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2009, 113, 9050–9054 Published on Web 06/17/2009
Role of Tyrosine Residue in the Activation of Co-C Bond in Coenzyme B12-Dependent Enzymes: Another Case of Proton-Coupled Electron Transfer? Manoj Kumar and Pawel M. Kozlowski* Department of Chemistry, UniVersity of LouisVille, LouisVille, Kentucky 40292 ReceiVed: April 27, 2009; ReVised Manuscript ReceiVed: June 2, 2009
X-ray structural data along with density functional theory-based computations have been used to probe the role of tyrosine residue in the activation of Co-C bond in adenosylcobalamin (AdoCbl) -dependent enzymes. DFT computations have been carried out for tyrosine being in the immediate vicinity of AdoCbl using the structural mimics of the active sites of methylmalonyl CoA mutase and glutamate mutase enzymes. The calculations indicate the diradical nature of the deprotonated tyrosine-cofactor complex implying the possibility of electron transfer from tyrosine to the AdoCbl. Thus, the tyrosine residue may serve like an internal redox center to transfer an electron to the AdoCbl cofactor that can be critical for the activation of Co-C bond in B12-dependent enzymes. The local environment around the active site reveals that deprotonation of tyrosine motif may take place upon substrate binding, implying the possibility of proton-coupled electron transfer (PCET) in AdoCbl-dependent enzymes. Thus, it is proposed that PCET can have implications in the activation of Co-C bond in AdoCb1-dependent enzymes as the electron transfer from tyrosine to AdoCbl helps remarkably in cleaving the Co-C bond. While various issues connected with enzymatic catalysis involving adenosylcobalamin (AdoCbl) as cofactor remain elusive,1 our knowledge of AdoCbl-dependent enzymes has been vastly improved by the X-ray crystallographic studies.2,3 Closer inspection of crystallographic data reveals a very interesting and an extremely important thread connecting all these enzymes, namely a tyrosine residue (Y) is present in the immediate surrounding of the active site at an approximate distance of ∼7.5 Å with respect to the metal center (see Table 1 and for further details Table S1 in the Supporting Information). On the basis of structural information stored in protein data bank, Figure 1 sketches an overview of the local environment of the active site capturing the location of Y component in different enzymes. The -OH group of Y residue is directed toward the metal center of cofactor, and the projection of Y in most of cases lies in a very specific region around the active site (see Supporting Information, Figure S1-S5). Furthermore, mutation of tyrosine (Y89), for example by phenylalanine (F) in case of methylmalonyl CoA mutase, leads to 103-104 reduction in the enzymatic activity.4 The following important question arises: what can be the role and involvement of Y residue in the possible mechanism of Co-C bond activation accounting for ∼1012 enzymatic rate enhancement? Before turning our attention to this issue, it is important to emphasize that deprotonation of Y residue and its subsequent oxidation leading to the formation of neutral radical, Y f Y- f Y•, constitutes a key step in numerous enzymatic processes.5 The participation of Y• has been confirmed in many enzymes including photosystem II,6 prostaglandin H synthase,7 galactose oxidase,8 cytochrome c oxidase,9 or ribonucleotide * Author to whom correspondence should be addressed. Telephone (502) 852-6609. Fax (502) 852-8149. E-mail:
[email protected].
10.1021/jp903878y CCC: $40.75
TABLE 1: Co · · · O(Y) Distances (Å) in Selected AdoCbl-Dependent Enzymesa enzymesb
Pdb-ID
Tyr-ID
Co · · · O(Y)
ref.
MCM
3REQ 4REQ 1CB7 1CCW 1I9C 1XRS 1DIO 1EEX 1EGM 1IWP 1MMF
Y89, Y243 Y89, Y243 Y181 Y181 Y181 Y193 Y226 Y226 Y226 Y227 Y227
8.71, 8.13 8.08, 6.95 7.54 7.43 7.21 6.95 7.20 7.23 7.19 7.36 7.42
2a 2a 2b 2b 2c 2d 2e 2f 2f 2g 2h
GLM LAM DDH GDH
a Only Y residues lying within a distance of 10 Å, from the metal center (Co) have been considered. b MCM ) Methylmalonyl CoA Mutase; GLM ) Glutamate Mutase; LAM ) Lysine Amino Mutase; DDH ) Diol Dehydratase; GDH ) Glycerol Dehydratase.
