A supramolecular bifunctional artificial enzyme with superoxide dismutase and glutathione peroxidase activities

Article abstract of DOI:10.1016/j.bioorg.2010.03.001

For constructing a bifunctional antioxidative enzyme with both superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities, a supramolecular artificial enzyme was successfully constructed by the self-assembly of the Mn(III)meso-tetra[1-(1-adamantyl methyl ketone)-4-pyridyl] porphyrin (MnTPyP-M-Ad) and cyclodextrin-based telluronic acid (2-CD-TeO₃H) through host-guest interaction in aqueous solution. The self-assembly of the adamantyl moieties of Mn(III) porphyrin and the β-CD cavities of 2-CD-TeO₃H was demonstrated by the NMR spectra. In this supramolecular enzyme model, the Mn(III) porphyrin center acted as an efficient active site of SOD and tellurol moiety endowed GPx activity. The SOD-like activity (IC₅₀) of the new catalyst was found to be 0.116 μM and equals to 2.56% of the activity of the native SOD. Besides this, supramolecular enzyme model also showed a high GPx activity, and a remarkable rate enhancement of 27-fold compared to the well-known GPx mimic ebselen was observed. More importantly, the supramolecular artificial enzyme showed good thermal stability.

Full text of DOI:10.1016/j.bioorg.2010.03.001

Bioorganic Chemistry 38 (2010) 159–164
Contents lists available at ScienceDirect
Bioorganic Chemistry
journal homepage: www.elsevier.com/locate/bioorg
A supramolecular bifunctional artificial enzyme with superoxide dismutase
and glutathione peroxidase activities
Shuangjiang Yu, Xin Huang, Lu Miao, Junyan Zhu, Yanzhen Yin, Quan Luo, Jiayu Xu, Jiacong Shen,
Junqiu Liu *
State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun 130012, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 February 2010
Available online 11 March 2010
For constructing a bifunctional antioxidative enzyme with both superoxide dismutase (SOD) and gluta-
thione peroxidase (GPx) activities, a supramolecular artificial enzyme was successfully constructed by
the self-assembly of the Mn(III)meso-tetra[1-(1-adamantyl methyl ketone)-4-pyridyl] porphyrin
(
MnTPyP-M-Ad) and cyclodextrin-based telluronic acid (2-CD-TeO
in aqueous solution. The self-assembly of the adamantyl moieties of Mn(III) porphyrin and the b-CD cav-
ities of 2-CD-TeO H was demonstrated by the NMR spectra. In this supramolecular enzyme model, the
Mn(III) porphyrin center acted as an efficient active site of SOD and tellurol moiety endowed GPx activity.
The SOD-like activity (IC50) of the new catalyst was found to be 0.116 M and equals to 2.56% of the activ-
3
H) through host–guest interaction
Keywords:
Porphyrin
Cyclodextrin
Self-assembly
Superoxide dismutase
Glutathione peroxidase
3
l
ity of the native SOD. Besides this, supramolecular enzyme model also showed a high GPx activity, and a
remarkable rate enhancement of 27-fold compared to the well-known GPx mimic ebselen was observed.
More importantly, the supramolecular artificial enzyme showed good thermal stability.
Ó 2010 Elsevier Inc. All rights reserved.
1
. Introduction
Although native antioxidant enzymes are extremely efficient for
defensing against oxidative stress, effective therapies utilizing na-
It has been established that a variety of human diseases have
been generated by oxidative stress of reactive oxygen species
ROS), such as superoxide anion, H , organic peroxide, and hy-
tive antioxidant enzymes may be problematic due to concerns
with protein instability, short circulation half-lives, high produc-
tion costs, and potential antigenicity [11], leading to the develop-
ment of various antioxidant mimetics.
