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Article history: Catalases are ubiquitous enzymes that prevent cell oxidative damage by degrading hydrogen peroxide to
Available online 10 April 2012 water and oxygen (2H2O2 ? 2H2O + O2) with high efficiency. The enzyme is first oxidized to a high-valent
iron intermediate, known as Compound I (Cpd I, Por+–FeIV=O) which, at difference from other hydroper-
Keywords: oxidases, is reduced back to the resting state by further reacting with H2O2. The normal catalase activity
Ab initio molecular dynamics is reduced if Cpd I is consumed in a competing side reaction, forming a species named Cpd I⁄. In recent
Density Functional Theory years, Density Functional Theory (DFT) methods have unraveled the electronic configuration of these
Hydroperoxidases
high-valent iron species, helping to assign the intermediates trapped in the crystal structures of oxidized
Catalases
Peroxidases
catalases. It has been demonstrated that the a priori assumption that the H+/H type of mechanism for
Enzyme catalysis Cpd I reduction leads to the generation of singlet oxygen is not justified. Moreover, it has been shown
by ab initio metadynamics simulations that two pathways are operative for Cpd I reduction: a His-med-
iated mechanism (described as H/H+ + e) in which the distal His acts as an acid–base catalyst and a
direct mechanism (described as H/H) in which the distal His does not play a direct role. Independently
of the mechanism, the reaction proceeds by two one-electron transfers rather than one two-electron
transfer, as previously assumed. Electron transfer to Cpd I, regardless of whether the electron is exoge-
nous or endogenous, facilitates protonation of the oxoferryl group, to the point that formation of Cpd
I⁄ may be controlled by the easiness of protonation of reduced Cpd I.
Ó 2012 Elsevier Inc. All rights reserved.
0003-9861/$ - see front matter Ó 2012 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.abb.2012.04.004
122 M. Alfonso-Prieto et al. / Archives of Biochemistry and Biophysics 525 (2012) 121–130
(a) (b)
Ser 95
His56 Asn129 Ser 103
O Asn137
water III II His64 O
O N N IV I
water O N N
Fe
heme b Fe
N N
heme d N N
IV I
III II
O
O
O HO
Tyr339 Arg335 O heme bb
heme heme d
heme d
Tyr351 Arg347
Fig. 1. (a) Structure of native Helicobacter pylori catalase (HPC, PDB entry 2IQF). Top: Cartoon picture of the protein, with the four subunits colored in blue, red, yellow and
green, respectively. Bottom: Heme binding pocket of one of the subunits (blue) and molecular structure of heme b. (b) Same representation for Penicillium vitale catalase (PVC,
PDB entry 2IUF) and molecular structure of heme d. Reprinted with permission from reference [5]. Copyright 2009 American Chemical Society.
Cpd I is characterized to be an oxoferryl porphyrin cation radi- Although the main activity of catalases is the decomposition of
cal (Por+–FeIV=O), [7] and it is formed not only in catalases but also H2O2, under certain conditions catalases can undergo undesired
by other heme proteins, such as peroxidases or cytochrome P450. side reactions that can eventually inactivate the enzyme. For in-
The subsequent Cpd I reactivity is determined by the protein frame stance, at low hydrogen peroxide concentrations and in the pres-
in which the heme is buried and research aimed to grasp the origin ence of certain organic substrates (AH, e.g. phenols), Cpd I can
of this functional diversity is an extremely active field [8–10]. undergo a one-electron reduction to form Compound II (Cpd II).
Kinetics studies [11] have shown that once catalase Cpd I forms
(Reaction (1)) [12], it rapidly reacts with another molecule of H2O2 Cpd IðPorþ —FeIV ¼ OÞ þ AH ! Cpd IIðPor—FeIV —OHÞ þ A ð3Þ
to generate a water molecule and O2 (Reaction (2)). Isotope label-
Similarly, when no substrate (electron donor) is present, the
ing studies demonstrated that both oxygen atoms of the O2 mole-
highly reactive Cpd I can oxidize a residue of the protein (aa), typ-
cule originate from the same H2O2 molecule [13,14].
ically Tyr or Trp, forming another intermediate named Compound
I⁄.