reductase.10 In all these enzymes, Y• takes part in biological reactions via proton-coupled electron transfer (PCET), a phenomenon ubiquitous in biological systems and a topic of intense experimental and theoretical scrutiny.11 To investigate the significance of Y being in the immediate vicinity of AdoCbl (Figure 1), we have carried out DFT-based computations using the structural models mimicking the active sites of methylmalonyl CoA mutase (MCM) and glutamate mutase (GLM) enzymes (Table 1), employing 4REQ2a and 1I9C2c-based structures, which contain relatively well-resolved Ado ligand. The models have been constructed, first optimizing the structure of AdoCbl (simplified with respect to the side chains of corrin ring) and then placing the ArOH (an ideal model compound to represent Y moiety) in locations consistent with the available crystallographic information (Figure 1). Both 2009 American Chemical Society
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Figure 1. Close-up of the active site in AdoCbl-dependent enzymes where locations of Y residue relative to cobalt center have been shown. The Figure was generated by superimposing different enzymes listed in Table 1 (see also Supporting Information, Figure S1-S5). As reference, the corrin ligand is shown only for MCM.
neutral and deprotonated phenol (ArO-) were employed in the present theoretical note. We have made use of Becke-Perdew (BP86) functional12 along with 6-31G(d) basis set (see Computational Section for details). This level of theory was found to be appropriate for structural and electronic properties calculations of B12 cofactors.13 DFT calculations have been performed assuming singlet electronic state, consistent with even number of total electrons, while allowing spin polarization between different molecular entities via unrestricted Kohn-Sham formalism. For models containing neutral phenol (ArOH), electronic configuration having spin polarization was not found while in the case of deprotonated residue (phenolate anion, ArO-) spin polarized solution gives the lowest electronic energy. Such spin polarization is indicative of the fact that the electronic configuration needed to describe ArO-/AdoCbl system (Figure 1) may require multiconfigurational wave function. Careful analysis of spin polarized results reveals that the oxidation of phenolate anion takes place and the complex has a diradical character. More precisely, the complex ArO-/AdoCbl is better described as a diradical species, ArO•/[AdoCbl]•-, consistent with an open-shell singlet electronic configuration. Similar calculations have been carried out using hybrid B3LYP functional and results were fully consistent with BP86 based predictions although the values were slightly different (Supporting Information, Table S2). In both types of computations (using BP86 and B3LYP functionals), the diradical character of the complex was further confirmed by calculations of the triplet state, which was found to be energetically higher (the energy gap is ∼7.0 kcal/mol in case of B3LYP functional while its ∼9.5 kcal/mol in the case of BP86 functional) as compared to open shell singlet state of the complex (for further details see Supporting Information, Table S2). This analysis gives further support that the presence of deprotonated Y residue in vicinity of AdoCbl cofactor induces electron transfer (ET) between the two units, thus forming a diradical state. The formation of diradical is highly sensitive with respect to the location as well as orientation of Y residue. When Y motif was placed in orientation consistent with X-ray data, spin density was found to be equally distributed between Y and AdoCbl (Supporting Information, Table S2) but as the orientation of Y motif was altered by means of rotation through different angles (but keeping the same location), we could not find the diradical state of the complex pointing that only a specific location and orientation of Y can induce the ET between the two motifs highlighting the degree of specificity associated with the
Figure 2. Spin density distribution in the structural active site models of MCM (upper panel) and GLM (lower panel) computed at BP86/631G(d) 5d level of theory where red and blue colors represent alpha and beta spin density distributions, respectively.
