fmoc-Y(OMe),
and probable mechanism of activation in presence of Fmoc-Y (inset).
with methyl group (Fmoc-Y-OMe). The lack of the hydrogen bond
donor for Fmoc-Y-OMe resulted in no enhancement of rate
constant for the retro-aldol reaction (Figure 3b, Table S1, SI,
Fmoc deprotection was not seen till the course of the reaction,
Figure S18, SI).
Aldolases have the ability to catalyze both the forward and the
reverse steps of the condensation reaction based on the
substrates and hence have profound importance in extant
metabolism. We wanted to check whether the designed
nanotubes can catalyze the forward aldol as well with the
possibility of selectivity. To check the forward activity, reaction
mixture containing Ar-CHO and acetone was interfaced with the
nanotubes. However, no condensation product could be observed
Rate enhancement was seen for A2 as well when Fmoc-Y [kcat
=
(0.37±0.10) × 10-3 min -1] was used (S6, S17, Table S1, SI). For
controls, we used Fmoc protected phenyl alanine (Fmoc-F)
where the phenolic -OH moiety was absent (Figure 3b, Table S1,
SI). Fmoc-F was unable to enhance the retroaldolase rates
(Figure 3b). Further, we designed an additive having the Fmoc-
tyrosine moiety where the acidic phenolic proton was substituted
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till 48 h. Likewise, a mixture of 2-hexanone with Ar-CHO did not
yield aldol adduct even after 48 h. At this point we thought of
adding an aromatic ketone, 2-acetonaphthone (Ar-COMe) to Ar-
CHO in presence of nanotubes. Notably, we could see generation
of the aldol adduct A3 with time in HPLC (Figure 1). The rate of
formation (0.24M/min) was calculated from HPLC (at 200M
each of Ar-CHO and Ar-COMe, standard plot of A3 in Figure S19,
SI).
At this point, we were curious to test the capability of the
nanotubes to simultaneously perform the forward and reverse
aldol and whether these assemblies can promote cascade
reactions. For that, we interfaced the nanotubes with mixture of
substrates having aldol adduct along with ketones. We started
with A1, acetone, 2-hexanone and Ar-COMe. Expectedly, from
HPLC there were three peaks having retention time of 5 min, 11.5
min and 20 min which corresponded to Ar-COMe, C10-FFVK and
A1 respectively (Figure 4a). After 6 h, a new peak eluted with
retention time 15 min which corresponded to the intermediate Ar-
CHO and simultaneously the absorbance of A1 peak decreased
due to its conversion into Ar-CHO (Figure 4a). After 12 h, the
decrease of intensity of the Ar-CHO and Ar-COMe peaks were
observed with a gradual elution of a new peak at 22 min (Figure.
4a). Mass spectrometry confirmed the formation of the adduct
between Ar- CHO and Ar- COMe (Figure S20, SI). The rate of
formation of the adduct was measured to be 0.07M/min. To the
best of our knowledge, this is the first report of a short peptide-
based assembly which can successfully manipulate both the
cleavage and formation of the C-C bond for cascade reaction.
Notably, after the generation of the Ar-CHO, despite the
possibility of formation of multiple adducts in presence of three
different ketones, the formation of one adduct underpins the
importance of the binding surface. As controls, instead of using
Figure 4. a) HPLC chromatograms of cascade reaction mixture containing A1, assembled C10-FFVK (nanotube), Ar-COMe, 2-hexanone and acetone in 10mM
HEPES buffer pH 7.45 with time 1) initial, 2) 6 h, 3) 12 h, and the same reaction mixture in presence of NaOH instead of using nanotube at 12 h (down) b)
Representative epifluorescence images to monitor cascade reaction in presence of nanotube at time 1) 30 min, 2) 6 h and 3) 12 h taken in 20 random field of views.
c) Intensity profile diagram of same reaction mixture at time 1) 30min, 2) 6 h and 3) 12 h in 20 random field of views to avoid photobleaching.
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10.1002/anie.201914633
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nanotubes, the one pot reaction was carried out using 1M NaOH.
After 12 h, the HPLC analysis of the reaction mixture showed
multiple peaks of dehydrated aldol adducts (Figure 4a).
Significantly these results suggested that the peptide nanotubes
were not only promoting selective aldol adduct formation but
importantly impeding the dehydration step in the cascade process.
The catalytic ability shown by C10-FFVK of templating the forward
and retro steps was also monitored through epifluorescence
microscopy (Figure. 4b, c). Time resolved epifluorescence
microscopy was done with an aqueous buffered solution
containing the mixture of A1, acetone, 2-hexanone and Ar-COMe
along with the peptide nanotubes. Twenty random fields of
images in triplicate of samples were recorded to rule out the
effects of photobleaching (representative images in Figure 4b).
Interestingly, gradual emergence of fluorescent nanostructures
could be observed. This suggested the formation of fluorescent
intermediate Ar-CHO over time on the surface of nanotubes. The
intensity and density of the fluorescent nanostructures peaked at
6 h. Afterwards, the intensity gradually started to decrease,
implying consumption of the intermediate aldehyde due to the
ongoing forward aldol reaction on the surface of the nanotubes
and subsequent formation of the cascade product A3. Control
experiment was carried out with peptide nanotubes mixed with A1,
acetone and 2-hexanone in absence of Ar-COMe. This mixture
showed only the increase of intensity of fluorescent
nanostructures which plateaued after 6 h (Figure S21, SI). The
C10-FFVK nanotubes were also found to catalyze the cleavage
of the adduct A3 with kcat = (0.072±0.002) X10-3 min-1 (Figure S23,
SI). Finally, to check the capability of the C10-FFVK nanotubes to
DD is thankful to SERB (EMR/2017/005126), DST, GOI. AR and
SPA acknowledge IISER Kolkata and UGC for fellowships
respectively.
Conflict of interest
The authors declare no conflict of interest.
Keywords: Peptide-amphiphile • Self-assembly • Cascade •
Retro-aldolase • Catalysis
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10.1002/anie.201914633
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
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COMMUNICATION
Aldolase Cascade:
Amyloid like lipidated
peptide nanotubes
Antara Reja, Syed
Pavel Afrose and
Dibyendu Das*
have been shown to
demonstrate aldolase
cascade activity with
selectivity. Nanotubes
having lysines as
exposed residues bind
to tyrosine to create
an efficient catalyst to
show aldolase activity.
Page No. – Page No.
Aldolase Cascade
by Self Assembled
Nanotubes of Short
Peptide Amphiphile
This article is protected by copyright. All rights reserved.