Cpd IðPorþ —FeIV ¼ OÞ þ H2 O2 ! EnzðPor—FeIII Þ þ H2 O þ O2 ð2Þ
Reaction (2), extremely efficient in catalases, occurs at a much Cpd IðPorþ —FeIV ¼ OÞ þ Hþ þ aa
slower pace in a few other heme enzymes (e.g. chloroperoxidase
! Cpd I ðPor—FeIV —OH þ aaðþÞ Þ ð4Þ
(CPO), catalase–peroxidase (KatG) and myoglobin (Mb)) [15]. The
⁄
origin of this disparity has long been sought and, even though The formation of Cpd I can be detected by a change in the UV–
the catalase reaction has been known since 1940s [16] (see also visible spectrum (from a green to a red colored intermediate) [16]
the contribution by P. Nicholls in this issue), the detailed mecha- and in the EPR signature (from a porphyrin radical to a protein rad-
nism of Cpd I reduction by H2O2 remained a challenge until re- ical, aa(+) in Eq. (4)) [17]. Structurally, Cpd I⁄ typically contains an
cently [5]. Reaction (2) is a two-electron redox process (i.e. a hydroxoferryl porphyrin with a protein radical instead of the oxo-
single H2O2 molecule provides the two electrons needed to reduce ferryl porphyrin cation radical of Cpd I. In catalases, formation of
Cpd I back to the resting state) and clarifying whether the two elec- Cpd I⁄ is a side reaction that consumes Cpd I, decreasing the effi-
trons are actually transferred together in a single elementary step ciency of the decomposition of hydrogen peroxide. Therefore, one
would pose catalases in clear contrast with peroxidases, for which would like to understand the factors that drive Cpd I⁄ formation
the resting state is recovered through two consecutive one-elec- in order to find strategies to minimize this undesirable side reac-
tron reduction processes, each requiring one molecule of an organ- tion and design more efficient catalases to be used in biosensors
ic donor [12]. and bioreactors. Interestingly, it has been observed that Cpd I⁄
M. Alfonso-Prieto et al. / Archives of Biochemistry and Biophysics 525 (2012) 121–130 123
Table 1
Reported crystal structures of the oxidized intermediates of catalases.
Protein PDB accession No. Type of heme Resolution (Å) Fe–O length (Å) Reference
a
PMC [1MQF] Heme b 2.5 1.76 [80]
MLC [1GWF] Heme b 2.0 1.87 [81]
HPC [2IQF] Heme b 1.8 1.80/1.85b [4]
PVC [2IUF] Heme d 1.7 1.72/1.72b [4]
a
This distance is intermediate between a Fe=O double bond and a Fe–OH single bond. Unfortunately, the low resolution of 2.5 Å and use of restraints precludes drawing
firm conclusions on the nature of the Fe–O bond.
b
Values corresponding to the two independent protein subunits.
Table 2
Fe–O distance (in Å) for the possible oxidized intermediates of HPC and PVC.
Fig. 3. Computed spin distributions of Cpd I (Por+–FeIV=O) for HPC (left) and PVC (right). Adapted with permission from reference [4]. Copyright 2007 American Chemical
Society.
as reflected in the A2u symmetry of the spin density distribution on one contributes to the change of oxidation state of the iron atom
the porphyrin (Fig. 3a). The loss of ring aromaticity of the porphy- (from FeIV to FeIII). The transfer of two electrons from H2O2 is asso-
rin in PVC affects mainly the a1u porphyrin orbital which has con- ciated with the transfer of two protons, forming O2 (the details of
tributions from the pyrrole b carbon atoms. As a consequence, the the reaction pathway are presented in the next section). Neverthe-
energy of the a1u orbital increases relative to the a2u orbital and the less, for some time it was unclear whether H2O2 loses the two elec-
second oxidation equivalent during Cpd I formation in PVC is taken trons as H/H+ (transfer of a hydride ion and a proton), H/H
from the a1u orbital. Unlike a2u, this orbital can mix with one p (double transfer of one hydrogen atom) or other mechanisms. It
imidazole orbital and, therefore, the oxidation equivalent from was early proposed by Fita and Rossmann [45], and recently sup-
the porphyrin of heme d in PVC is removed from a mixed orbital ported by Watanabe et al. [46], that the distal His is also involved
(a1u–pHis), as reflected in the spin density distribution (Fig. 3b). in the catalatic reaction. In view of the known ability of histidines
In summary, the calculations support that oxidized PVC con- to mediate the transfer of protons, a H/H+ scheme was assumed,
tains the typical oxoferryl bond and porphyrin radical (with the in which H is transferred directly to the oxoferryl unit and the
particularity that the radical is partially delocalized on the distal transfer of H+ is mediated by the distal His (Fig. 5).
