Redox Activity of Ce(IV)-Substituted Polyoxometalates toward Amino Acids and Peptides

Article abstract of DOI:10.1021/acs.inorgchem.0c00993

Redox reactions between polyoxometalates (POMs) and biologically relevant molecules have been virtually unexplored but are important, considering the growing interest in the biological applications of POMs. In this work we give a detailed account on the redox behavior of Ce^IV-substituted polyoxometalates (Ce^IV-POMs) toward a range of amino acids and peptides. Ce^IV-POMs have been shown to act as artificial proteases that promote the selective hydrolysis of peptide bonds. In presence of a protein, a concomitant reduction of Ce^IV to Ce^III ion is frequently observed, leading us to examine the origins of this redox reaction by first using amino acid building blocks as simple models. Among all of the examined amino acids, cysteine (Cys) showed the highest activity in reducing Ce^IV-POMs to Ce^III-POMs, followed by the aromatic amino acids tryptophan (Trp), tyrosine (Tyr), histidine (His), and phenylalanine (Phe). While the redox reaction with Cys afforded the well-defined product cystine, no oxidation products were detected for the Trp, His, Tyr, and Phe amino acids after their reaction with Ce^IV-POMs, suggesting a radical pathway in which the solvent likely regenerates the amino acid. In general, the rate of redox reactions increased upon increasing the pD, temperature, and ionic strength of the reaction. Moreover, the redox reaction is highly sensitive to the type of polyoxometalate scaffold, as complexation of Ce^IV to a Keggin (K) or Wells-Dawson (WD) polyoxotungstate anion resulted in a large difference in the rate of redox reaction for both Cys and aromatic amino acids. The reduction of Ce^IVK was at least 1 order of magnitude faster in comparison to Ce^IVWD, in accordance with the higher redox potential of Ce^IVK in comparison to Ce^IVWD. The reaction of Ce^IVPOMs with a range of peptides containing redox-active amino acids revealed that the redox reaction is influenced by their coordination mode with Ce^IV ion, but in all examined peptides the redox reaction is favored in comparison to the hydrolytic cleavage of the peptide bond.

Full text of DOI:10.1021/acs.inorgchem.0c00993

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Article
Redox Activity of Ce(IV)-Substituted Polyoxometalates toward
Amino Acids and Peptides
Shorok A. M. Abdelhameed, Laurens Vandebroek, Francisco de Azambuja, and Tatjana N. Parac-Vogt*
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ABSTRACT: Redox reactions between polyoxometalates
(POMs) and biologically relevant molecules have been virtually
unexplored but are important, considering the growing interest in
the biological applications of POMs. In this work we give a
detailed account on the redox behavior of CeIV-substituted
polyoxometalates (CeIV-POMs) toward a range of amino acids
and peptides. CeIV-POMs have been shown to act as artificial
proteases that promote the selective hydrolysis of peptide bonds.
In presence of a protein, a concomitant reduction of CeIV to CeIII
ion is frequently observed, leading us to examine the origins of this
redox reaction by first using amino acid building blocks as simple
models. Among all of the examined amino acids, cysteine (Cys)
showed the highest activity in reducing CeIV-POMs to CeIII-POMs,
followed by the aromatic amino acids tryptophan (Trp), tyrosine (Tyr), histidine (His), and phenylalanine (Phe). While the redox
reaction with Cys afforded the well-defined product cystine, no oxidation products were detected for the Trp, His, Tyr, and Phe
amino acids after their reaction with CeIV-POMs, suggesting a radical pathway in which the solvent likely regenerates the amino acid.
In general, the rate of redox reactions increased upon increasing the pD, temperature, and ionic strength of the reaction. Moreover,
the redox reaction is highly sensitive to the type of polyoxometalate scaffold, as complexation of CeIV to a Keggin (K) or Wells−
Dawson (WD) polyoxotungstate anion resulted in a large difference in the rate of redox reaction for both Cys and aromatic amino
acids. The reduction of CeIVK was at least 1 order of magnitude faster in comparison to CeIVWD, in accordance with the higher
redox potential of CeIVK in comparison to CeIVWD. The reaction of CeIVPOMs with a range of peptides containing redox-active
amino acids revealed that the redox reaction is influenced by their coordination mode with CeIV ion, but in all examined peptides the
redox reaction is favored in comparison to the hydrolytic cleavage of the peptide bond.