(
2 2
O
droxyl radical. ROS were generated as byproducts of cellular
metabolism and were mainly controlled by antioxidative defense
system, especially by antioxidant enzymes [1,2]. In biological
organism, the antioxidant enzymes, superoxide dismutase (SOD),
catalase (CAT), and glutathione peroxidase (GPx) contribute domi-
natingly to enhance cellular antioxidative defense against oxida-
tive stress [3–7]. SOD is a metalloenzyme that catalyzes the
In recent years, there were considerable interests in preparing
the enzyme mimics with the properties of SOD or GPx for elucidat-
ing catalytic mechanism and for potential pharmaceutical applica-
tion [12,13]. In order to further study the cooperation of these
enzymes in antioxidation and to generate efficient therapeutic
agents, bifunctional enzymes with both SOD and GPx activities
have been constructed by chemical methods in our group and oth-
ers. For example, a bifunctional enzyme with SOD and CAT activi-
ties was prepared by cross-linking of SOD and CAT [14]. The
bifunctional enzymes with both SOD and GPx activities have been
designed by using chemical synthesis and mutation of native SOD
[15,16]. However, successful construction of a bifunctional enzyme
which has both SOD and GPx activities by using a supramolecular
method remains a challenge.
Porphyrins are ‘the pigments of life’ [17]. Due to their high stabil-
ity and chemical versatility, manganese porphyrins are a promising
group of compounds for developing as SOD mimics [18]. Since the
earliest report of SOD activity by a manganese porphyrin complex
by Pasternack and co-workers with the tetrakis (4-N-methylpyr-
idyl)porphine complex of Mn(III) [19], the Mn(III) (porphyrinato)
complexes have been studied by several groups as SOD mimics
ꢀ
:
dismutation of superoxide radical anion ðO Þ to H
2 2 2
O and O .
2
And GPx, a selenium-containing enzyme, functions to catalyze
2 2
the reduction of H O and other harmful hydroperoxides by gluta-
thione (GSH) (Scheme 1) [8,9]. Studies indicated that each enzyme
has a specific as well as an irreplaceable function and they act in a
cooperative or synergistic way to ensure a global cell protection. It
seems that there is a balance between both the activities and the
intracellular levels of these antioxidants that are essential for the
survival of organisms and their health. This balance was proved
to be more important for protection against oxidative stress than
the level of any single antioxidant enzyme [10].
*
Corresponding author.
E-mail address: junqiuliu@jlu.edu.cn (J. Liu).
0
045-2068/$ - see front matter Ó 2010 Elsevier Inc. All rights reserved.
doi:10.1016/j.bioorg.2010.03.001

1
60
S. Yu et al. / Bioorganic Chemistry 38 (2010) 159–164
2
. Experimental
2.1. Materials
Dimethylbenzene, ethanol, chloroform were purchased from
Beijing Chemical Plant. Pyrrole was acquired from Fluka (AR
grade). 4-pyridinecarboxaldehyde was purchased from J&K Chem-
ical LTD and used without further purification. 1-adamantyl bro-
momethyl ketone, xanthine oxidase (XOD) and xanthine were
purchased from Aldrich Chemical Co. Ammonium hexafluorophos-
phate (NH
4 6
PF ) was obtained from Alfa. Tetrabutylammonium
chloride (TBAC) was purchased from Tianjinguangfu Chemical
Plant and was used without further purification. b-cyclodextrin
Scheme 1. Catalytic reactions of cooperative action of SOD and GPx.
(
b-CD) was purchased from Tianjin Chemical Plant, and recrystal-
lized three times from distilled water and dried for 12 h at
20 °C in vacuo. DMF was dried by distilling from CaH under
1
2
and were reported to be 0.2–12% of the native SOD activity. The
Mn(III) (porphyrinato) complexes have clearly been shown to pos-
sess true catalytic and biologic function of SOD mimic by many
researchers [12].
the reduced pressure. Column chromatography was performed
on silica gel (200–300 mesh) or Sephadex G-25.
2.2. Instruments and measurements
b-Cyclodextrin is a cyclic compound consisting of seven glucose
units, it is water-soluble and nontoxic. Therefore, it can be used in
the human body, such as drug delivery systems [20]. On the other
hand, it is known to form inclusion complexes with various low-
molecular-weight compounds, ranging from nonpolar aliphatic
molecules to polar amines and acids [21]. Thus, it has been used
to construct various supramolecular architectures through host–
guest interaction [22,23]. For b-cyclodextrin and adamantane
derivatives, a typical host–guest pair have induced a lot of interest-
ing development of supramolecular systems for their high associa-
tion constant [24–26]. Herein, utilizing a ‘supramolecular linker’
which constructed through the host–guest interaction between
adamantane and b-cyclodextrin, a bifunctional artificial enzyme
with a porphyrin core and four cyclodextrin-based suspensory tell-
urol moieties has been designed and prepared. The Mn(III) porphy-
rin acted as an efficient active site of SOD, and tellurol moiety
endowed GPx activity. The catalytic behaviors and the kinetics of
the bifunctional enzyme model with both SOD and GPx activities
were investigated in detail.