His) while oxidized HPC contains a hydroxoferryl bond and a pro- One aspect of the catalase reaction that has generated certain
tein radical. The particular electron distribution of PVC Cpd I may controversy is the spin state of the oxygen molecule released in
be probed by EPR experiments. the reaction. Based on spin conservation arguments, some authors
[47–50] have suggested that the H/H+ mechanism proposed in the
Electronic state of the oxygen released by catalase: triplet or literature generates singlet oxygen,
singlet?
H2 O2 ðS ¼ 0; "#Þ ! Hþ ðS ¼ 0Þ þ H ðS ¼ 0; "#Þ þ 1 O2 ðS ¼ 0; "#Þ ð5Þ
As shown in Reaction (2) (hereafter referred to as the catalatic where S is the spin quantum number, " represent the a spin (spin-
reaction), H2O2 serves as a two-electron reductant in the catalatic up electron) and ; the b spin (spin-down electron). In contrast,
reaction (i.e. Cpd I reduction by H2O2 back to the resting state). For- simultaneous uptake of two hydrogen atoms from H2O2 (i.e. a H/
mally, one electron reduces the porphyrin radical, and the other H mechanism) would generate triplet oxygen:
M. Alfonso-Prieto et al. / Archives of Biochemistry and Biophysics 525 (2012) 121–130 125
Fig. 4. Changes on the relative energy of the a1u and a2u orbitals of the oxoferryl porphyrin species as a result of the heme modification (indicated by an arrow) and possible
mixing with other orbitals (pTyr and pHis).
Fig. 6. Possible electronic configurations of the reactants (R, i.e. Cpd I + H2O2) and products (P, i.e. Por–FeIII + H2O + O2) of the catalatic reaction in monofuntional catalases.
The number in the left upper side (2, 4, 6 or 8, i.e. doublet, quartet, sextet and octuplet) denotes the spin multiplicity and the letter in the right lower side (a, b or c) indicates
the different electronic configurations compatible with the overall spin multiplicity. The a spin (spin-up electron) is represented by " and the b spin (spin-down electron) by ;
.
Poulos and Kraut [64], the distal His acts as an acid–base catalyst. as in the F43H/H64L Mb mutant, involves the transfer of a hydride
In addition, the calculations show that a water molecule is essen- ion from H2O2 to Cpd I and the transfer of a proton mediated by the
tial for the reaction to proceed with a low barrier [61,63]. It is ex- distal His (Fig. 7a, hereafter named as the His-mediated mecha-
pected that the same mechanism is operative in catalases, although nism). This mechanism thus follows the Fita–Rossmann model
without the participation of water, as the catalase active site is not [45], with the distal His acting as an acid–base catalyst. Besides,
solvent exposed [2]. for certain Mb mutants lacking a distal residue that could act as
Although there had been preliminary suggestions from kinetic acid–base catalyst, an alternative mechanism was proposed
data [54], Cpd I reduction was first considered at a molecular level [46,65], in which two hydrogen atoms of H2O2 are directly trans-
in 1985 by Fita and Rossmann [45]. On the basis of the crystal ferred to the oxoferryl group (Fig. 7b, from now on referred to as
structure of beef liver catalase, Fita and Rossmann proposed that the direct mechanism).