While CeIV-substituted POMs (CeIV-POMs) have been
established as catalysts for different organic transformations,
INTRODUCTION
Cerium is among the most abundant rare-earth elements1,2 and
■
their application as catalysts for biologically relevant reactions
has found extensive uses in materials chemistry,3,4 catalysis,5
and synthetic organic chemistry.6,7 In catalysis, the application
has been scarcely explored. Incorporation of redox or Lewis
acidic metals into POM scaffolds results in a subgroup known
of cerium compounds, particularly CeIV, has been motivated
either by its prominent redox properties (E°Ce
as metal-substituted POMs (MS-POMs), which is considered
IV/CeIII
≈ +1.44 V
vs NHE)2,8,9 or its pronounced Lewis acidity.10,5,11 With
regard to reactions performed in water, which are highly
relevant for bioinorganic applications such as dephosphor-
ylation12 and peptide bond hydrolysis reactions,5 the use of
simple CeIV salts as catalysts has been largely limited to acidic
media,2 as in neutral and alkaline pH conditions the formation
of insoluble hydroxide gels drastically limits their reactivity.5,11
This tendency to form insoluble gels can be circumvented by
complexing the CeIV cation to ligands such as polyoxometa-
lates (POMs). POMs are a large and diverse group of early-
transition-metal−oxygen anionic clusters with unique chemical
and physical properties,13−15 and imbedding CeIV in POMs
results in rather robust, selective, and homogeneous catalysts
with a wide range of applications.16−20
to be an effective strategy to tune POM reactivity toward
biomolecules.21,22 In recent years, our group has intensely
studied the interactions of MS-POMs with biomolecules by
performing crystallographic23,24and spectroscopic25−27 studies,
as well as investigating MS-POM hydrolytic activity toward
phosphodiester28,29 and peptide bonds.30−35 In this context,
we have disclosed the selective hydrolysis of hen egg white
Received: April 3, 2020
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lysozyme (HEWL),36 transferrin (Tf),19 and cytochrome c (cyt
c)3 0 , 3 7 proteins under mild conditions using
K10[CeIV(PW11O39)2] as a catalyst. Interestingly, partial
reduction of the CeIV-POM to the hydrolytically inactive
CeIII-POM was also detected in the course of protein
hydrolysis.36,38 In the absence of a protein, the CeIV-POMs
were stable in aqueous solution,29 suggesting that the protein
itself was responsible for the observed reduction. In nature,
proteins engage in several oxidation−reduction reactions
mainly through their redox-active amino acids.39 This feature
is also the basis of redox proteomics, a branch of proteomics
which is used to identify oxidized proteins and determine the
extent and location of oxidative modifications.40
Scheme 1. Screening of the Redox Activity of CeIVK toward
Amino Acids
b
In this context, we realized that optimization of CeIV-POM
artificial protease activity required a deeper molecular level
understanding of its redox activity in the presence of proteins.
Furthermore, redox reactions between MS-POMs and proteins
have been virtually unexplored, which is an important
knowledge gap in the literature considering the growing
interest in the biological applications of POMs.22,24,33,37,41,42
Moreover, the versatility of cerium in catalysis and the limited
data available on Ce-POM chemistry involving proteins and
other biomolecules further inspired us to provide this detailed
account of the redox reactivity between CeIV-POMs and amino
acids and peptides. Approaches to tune the redox activity of
CeIV ions toward amino acids by adjusting the reaction
parameters and the nature of the POM ligand have been also
examined.
a
Other amino acids tested: Gly, Ala, Leu, Pro, Met, Asp, Ser, Thr,
b
Asn, Arg. Reaction conditions: CeIVK (2 mM), amino acid (2 mM),
pD 7.4, 60 °C, 7 days (31P NMR yield).
ature, concentration, and ionic strength on the reduction rate
of CeIVPOM was also investigated.
Redox Reaction between CeIVK and Cys. Among all
amino acids that induced cerium reduction, cysteine provided
the fastest reaction rates, and it was the only amino acid to
form a clear product: i.e., cystine. Given the high reactivity
observed in the initial screening experiments, the reaction
between CeIVK and Cys was studied at room temperature
(Scheme 2). When equimolar amounts of CeIVK and Cys were
Scheme 2. Oxidation of Cys to Cystine by CeIVK
RESULTS AND DISCUSSION
■
Screening Redox Activity of Ce-POM toward Amino
Acids. The reduction of CeIV ion in K10[CeIV(PW11O39)2]
(CeIVK) to CeIII results in K11[CeIII(PW11O39)2] (CeIIIK) and
can be conveniently detected by 31P NMR spectroscopy.