1H NMR was measured on a Bruker AM-500 spectrometer. The
spectrometric measurements were carried out with a Shimadzu
100 UV–Vis-NIR Recording Spectrophotometer interfaced with a
personal computer. Data were acquired and analyzed by using
ultraviolet spectroscopy software. The temperature for UV time
course studies was controlled within (±) 0.5 °C by use of a LAUDA
compact low-temperature thermostat RC6 CP. The buffer pH values
were determined with a METTLER TOLEDO 320 pH Meter. Molecu-
lar weights of the compounds were measured on an APPLIED BIO-
SYSTEMS Q TRAP.
3
2
2
.3. Synthesis
.3.1. Synthesis of MnTPyP-M-Ad (Scheme 2a)
Meso-tetra(4-pyridyl)porphine (TPyP) was prepared by the lit-
erature methods [27–29]. Synthesis of meso-tetra[1-(1-adamantyl
methyl ketone)-4-pyridyl] porphyrin (TPyP-M-Ad) followed the
known procedures as described in the literature with some alter-
3
Scheme 2. Synthetic route for MnTPyP-M-Ad (a) and 2-CD-TeO H (b).

S. Yu et al. / Bioorganic Chemistry 38 (2010) 159–164
161
ation [25,30]. The pyridyl groups in TPyP (203 mg, 0.328 mmol)
were quarternized with 1-adamantyl bromomethyl ketone
solution was freeze-dried, and then the residue was purified on a
column of Sephadex G-25 with distilled water as an eluent. The
(
408 mg, 1.586 mmol) in DMF (40 mL) for 20 h at 100 °C to synthe-
resulting solution was freeze-dried, and a pure sample was ob-
1
size TPyP-M-Ad under a nitrogen atmosphere. After being cooled
to room temperature, the brown precipitate was collected by filtra-
tion and washed with diethyl ether to yield crude product. The
crude product was purified by recrystallization from methanol
and chloroform (1:2) to yield 300 mg of desired product as a brown
tained in 72% yield as a white powder. H NMR (500 MHz, D
2
O):
d = 3.31–4.26 (m, 42H), 4.71–5.14 (m, 7H). MALDI-MS: 1295.6
found: 1296.3.
2.3.3. Preparation of the enzyme model [35]
1
solid. H NMR (500 MHz, DMSO-d6, 25 °C) d = –3.03 (s, 2H, –NH),
An aqueous solution of MnTPyP-M-Ad (0.2 mmol, 5 mL) was
1
.80–1.86 (s, 24H, adamantane), 2.12 (s, 24H, adamantane), 2.18
s, 12H, adamantane), 6.40 (s, 8H, –COCH –), 9.142–9.155 (d,
J = 5.0 Hz, 8H), 9.182 (d, J = 5.0 Hz, 8H) 9.42 (s, 8H). MALDI-MS:
added dropwise to an aqueous solution of 2-CD-TeO
mL), followed by mild ultrasonication for 2 h, giving the inclusion
complex (the enzyme model). Model compounds were prepared
from TPyP-M-Ad (0.2 mmol, 5 mL) and 2-CD-TeO H (0.8 mmol,
mL), according to a similar procedure as described earlier
Scheme 3).
3
H (0.8 mmol,
(
2
5
1
327.7 found: 1327.3 (Fig. S1).