enzymatic machineries. To gain further insight, the isosurface spin density profiles were generated for structural models under consideration (Figure 2). In both cases, an unpaired electron is localized on Y component with spin density distribution in oddalternant manner, a typical characteristic of neutral tyrosyl radicals,6b,14 while the other electron is transferred onto the AdoCbl where it is mainly delocalized on the corrin ligand. The latter case represents a distribution consistent with the corrin-ring based π-radical anion. Clearly, presence of deprotonated ArOH (ArO-) within ∼7.5 Å distance from AdoCbl alters the electronic structure of the cofactor and consequently enzymatic cleavage of the Co-C bond is more in line with one-electron-reduced form of AdoCbl (i.e., [AdoCbl]•-) rather than the neutral analogue. It has been known for a long time15 that the electrochemical addition of an electron to cobalamins leads to significant lowering in the bond dissociation energy (BDE) of Co-C bond. However, it was argued that species like [AdoCbl]•- cannot be involved in B12depedendent enzymatic catalysis because biological systems are not sufficiently strong to reduce B12 cofactors.16 This argument is based on redox potentials obtained from electrochemical measurements in solution, which cannot be directly applied to the situation inside the enzyme.17 Evidently interactions among the active site residues can appreciably alter the redox potential of the tyrosine as well as that of the cofactor. For example, in case of PSII,18 the redox potentials of tyrosine as well as that of P680+ are appreciably tuned by the local protein invironment. Thus, as has been found here, the presence of Y residue in the vicinity of AdoCbl might play the crucial role of a reducing agent causing the formation of radical anion in AdoCbl-
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Figure 3. Co-C bond dissociation energy curves corresponding to models of neutral cofactor (AdoCbl), one-electron-reduced analogue ([AdoCbl]•-) and ArO-/AdoCbl complex computed at BP86/6-31G(d) 5d level of theory. In all calculations hydrogen atoms have replaced the corrin side chains; structural simplifications that do not alter the properties of Co-C bond cleavage.13c The calculations involving [AdoCbl]•- species have been carried out using the base-off form in accordance with our previous work on MeCbl and Pc based oneelectron-reduced models.20 The BDE of Co-C bond, in case of ArO-/ AdoCbl model complex, has been computed using interpolation procedure that comes out to be ∼20.0 kcal/mol. Calculations for ArO-/ AdoCbl complex have been carried out allowing spin polarization that formally leads to ArO•/[AdoCbl]•-. The corresponding energy curve has been corrected using Yamaguchi’s spin projection procedure.21
dependent enzymes. To further elaborate this proposal, we have performed three series of calculations: (1) dissociation energy curve was computed for neutral cofactor (2) similar analysis was performed for [AdoCbl]•- in accordance with electrochemical measurements, and (3) energy curve was computed for AdoCbl in presence of ArO-, using structural model of AdoCbl and phenolate anion (ArO-). Last series of calculations were performed with an additional constraint imposed on the orientation of ArO- with respect to the metal center in accordance with 1l9C structure. In all calculations the BP86/6-31G(d) 5d level of theory was applied which is considered an appropriate functional in reproducing structural properties and cleavage of the Co-C bond in case of B12 cofactors.13 Figure 3 displays the corresponding dissociation energy curves. In case of neutral cofactor, the energy required to cleave Co-C bond homolytically is 31.9 kcal/mol, in excellent agreement with experimental value of 31.5 ( 1.3 kcal/mol.19 However, in the case of [AdoCbl]•-, the BDE of Co-C bond is significantly reduced due to involvement of two electronic states; initially a π*-anion radical state is formed with the extra electron delocalized over the corrin ligand, but as the Co-C bond is stretched (at ∼2.50 Å), the extra electron transfers to the σ*Co-C state. The mechanism of reductive cleavage for AdoCbl follows closely what has recently been reported for MeCbl and their Pc analogue.20 Since the final cleavage involves three electron bond (σ)2 (σ*)1, the BDE of Co-C bond decreases to 18.0 kcal/mol, implying 44% bond strength reduction. Interestingly, the dissociation energy curve for Co-C bond estimated in case of ArO•/[AdoCbl]•- complex resembles very closely to that obtained for [AdoCbl]•-, and BDE lowering essentially follows the same protocol. This finding signifies the role of Y when the enzymatic environment near AdoCbl cofactor is taken into consideration. In consequence, almost 41% lowering in the BDE of Co-C bond is observed, which provides the logistic explanation to the proposal that the formation of [AdoCbl]•can be one of the key ingredients of catalytic effect affiliated with AdoCbl-dependent enzymes.
Figure 4. Selected bond distances in two AdoCbl-depdendent mutases: active sites of MCM (upper panel) and GLM (lower panel), respectively.