CeIVK is characterized by a single 31P peak at −13.4 ppm, while
CeIIIK exhibits a 31P signal at −18.7 ppm.43 Thus, 31P NMR
spectroscopy can be used as an excellent tool to investigate the
redox activity of CeIVK in the presence of selected naturally
occurring amino acids and short peptides.
mixed, at pH 7.4 and 25 °C, a fast reduction to CeIIIK was
detected by 31P NMR spectroscopy (Figure 1a). The 50%
amount of CeIVK was observed directly after mixing and
recording the 31P NMR spectrum, and complete reduction was
achieved after 2.5 h. Concomitant with the reduction of CeIVK,
Using reaction conditions similar to those for the hydrolysis
reaction performed previously,36 we initially tested the redox
activity of CeIVK in the presence of naturally occurring amino
acids (Table S1). Among all examined amino acids, only
cysteine (Cys), tryptophan (Trp), tyrosine (Tyr), histidine
(His), and phenylalanine (Phe) caused the detectable
reduction of CeIVK to CeIIIK (Scheme 1). The highest activity
was observed in the presence of Cys, which resulted in ca. 50%
conversion of CeIVK to CeIIIK directly after mixing at room
temperature. For comparison, upon addition of Trp and Tyr
only 14% and 7% of CeIVK was reduced, respectively, directly
after mixing, and addition of His and Phe showed no evidence
of CeIVK reduction at room temperature. In fact, reactivity in
the presence of His (10%) and Phe (5%) was only observed
after 7 days of incubation at 60 °C. Although the redox
potential of amino acids depends on the medium, these results
follow a general trend that can be extracted from the literature,
with the redox potential increasing in the following order:
Cys44,45 < Trp ≈ Tyr46−48 < His49,48,50 < Phe.51 Given the
striking difference in the CeIVK reduction in the presence of
different amino acids, a detailed kinetic study was performed
with each amino acid that exhibited a redox behavior. The
influence of several reaction parameters such as pD, temper-
1
the oxidation of Cys to cystine was observed by H NMR by
the decrease in peaks from Cys (δ 3.00−3.13 and 3.96−3.99
ppm), and the appearance of new peaks (δ 3.17−3.23, 3.38−
3.44, and 4.11−4.14 ppm), which could be unambiguously
assigned to cystine (Figure 1b).52
The rate of the reaction between CeIVK and Cys followed a
second-order kinetics, which is consistent with previous studies
on the oxidation of thiols to disulfide products.53−55
Interestingly, the rate constant (kobs) of CeIVK reduction
((35 0.03) × 10−3 mM−1 min−1) was found to be nearly 2.5
times faster than kobs for Cys oxidation ((13 0.005) × 10−3
mM−1 min−1). This curious discrepancy suggests that the
cysteinyl radical might be partially regenerated by the reaction
medium. Consistent with this hypothesis, we still observed
∼20% of Cys unconverted in solution after the reduction of
CeIVK was complete. On the other hand, this observation
could be attributed to the ability of CeIV ions to break a
disulfide bridge and oxidize it to other products,56 since a
disulfide bond is considered to be one of the weakest covalent
bonds.57 However, no other oxidation products were detected
in the reaction mixture, and no other POM-related products
were detected by 31P NMR. This is consistent with the lack of
B
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1
Figure 1. Cys and CeIVK redox reaction at pD 7.4 and 25 °C: (a) 31P NMR spectra showing fast reduction of of CeIVK to CeIIIK; (b) H NMR
spectra evidencing Cys oxidation to cystine along with the cerium reduction (asterisks denote cystine peaks).
reactivity with methionine (Met) observed in the initial
screening (Table S1). Unlike CeIV salts,58 CeIVK showed no
redox activity toward the thioether group of methionine (Met)
amino acid, which could be ascribed to the fact that
incorporation of CeIV ion into the POM ligand leads to
formation of a milder oxidant that is unable to oxidize a
thioether group.59,60 This indicates that CeIVK is probably not
involved in other side reactions and again suggests that
regeneration of the cysteinyl radical is the probable cause of
the distinct rate constants between CeIVK reduction and Cys
oxidation.