Metallation of TPyP-M-Ad: Metallation of TPyP-M-Ad pro-
3
5
(
ceeded following standard procedures [31]. Briefly, TPyP-M-Ad
100 mg) and MnCl O (200 mg, ꢂ20 ꢃ eq.) were dissolved in
ꢁ4H
methanol/H O (6:1, 35 mL) with 1 M NaOH (200 L) and mixed
(
2
2
2
l
2.3.4. Determination of SOD activity
under refluxing conditions to form MnTPyP-M-Ad. The degree of
metallation was assessed by monitoring the soret band shift from
4
after approx. 30 min. The MnTPyP-M-Ad was then purified, with
the addition of NH
lowed by washing with H
achieved by dissolving the product in acetone and metalloporphy-
rin precipitation upon the addition of TBAC. The final Cl form of
MnTPyP-M-Ad was then desiccated to dryness 12 h. MALDI-MS:
1
Superoxide radical anions generated by the xanthine/xanthine
oxidase system at pH 7.8 (phosphate buffer, 25 °C) were detected
26.5 nm to 463 nm (Fig. 1), with complete metallation observed
by following spectrophotometrically the reduction of nitro blue
+
tetrazelium (NBT) to blue formazane (MF ) [8,36,37]. The appropri-
4
PF
6
to precipitate the metalloporphyrin, fol-
ate amount of xanthine oxidase (final concentration of
ꢀ
2
O. Counterion exchange to Cl was then
ꢀ1
0
.025 U ml ) was added to an aqueous solution of 100
l
M NBT,
3
00 lM xanthine, 0.1 mM EDTA, and 50 mM phosphate buffer (fi-
ꢀ
560
nal volume of 1 mL) to cause a variation of absorbance (DA /
min) of 0.013. The reaction rate in blank samples and in the pres-
ence of model catalyst was measured for 300 s only, in order to
avoid problems coming from the natural inactivation of the enzy-
matic system.
379.7 found: 1377.3.
2
.3.2. Synthesis of 2-CD-TeO
Dicyclodextrinyl ditelluride (2-TeCD) was prepared as de-
scribed previously [33,34]. 2-TeCD (100 mg) was dissolved in
5 mL of deionized water with a large excess amount of H
30%, 150 L) and mixed under stirring condition. The solution
3
H (Scheme 2b) [32]
2.3.5. Determination of GPx activity
1
(
2 2
O
The catalytic activity was assayed according to a modified
method reported by Hilvert et al. [38–41]. The reaction was carried
out at 25 °C in 1.0 mL of phosphate buffer (pH 7.0, 50 mM) contain-
l
was stirred at temperatures between 4 °C over night. The mixture
ing 0.25 lM compounds catalyst and 115 lM ArSH and 250 lM cu-
mene hydroperoxide (CUOOH). The initial rates for the reduction of
CUOOH by were determined by monitoring the disappearance of
–
l
ꢀ1
ArSH at 410 nm (
e410 = 14,500 M cm , pH 7.0) with a Shimadzu
3
100 UV–Vis-NIR spectrophotometer. Appropriate control of the
nonenzymatic reaction was performed and subtracted from the
catalyzed reaction.
Determination of GPx activity by using 4-nitrobenzenethiol
(
ArSH) as a substrate (Eq. 1).
catylst
CUOOH þ 2ArSH ! CUOH þ ArSSAr þ H
2
O
ð1Þ
3
. Results and discussion
3.1. Design and preparation of the artificial enzyme
Fig. 1. Absorbance spectra for porphyrin compounds between 380 and 700 nm. The
concomitant soret band shift was observed from 426.5 nm (TPyP-M-Ad) to 463 nm
b-Cyclodextrin, a type of cyclodextrin with seven glucose units,
can recognize adamantal moiety well (association constant:
(
MnTPyP-M-Ad) upon porphyrin metallation.
Scheme 3. Schematic representation of the preparation of the enzyme model.

1
62
S. Yu et al. / Bioorganic Chemistry 38 (2010) 159–164
03–4
M ), and this typical host–guest pair has been widely uti-
ꢀ1
1
lized to build up supramolecular materials and devices [22,24].