Up to now we have presented crystallographic details and computational evidences highlighting the critical importance of Y in the activation of Co-C bond. According to DFT calculations, ET occurs only in the case of deprotonated phenol (Figure 2), which makes the proton abstraction prerequisite for ET. Since Y is present as a neutral residue inside the enzyme, it is reasonable to postulate that upon substrate binding, the tyrosine residue gets deprotonated. The local environment around the active site provides important insight how actually the deprotonation step may take place (Figure 4). In case of MCM enzyme,2a Y89 residue lies in close proximity of the substrate (MCA802) and a solvent molecule (HOH170) with tyrosine being at a distance of 2.62 and 2.77 Å from the substrate and water molecule, respectively. On the other hand, in the case of GLM,2c Y181 residue is at a distance of 3.38 Å from the substrate while it is 3.41 Å in distance with respect to the proximal histidine (HIS150). Thus, it is expected that deprotonation of Y occurs upon substrate binding, which serves to complete the proton transfer pathway thereby promoting ET to cofactor. It is therefore reasonable to further postulate that proton transfer step is coupled to electron transfer, which can be termed as PCET.22 There are two experimental findings that lend further support to PCET mechanism in the case of AdoCbl-dependent mutases. In the case of MCM enzyme, mutation of Tyr (Y89) by Phe (F) leads to decrease in enzymatic activity by 3-4 orders of magnitude.4 Although this has been interpreted as the loss of stablising interactions upon mutation, the replacement Y- f F- appears to be more consistent with decrease in the rate of ET as Y- is a comparatively electron rich systems due to the presence of heteroatom in its structure.
Letters This implies that Y here acts as a redox center transferring an electron to the cofactor, instead of just stabilizing the radicals formed during the homolysis of Co-C bond. The further evidence supporting PCET proposal comes from another experimental study23 based on MCM enzyme where the sensitivity of enzyme activity with respect to substrate modification was addressed. It was observed that the slight modifications in the structure of the substrate lead to substantial decrease in the catalytic rate, which also underlines the significance of substrate in the activation process.22 The key feature of present proposal is that the tyrosine motif acts as an internal redox center, which transfers an electron to the AdoCbl cofactor leading to the formation of corrin-ring, based π-radical anion. Once the electron is transferred, the cleavage of the Co-C bond occurs from [AdoCbl]•- involving three electron bond (σ)2(σ*)1, thereby yielding cob(I)alamin and Ado radical. Although the tyrosyl radical as well as cob(I)alamin have never been observed during the experimental studies of AdoCbl-dependent enzymes, it does not rule out the possibility of the involvement of the tyrosine motif in the activation of Co-C bond. Lack of experimental Y• detection can be explained by the back electron transfer involving Cob(I)alamin and Y• radical, that is, cob(I)alamin/Y• f cob(II)alamin/Y, which is a thermodynamically feasible reaction because cob(I)alamin is a powerful reducing agent that favors the electron transfer to the tyrosyl radical. Thus the experimentally observed species would be cob(II)alamin instead of cob(I)alamin. This type of electron transfer reaction has chemical precedence in case of cobalamin-dependent methionine synthase where cob(I)alamin is oxidized to cob(II)alamin in every 200 catalytic cycles.24 Since it will comparatively be easy to reduce Y• than O2, the back electron transfer reaction should be a favorable reaction based upon thermochemical information. This back electron transfer step may also be coupled with H-abstraction from substrate (Sub), thus effectively what is seen in experiment is cob(II)alamin/Sub•. Extensive computational work is underway in our lab to address this issue from various angles like measuring the rate of ET and performing QM/MM study of B12-dependent enzymes considering tyrosine residue in the QM domain. Computational Section All calculations reported in the present work have been carried out using the Gaussian0325 suite of programs for electronic structure calculations. UBP86 and UB3LYP based density functionals along with 6-31G(d) basis set (5d components) were used throughout the calculations. The structural models were simplified with respect to side chains of corrin (see refs 20a and 20b for details) as well as tyrosine residues (were replaced by hydrogens). Supporting Information Available: X-ray based details of the active sites of B12-dependent enzymes and spin density distribution in the structural mimics of GLM and MCM. This material is available free of charge via the Internet at http:// pubs.acs.org. References and Notes (1) (a) Marzilli, L. G. In Bioinorganic Catalysis; Reedijk, J., Ed.; Marcel Dekker: New York, 1993; pp 227-259. (b) Vitamin B12 and B12 Proteins; Kra¨utler, B., Arigoni, D., Golding, B. T., Eds.; Wiley-VCH: New York, 1998. (c) Banerjee, R. Chemistry and Biochemistry of B12 Wiley, New York, 1999; (d) Toraya, T. Chem. ReV. 2003, 103, 2095–2127. (e)
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