Scheme 3. Simplified Mechanism for the Formation of
Cystine in the Redox Reaction Between CeIVK and Cys
anion (Cys-S−) by CeIVK.61 This oxidation has been reported
as the rate-determining step of this reaction.55 Given the
dependence of the reaction rate on the availability of the Cys-
S−, we probed the effect of pD on the redox reaction kinetics.
Within the examined range of pD (3.4−8.4), the rate of the
reaction was found to linearly increase upon an increase in pD.
The formation of cystine likely takes place through the
homocoupling of cysteinyl radicals (Cys-S•) (Scheme 3),
which are probably formed through the oxidation of a cysteinyl
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This is in full agreement with the simplified proposed
mechanism in Scheme 3, in which the production of Cys-S−
species in step 1, which later produces the cysteinyl radical, is
favored at low [H+] (Figure 2).
and POM surface, facilitating the reagent approximation
interaction and thereby accelerating the reaction.62,29,63,64
Redox Activity of CeIVK toward Aromatic Amino
Acids (Trp, Tyr, Phe, and His). In contrast to the fast
reaction between CeIVK and Cys yielding CeIIIK and cystine,
the reduction of CeIVK in the presence of the redox-active
aromatic amino acids Trp, Tyr, Phe, and His was much slower,
and no products of amino acid oxidation could be detected.
When equimolar amounts of Trp or Tyr were mixed with
CeIVK at pD 7.4 and room temperature, 14% and 7% reduction
to CeIIIK was observed shortly after mixing, respectively. On
the other hand, in the presence of His and Phe the reactivity
was observed only after 7 days at pD 7.4 and 60 °C (Scheme
1). Further, although the CeIVK reduction was evident by 31P
NMR spectroscopy, no changes in the aromatic amino acid
1
structures could be detected by H NMR and ESI(+)/MS,
suggesting that aromatic amino acids mediate the reduction of
CeIVK to CeIIIK in a catalytic fashion. By changing the
stoichiometry between Trp or Tyr and CeIVK, we confirmed
the catalytic nature of this reduction, as complete reduction of
CeIVK to CeIIIK occurred in the presence of 25 mol % of Trp,
and partial reductions were detected with even lower Trp
loadings (Figure 4 and Scheme S1). Given the precedents
Figure 2. Effect of pD on the rate constant of CeIVK reduction in the
presence of Cys.
Higher temperatures and ionic strength accelerated the
CeIVK reduction in the presence of Cys. Kinetic measurements
of the CeIVK/Cys redox reaction at temperatures between 25
and 50 °C showed that an increase in temperature leads to
increase in kobs (Figure 3 and Figure S1 and Table S3). Using
Figure 4. Reduction of CeIVK with different Trp concentrations.
Reaction conditions: CeIVK (2 mM), amino acid (see chart), pD 7.4,
60 °C, 20 h (31P NMR yield).
Figure 3. Eyring plot of ln(kobs/T) as a function of 1/T (R2 = 0.954)
confirming the formation of a Trp radical upon reaction with
CeIV salts using fast-flow electron spin resonance (ESR)
spectroscopy65 and resonance Raman spectroscopy,66 it is very
likely that this amino acid catalyzed reduction follows a radical
pathway, and the medium of the reaction contributes to the
fast regeneration of the amino acid structures.
Using Trp as a model substrate for the aromatic amino acids,
kinetic measurements were performed to evaluate the effect of
concentration, pD, temperature, and ionic strength in the
reduction of CeIVK in the presence of aromatic amino acids.
Overall, the redox reaction between Trp and CeIVK followed a
first-order kinetic law with respect to CeIVK. Interestingly, the
rate of reaction is largely affected by the pD value (Figure 5a).