the two hydrogens of H2O2 are sequentially transferred to the oxo- As a follow-up to our experimental and computational study of
ferryl unit of Cpd I, with the distal His playing an active role in the HPC and PVC Cpd I [4], we recently applied QM/MM metadynamics
reaction. Nevertheless, the precise mechanism how the two pro- simulations to investigate the reduction of Cpd I in catalase. The
tons and two electrons of H2O2 are transferred to Cpd I was not dis- calculations show that the H2O2 spontaneously transfers one
cussed. Recently, the group of Watanabe, by means of a detailed hydrogen atom to the oxoferryl of Cpd I, forming a Cpd II-like spe-
kinetic study, was able to disentangle the rate constants of Cpd I cies. To complete the reaction, two mechanisms may be operative:
formation and reduction for Micrococcus lysodeikticus catalase a His-mediated or a direct mechanism. The former involves the dis-
(MLC) and a series of Mb mutants [46,65]. Two different kinetic tal His as an acid–base catalyst, mediating the transfer of a proton
behaviors were observed in H2O and D2O for Reaction (2), which associated with an electron transfer (pathway A in Fig. 8). By con-
were interpreted as two different mechanisms. Namely, it was pro- trast, a hydrogen atom transfer occurs in the direct mechanism
posed that the reduction of Cpd I by H2O2 in native catalase, as well (pathway B). Therefore, the catalatic reaction may take place by
M. Alfonso-Prieto et al. / Archives of Biochemistry and Biophysics 525 (2012) 121–130 127
(a)
H H H
N N N
HOOH O2 O2
N NH N
H H H
O O O
(b) H H H
N N N
HOOH HOO O2
N N N
H H H
O O O
Fig. 7. (a) The His-mediated mechanism of Cpd I reduction (Fita–Rossmann) (b) The direct mechanism (Watanabe).
two different mechanisms, which can be described as H/ET + H+ been suggested to be the main catalase mechanism for Cpd I reduc-
(A) or H/H (B), respectively (ET = electron transfer). Independently tion in cells with low H2O2 concentrations [71,72]. Under these
of the mechanism, the reaction proceeds by two one-electron conditions, Cpd I reduction by hydrogen peroxide is slow and the
transfers, rather than one two-electron transfer, as has long been alternative reduction by protein residues could avoid a prolonged
assumed. It is also worth noting that the steps with the highest en- or frustrated Cpd I state that would result in an irreversible inacti-
ergy barrier along each pathway (steps identified by an asterisk in vation of the enzyme. Besides, in peroxidases, it has been proposed
Fig. 8) do not correspond to hydrogen atom transfer processes, but that Cpd I⁄ is an alternative reactive intermediate in the oxidation
rather to changes of the hydrogen bond pattern. This is consistent of bulky substrates that cannot access the heme active site
with the small kinetic isotope effect (KIE) determined for catalase [16,18,19]. Therefore, understanding the factors leading to radical
[46]. Interestingly, the distal Asn changes conformation gradually migration could help to engineer new catalytically competent pro-
(from the Cpd II-like configuration to the products), allowing the tein radical sites for the oxidation of substrates that cannot be oxi-
release of the product oxygen toward the main channel. Finally, dized at the heme active site [19].
our results also confirmed that the oxygen molecule released by By combining QM/MM calculations, UV–visible spectroscopy
catalase is in the triplet state [5]. and X-ray crystallography, we previously suggested that HPC
Additional calculations on an in silico mutant of the distal histi- forms a protein radical, in contrast to PVC, where the radical re-
dine (H56G) for HPC show that the hydrogen-bond network at the mains on the heme [4]. The different type of intermediate that is
distal site plays a key role in positioning the peroxide such that the formed (Cpd I⁄ for HPC and Cpd I for PVC) could be related to the
reaction can proceed with a low barrier. For the H56G HPC mutant, type of heme present, heme b in HPC and heme d in PVC (Fig. 1).