Through the host–guest interaction between adamantane and b-
CD, a bifunctional antioxidant enzyme mimic was constructed by
self-assembly of the MnTPyP-M-Ad and 2-CD-TeO
Scheme 3). In order to confirm the host–guest complexation of
-CD-TeO and the adamantane-containing porphyrin
MnTPyP-M-Ad), model compounds were prepared, and NMR mea-
surements were carried in D O at different temperatures. As shown
in Fig. S2, the ratio between CD’s C –H and methylene protons (c)
3
H in water
(
2
3
H
(
2
1
of adamantly group was 7:6, indicating the formation of a 1:4 com-
plex. Furthermore, the signals of methine and methylene protons
(
a, b, c) of the adamantly group in the supramolecular model shift
downfield with an increase in the concentration of 2-CD-TeO H at
5 °C, 50 °C and 60 °C, respectively (Fig. 2). It revealed that the
3
2
inclusion complexation between adamantal moiety and cyclodex-
trin indeed occurred, and the supramolecular complex showed
very good thermal stability [25].
3
3
.2. Catalytic behavior of the artificial enzyme
.2.1. SOD activity
The SOD activity of the enzyme model was quantified using the
standard xanthine/xanthine oxidase assay system first developed
by McCord and Fridovich [8,36]. Superoxide anion generation by
the xanthine/xanthine oxidase system was detected by following
spectrophotometrically the reduction of nitro blue tetrazelium
+
(
NBT) to blue formazane (MF ) at 560 nm. In order to determine
the concentration of the catalyst which achieves 50% inhibition
IC50) of the reaction (a generally used indicator for comparing
(
the efficiencies of enzymes and enzyme mimics), the percentage
of inhibition against model catalyst concentration was plotted in
Fig. 3, and the concentration of catalyst (IC50) which inhibits the
rate of the reduction of NBT by 50% (IC50) was found to be
0
(
.116
Table 1). However, the SOD activity (IC50) of the guest molecule
MnTPyP-M-Ad was only found to be 0.132 M, and it was lower
than the SOD-like activity of the enzyme model. Neither the me-
tal-free ligand nor 2-CD-TeO H exhibited any SOD-like activity in
subsequent experiments under the same conditions.
lM, it equals to 2.56% of the activity of native SOD enzyme
l
3
3
3
.2.2. GPx activity
.2.2.1. Catalytic activity. To probe the mechanism of tellurium in
catalysis, some of the intermediates possibly involved in the cata-
lytic cycle were characterized. When 2-CD-TeO H was added to
3
ArSH in PBS (pH 7.0), the ArSH quickly disappeared by monitoring
the UV absorbance at 410 nm, and intermediate telluro-sulfide ap-
peared (Fig. 4) [42]. From this observation, it showed that the
Te(VI) of the 2-CD-TeO H could be deoxidized into Te(IV), then
3
joined to the catalytic cycle [32].
The GPx activity of catalyst was studied according to a modified
method reported by Hilvert et al. [38–41], using 4-nitrobenzeneth-
iol (ArSH) as a thiol substrate. The relative activities of the mimics
are summarized in Table 1. For the peroxidase activity, the enzy-
matic rates were corrected for the background (nonenzymic) reac-
tion between hydroperoxide and thiol. The initial rate of the
background (nonenzymic) reaction between CUOOH and ArSH
Fig. 2. 1H NMR spectra of TPyP-M-Ad in 0.059 mM and the complex in 0.059 mM in
O at 25 °C, 50 °C, and 60 °C respectively.
D
2
than
= 9.6
3
shows a little lower than it (Fig. 5). Considering that 2-CD-TeO H
ebselen.
Compared
with
2-CD-TeO
3
H
catalyst
ꢀ1
(m
0
lM min ), the catalytic activity of the model catalyst
was very slow; the compounds catalyst (1
exhibits a remarkable rate enhancement (
l
= 7.1
M catalytic center)
ꢀ1
m
0
lM min ). For
had specific binding cavity for recognizing substrate (ArSH), it is
surprising that the model catalyst in which the cyclodextrin cavi-
ties were taken up by adamantal moieties displayed high catalytic
activity [32]. Compared with other reported GPx mimics, such as
telluromicelle [43], the catalytic activity of the compounds catalyst
is only a little lower than it. According to the former research [42],
electrostatic interaction may possibly play a great contribution to
the high catalytic behavior.
further evaluating the catalytic capacity of the model catalyst, a
well-known GPx mimic, ebselen was used for comparation. Under
identical conditions, a slight enhancement of the reaction rate was
ꢀ1
0
observed when ebselen (1.0 lM) was added (m = 0.26 lM min ).