While at pD 3.4 no CeIVK reduction could be detected after 24
h, the reaction half-life (t0.5) decreased dramatically from 165 h
at pD 4.4 to only 2 h 40 min at pD 8.4 (Table S5). This faster
for the reduction of CeIVK in the presence of Cys.
these results, the activation parameters of the reaction were
determined by plotting the data according to Arrhenius and
Eyring equations. This resulted in Ea = 50.7 kJ mol−1, ΔH⧧ =
53.3 kJ mol−1, and ΔS⧧ = −7.1 J mol−1 K−1, while the Gibbs
free energy of activation at 60 °C was calculated to be 55.7 kJ
mol−1. The negative entropic value suggests a complex
formation between CeIVK and Cys. Another indication of
complex formation between CeIVK and Cys was the faster
reduction of CeIVK observed upon increasing the ionic
strength of the solution by adding 0.05 M NaClO4. Increasing
the ionic strength helps in shielding the electrostatic repulsion
between the negatively charged carboxylate group of the Cys
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Figure 5. (a) pD dependence of the rate constant for the reduction of CeIVK (2 mM) by 2 mM Trp at rt. (b) Influence of ionic strength on the rate
constant of the reduction of CeIVK (2 mM) in the presence of Trp (2 mM) at pD 6.4 and rt.
reduction is consistent with the decrease in redox potential of
the Trp residue at higher pD values, strengthening the
hypothesis of a Trp radical involvement in the reduction of
CeIV to CeIII.47,46 Furthermore, when the reaction was carried
out at temperatures ranging from 25 to 60 °C at pD 7.4, an
increase in reaction rate upon an increase in temperature was
observed (Figure S2), similarly to the reaction involving Cys.
When the obtained data were plotted according to the
Arrhenius and Eyring equations (Figure 6 and Figure S2),
As expected, the presence of peptides led to the reduction of
CeIVK to CeIIIK, but the estimated rate constants and half-lives
were rather distinct from those of the isolated amino acids
(Table 1). While CeIVK reduction was slower in the presence
Table 1. Observed Rate Constants (kobs) and Half-Lives
(t0.5, min) for the Reduction of CeIVK in the Presence of
“Redox Active” Amino Acids and Their Related Peptides
amino acid
kobs
t0.5
peptide
kobs
t0.5
a
a
Cys
Tyr
Trp
35
1
13
580
968
GSH
Gly-Tyr
Gly-Trp
0.9
5.6
0.8
570
145
1008
a
a
b
b
0.9
a
b
In units of 10−3 mM−1 min−1. In units of 10−3 min−1.
of γ-Glu-Cys-Gly (glutathione, GSH) than in the presence of
Cys, Gly-Tyr provided a faster reaction rate than Tyr, and no
differences were detected between Trp amino acid and Gly-
Trp dipeptide. These behaviors are consistent with a previous
report in which the incorporation of Tyr into small peptides
lowered its redox potential, leading to a more favorable
oxidation, while that for Trp showed no significant difference,
especially if it was placed in the C-terminal position.47
Similarly, Cys has a redox potential lower than that of GSH
and the observed rate of CeIVK reduction in the presence of
GSH was approximately 1 order of magnitude slower in
comparison to that of Cys. This could be attributed not only to
the lower redox potential of Cys in comparison to GSH, which
makes it more likely to be oxidized,45,44 but also to the fact that
the larger size of GSH in comparison to Cys might cause steric
hindrance that affects its interaction with the CeIVK. Analogous
to the reactions with isolated amino acids, the formation of a
disulfide bridge was detected upon GSH oxidation (Figure S6),
while products resulting from Gly-Tyr and Gly-Trp dipeptides
were not observed. Interestingly, no hydrolysis of peptides was
detected, indicating that the redox reactions are much faster
than the hydrolytic cleavage. Furthermore, the redox reactions
Figure 6. Eyring plot of ln(kobs/T) as a function of 1/T (R2 = 0.980)
for the reduction of CeIVK at pD 7.4 in the presence of Trp.
the activation energy was found to be 68.3 kJ mol−1, while the
ΔH⧧ = 65.7 kJ mol−1 and ΔS⧧ = −83.9 J mol−1 K−1 (Table
S7). Finally, the addition of different concentrations of
NaClO4 (0.2−2 M) at pD 6.2 and 25 °C led to an increase
in the CeIVK rate of reduction (Figure 5b), which could be
rationalized as discussed above for Cys. A similar reaction
behavior was observed for the reduction of CeIVK in the
presence of Tyr (see the Supporting Information for details).
Redox Activity of Peptides. In addition to the amino
acids, the redox activity of CeIVK in the presence of peptides
containing Trp, Tyr, and Cys redox-active amino acids was also
probed. Solutions containing equimolar amounts (2 mM) of
CeIVK and peptide at pD 7.4 and room temperature (rt) were
prepared, and the kinetics of the redox reactions were studied.