the first hydrogen atom transfer becomes rate-limiting, explaining However, other heme b catalases different from HPC do form
the large KIE observed for the Mb mutants lacking the distal His canonical Cpd I upon PAA oxidation [26,27]. Therefore, other fac-
[46,65]. Therefore, in line with previous investigations [15,66], tors different than the type of heme are likely to influence radical
Cpd I reactivity depends on the shape and the nature of the distal migration in catalases. A possible influencing factor is the pH. For
pocket (i.e. the interactions between H2O2 and the distal residues). instance, EPR, UV–visible and Resonance Raman experiments have
shown that the heme b-containing bovine liver catalase (BLC)
Formation of Cpd I⁄ yields a tyrosyl radical at acidic pH [17,26,73], but a short-lived
Cpd I at basic pH [74,75]. Another factor may be the availability
As mentioned before, in the absence of either hydrogen perox- of electron-donating residues close to the heme b. E.g. wild-type
ide or external electron donors, an endogenous protein residue Proteus mirabilis catalase (PMC) forms a stable Cpd I upon PAA
(aa), usually Tyr or Trp, can reduce Cpd I (Reaction (4)). This intra- treatment, whereas its F194Y mutant forms a tyrosyl radical.
molecular electron transfer, often referred to as ‘‘migration of the Knowledge of the reduction potentials of the catalase Cpd I
porphyrin radical into the protein’’, is normally concomitant with intermediates of HPC and PVC would help to clarify why heme d
protonation of the oxoferryl bond [4,36–38,67]. In fact, radical catalases behave different from heme b catalases. Unfortunately,
migration in catalases [4] and other heme proteins [34,35] corre- these are not available in an experiment due to the short lifetime
lates with the observation of a lengthening of the Fe–O distance of the catalase redox intermediates. Computational methods,
(from 1.6–1.7 Å to 1.8–1.9 Å), indicative of a change from oxoferryl, where the redox state is controlled, can provide insight into this is-
Fe=O, to hydroxoferryl, Fe–OH. The most likely proton donor was sue. To this aim, we recently investigated the easiness of reduction
identified in reference [4] to be the (protonated) distal His. of HPC compared to PVC Cpd I [6]. In particular, we determined the
Whereas for some heme proteins (e.g. in CcP [34], KatG [35] or free energy of one-electron reduction of Cpd I (by means of the en-
lactoperoxidase [68]), formation of a protein radical (i.e. Cpd I⁄) is ergy gap method [76–78] based on Marcus theory [79] for electron
necessary for mediating the electron transfer between the heme transfer reactions), as well as the free energy of protonation of re-
and the substrate, radical migration in catalases [17,69] and P450 duced Cpd I (using metadynamics [22,23]) of both catalases. We
[70] is considered an undesirable side reaction that competes with found that the difference in free energy for pure one-electron
the main activity of the enzyme. Nevertheless, Reaction (4) has reduction of Cpd I (‘‘pure’’ means without coupled proton transfer)
128 M. Alfonso-Prieto et al. / Archives of Biochemistry and Biophysics 525 (2012) 121–130
is indeed very small and unlikely to be the reason for the different driven’’ by proton transfer to the oxoferryl. This prediction may
redox behavior of HPC and PVC. However, the subsequent proton be probed by performing EPR experiments at different pHs and
transfer step from the distal histidine residue to the ferryl oxygen the location of the tyrosyl radical confirmed by combining EPR with
is much more exothermic for HPC compared to PVC (see Fig. 9). This ENDOR and mutagenesis studies. In summary, our results indicate
larger free energy released by proton transfer in HPC is enough to that the major driving force for radical migration is the proton
compensate for the energy cost of removing an electron from the transfer to reduced Cpd I, supporting the former suggestion that
protein residue (most likely a tyrosine), as opposed to PVC. Accord- HPC forms a protein radical as opposed to PVC. Moreover, we ratio-
ingly, protein radical migration in HPC is ‘‘thermodynamically nalized the different basicity of the ferryl oxygen in the two
M. Alfonso-Prieto et al. / Archives of Biochemistry and Biophysics 525 (2012) 121–130 129
Fig. 9. Proton transfer from the distal histidine to the oxyferryl in one-electron reduced Cpd I (i.e. Cpd II). For HPC, the Fe–OH form is more stable by 15 kcal/mol, whereas the
energy gain is much smaller (4.5 kcal/mol) for PVC. Adapted with permission from reference [6]. Copyright 2011 American Chemical Society.
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