Assuming that the rate had a first-order dependence on the con-
centration of catalyst catalyzing the reduction of CUOOH by ArSH
(Table 1), the model catalyst was at least 27 times more efficient

S. Yu et al. / Bioorganic Chemistry 38 (2010) 159–164
163
Fig. 5. Plots of absorbance versus time during the catalytic reduction of CUOOH
(185 M) by ArSH (115 M) at pH 7.0 and 25 °C: (a) no catalyst, (b) 1 M MnTPyP-
M-Ad, (c) 1 M ebselen, and (d) 0.25 M model catalyst, (e) 1 M 2-CD-TeO H.
Fig. 3. Percentage of inhibition of NBT reduction by superoxide anion radical versus
different concentrations of compounds catalyst.
l
l
l
l
l
l
3
aver–Burk plots) of initial rate versus substrate concentration
(Fig. 7), indicating that this model is a real GPx mimic.
Table 1
SODa and GPxb activities of the catalyst.
Catalysts
GPx activity
M minꢀ1)
SOD activity
4
. Conclusion
0
v (l
IC50
(lM)
Relactive activity (%)
In this study, we have successfully designed and prepared an
artificial enzyme through host–guest interaction between the ada-
mantyl moieties of Mn(III) porphyrin and the b-CD cavities of 2-
Ebselen
Mn(III)-TPyP-M-Ad
0.26
ND
9.6
7.1
–
ND
0.132
ND
0.116
1.3 ꢃ 10
–
2.25
–
2.56
100
2
3
-CD-TeO H
Model catalyst
Cu, Zn-SODc
ꢀ3
a
SOD activity was carried out in the assaying solution (1 ml), containing 50 mM
phosphate buffer (pH 7.8), 0.025 U xanthine oxidase, 100 M NBT, 300 M xan-
thine, 0.1 mM EDTA, and an appropriate amount of catalyst at 25 °C.
l
l
b
GPx activity was assessed in phosphate buffer (50 mM, pH 7.0) at 25 °C with
ArSH (115 M) and CUOOH (0.185 mM), and was corrected for the spontaneous
l
oxidation in the absence of catalyst.
c
Refs. [8,9,44].
3
.2.2.2. Kinetics. To probe the mechanism of the model catalyst
promoting the peroxidase reaction, detailed kinetic studies were
undertaken. In the presence of the model catalyst (2.0 M catalytic
center) at pH 7.0 (50 mM PBS) and 25 °C, the apparent kinetic
l
ꢀ1
parameters of the catalyst were obtained,
m
(max) = 77.76 lM min ,
ðappÞ
ꢀ1
ðappÞ
k
1
1
= 38.88 min
,
KmCUOOH = 3.56 mM,
k
/KmCUOOH = 1.09 ꢃ
cat
cat
04 Mꢀ1 min
ꢀ1
(the initial concentration of ArSH fixed to
Fig. 6. Plots of initial rates (
presence of a compounds catalyst (2.0
25 °C. The initial concentration of ArSH was fixed to 100
m
0
) at different concentrations of CUOOH in the
M catalytic center) in PBS (pH 7.0) and
M. The concentration of
00
l
M). Typical saturation kinetics was observed in the NBT assay
l
system for the peroxidase-like reaction (Fig. 6). Additionally, a
straight line was obtained via double-reciprocal plots (Linewe-
l
ꢀ
1
CUOOH was 0.37, 0.74, 1.85, 3.7 and 7.4 mM , respectively.
Fig. 7. Lineweaver–Burk plots of the artificial enzyme-catalyzed the reduction of
CUOOH by ArSH (2.0
to 100 M. The concentration of CUOOH was 0.37, 0.74, 1.85, 3.7 and 7.4 mM,
respectively.
lM catalytic center). The initial ArSH concentration was fixed
Fig. 4. UV spectra of ArSH (140
TeO H (curve b).
lM) in water (curve a), and after adding 2-CD-
l
3

1
64
S. Yu et al. / Bioorganic Chemistry 38 (2010) 159–164
CD-TeO
3
H in aqueous solution. This new supramolecular enzyme
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bifunctional antioxidative enzyme mimics, this supramolecular
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