E
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result in the formation of the hydrolytically inactive CeIIIK, due
to the weaker Lewis acidity of CeIII in comparison to CeIV.5
Tuning the Redox Behavior of CeIV Ions. The loss of
active catalyst through reduction of CeIVK to CeIIIK motivated
us to attempt a further tuning of the redox activity through
exchange of the POM scaffold, as the Ce-POM redox potential
has been reported to depend on (i) POM charge and (ii) the
flexibility of POM ligand.67 For instance, complexation of
cerium ion to a Keggin or Wells−Dawson (WD) polyox-
otungstate anion (Figure 7) leads to a decrease in its redox
most likely via O or/and N atoms, consistent with the low
affinity of CeIV toward soft S ligands due to its intrinsic
hardness.70 The interactions between GSH and CeIVK were
also examined via 1H and 13C NMR spectroscopy (Table S15).
Consistently, the large Δδ values detected at the C-terminus
(C8 and C9) and at the carbonyl group (C5) of the γ-Glu-Cys
amide linkage pointed to GSH complexation to CeIVK via the
carbonyl group close to the S−H moiety, probably playing a
key role in positioning the reactive thiol group to the electron
transfer step. These results imply that the coordination modes
have an influence on the redox reaction kinetics, since it is
well-known that the distance between the electron donor and
acceptor plays a crucial role in the electron transfer step.71,72
This could also explain the different reactivities of Cys and
GSH. The distance between CeIVK and the Cys thiol group is
shorter when CeIVK is complexed to Cys than when it is
complexed to GSH, where the peptide coordination to CeIVK
also happens via the terminal carboxylate group of the Gly
residue. The presence of two coordination modes in the
GSH−CeIVK complex would require a reorganization prior to
the electron transfer step, thus slowing the redox reaction.
Aromatic Amino Acids. The 13C NMR spectroscopy of a
CeIVK and Trp equimolar mixture showed only small changes
in chemical shift values, indicating that the interactions
between Trp and CeIVK are likely electrostatic in nature.
The planar and rather bulky nature of the tryptophan indole
ring might prevent an effective interaction between the Ce ions
and the carboxylate group. In addition, a repulsion between the
negatively charged POM surface and the π cloud of aromatic
groups could also prevent the direct coordination of NH3+ and
COO− groups of Trp to CeIV metal. However, the slightly
higher 13C chemical shift value detected for C2 could be an
indication for an interaction occurring at the N indole atom,
most likely in the form of a hydrogen bond between NH
indole and a POM surface oxygen.73−75 To further probe the
electrostatic component of the interactions and its effect on the
redox reaction, we carried out control experiments using N-,
O-, and N,O-protected tryptophan derivatives (YHN-Trp-
COX), so that amino or carboxylate groups were blocked. 31P
NMR spectroscopy indicated that a very low percentage (16%)
of CeIVK was reduced when it was incubated with Boc-Trp-
OMe at 60 °C for 2 days, while incubation with H-Trp-OMe
or Boc-Trp-OH resulted in 86% and 99% reduction of CeIVK,
respectively (Figure S5). It is worth noting that the reaction
mixtures were homogeneous at 60 °C. These results indicate
that even 13C NMR spectroscopy indicated a weak interaction
between CeIVK and amino and carboxylate groups of Trp;
these groups are essential for the reaction between CeIVK and
amino acids and for the subsequent reduction of CeIVK to
CeIIIK. These results could also indicate that H-bonding
interactions might play a key role in this reactivity.
Figure 7. Difference in structures between (a) CeIVK,
[CeIV(PW11O39)2]10− and (b) CeIVWD, [CeIV(α2-P2W17O61)2]16−
.
The CeIV/III metal is represented by a purple ball. W groups are
represented by brown octahedra, oxygen is represented by red balls,
and the internal PO4 groups are represented by gold tetrahedra.
potential from +1.44 V vs NHE to +0.88 and +0.78 V vs NHE,
respectively (Table S11).59,68 Strikingly, the small 0.10 V
difference in the redox potential of CeIVK and CeIVWD
resulted in a large difference in the rate of the redox reaction
for both Cys and aromatic amino acids. The reduction of
CeIVK was at least 1 order of magnitude faster in comparison
to CeIVWD (Table 2), in accordance with the higher redox
Table 2. Rate Constants and t0.5 Values for the Reduction of
2 mM CeIVK/WD with 2 mM Amino Acids at pD 7.4 and
Room Temperature
CeIVK
CeIVWD
t0.5 (day)
5.5
19
9.5
amino acid
kobs
t0.5 (h)
kobs
a
a
Cys
Tyr
Trp
35
1
1
29
13
0.2
a
a
0.07
0.05
b
b
0.9
a
b
In units of 10−3 mM−1 min−1. In units of 10−3 min−1.
potential of CeIVK in comparison to CeIVWD. In addition to
the redox potential, other factors such as the different charges
and steric hindrances of CeIVK and CeIVWD may also account
for the observed difference in reactivity.
Interactions of CeIVK with Amino Acids and Peptides.
The reduction of CeIVK to CeIIIK observed in the presence of
amino acids suggests that they interact in solution. These
interactions were investigated using NMR spectroscopy69 to
1
follow the changes in H and/or 13C NMR chemical shifts
(Δδ) of amino acids in the presence of CeIV/IIIK. Generally,
CONCLUSION
■
1
only small changes were observed in the H NMR spectra of
In summary, a detailed account of the redox behavior of CeIV-
POMs toward amino acids and peptides has been described.
The reduction of CeIV-POMs to CeIII-POMs was observed in
the presence of cysteine and aromatic amino acids (relative
rates: Cys ≫ Trp > Tyr > Phe ≈ His). Interestingly, only Cys
afforded a new product (cystine), while no oxidation products
were detected for the aromatic amino acids, suggesting that the
reaction medium plays a role in the reaction mechanism. In all
cases, an increase in pD, temperature, and ionic strength
resulted in a faster redox reaction. Moreover, the incorporation
amino acids in the presence of CeIVK, while 13C NMR spectra
provided more information regarding the possible mode of
interaction, although multiple variables may affect the binding
and consequently the chemical shifts, such as the dynamic
nature of the complex formed between different amino acids
and CeIV-POMs, the presence of radical species, and the
presence of the paramagnetic CeIIIK complex.
1
Cysteine and GSH. H and 13C NMR chemical shift values
of Cys (Table S12) indicate its coordination with CeIV ion,
F
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of redox-active amino acids into peptides led to changes in the
redox reaction kinetics but provided a similar reactivity pattern.
It is worth noting that no hydrolysis of peptides was observed,
indicating the redox reaction is favored over the hydrolytic
pathway. Changing the POM scaffold from Keggin to Wells−
Dawson largely inhibited the reduction of the CeIV center,
showcasing the potential to tune CeIV redox activity and
opening a fertile niche to explore both the redox and Lewis
acidic activity of CeIV-POMs. Finally, amino acids and peptides
interacted with the CeIV-POM mainly through direct
coordination to the Ce ion, electrostatic interactions, and/or
hydrogen bonding depending on the nature of the amino acid.
In general, free carboxylate and amino groups of the amino
acids were crucial for an effective reduction of CeIV-POM.
Together, these results provide important insights into the
redox activity of Ce-POMs toward amino acids and peptides.
Further studies to tune this redox activity and further develop
Ce-POMs potential as artificial proteases are ongoing in our
laboratory and will be reported in due course.
ACKNOWLEDGMENTS
■
We thank the Research Foundation Flanders (FWO) and KU
Leuven for generous funding supporting this research.
S.A.M.A. and L.V. also thank the FWO for Ph.D. fellowships.
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ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.inorgchem.0c00993.
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AUTHOR INFORMATION
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Corresponding Author
(14) Pope, M. T.; Muller, A. Polyoxometalate Chemistry From
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Tatjana N. Parac-Vogt − KU Leuven, Department of
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Authors
Shorok A. M. Abdelhameed − KU Leuven, Department of
Chemistry, 3001 Leuven, Belgium
Laurens Vandebroek − KU Leuven, Department of Chemistry,
3001 Leuven, Belgium
Francisco de Azambuja − KU Leuven, Department of
Chemistry, 3001 Leuven, Belgium
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.inorgchem.0c00993
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Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
(20) Qasim, H. M.; Ayass, W. W.; Donfack, P.; Mougharbel, A. S.;
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Bhattacharya, S.; Nisar, T.; Balster, T.; Sole-Daura, A.; Romer, I.;
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Notes
The authors declare no competing financial interest.
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