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  • 1.
    Abelein, Axel
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Abrahams, Jan Pieter
    Danielsson, Jens
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Gräslund, Astrid
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Jarvet, Juri
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. National Institute of Chemical Physics and Biophysics, Estonia.
    Luo, Jinghui
    Tiiman, Ann
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Wärmländer, Sebastian K. T. S.
    The hairpin conformation of the amyloid beta peptide is an important structural motif along the aggregation pathway2014In: Journal of Biological Inorganic Chemistry, ISSN 0949-8257, E-ISSN 1432-1327, Vol. 19, no 4-5, p. 623-634Article, review/survey (Refereed)
    Abstract [en]

    The amyloid beta (A beta) peptides are 39-42 residue-long peptides found in the senile plaques in the brains of Alzheimer's disease (AD) patients. These peptides self-aggregate in aqueous solution, going from soluble and mainly unstructured monomers to insoluble ordered fibrils. The aggregation process(es) are strongly influenced by environmental conditions. Several lines of evidence indicate that the neurotoxic species are the intermediate oligomeric states appearing along the aggregation pathways. This minireview summarizes recent findings, mainly based on solution and solid-state NMR experiments and electron microscopy, which investigate the molecular structures and characteristics of the A beta peptides at different stages along the aggregation pathways. We conclude that a hairpin-like conformation constitutes a common motif for the A beta peptides in most of the described structures. There are certain variations in different hairpin conformations, for example regarding H-bonding partners, which could be one reason for the molecular heterogeneity observed in the aggregated systems. Interacting hairpins are the building blocks of the insoluble fibrils, again with variations in how hairpins are organized in the cross-section of the fibril, perpendicular to the fibril axis. The secondary structure propensities can be seen already in peptide monomers in solution. Unfortunately, detailed structural information about the intermediate oligomeric states is presently not available. In the review, special attention is given to metal ion interactions, particularly the binding constants and ligand structures of A beta complexes with Cu(II) and Zn(II), since these ions affect the aggregation process(es) and are considered to be involved in the molecular mechanisms underlying AD pathology.

  • 2. Banci, Lucia
    et al.
    Blazevits, Olga
    Cantini, Francesca
    Danielsson, Jens
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Lang, Lisa
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Luchinat, Claudio
    Mao, Jiafei
    Oliveberg, Mikael
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Ravera, Enrico
    Solid-state NMR studies of metal-free SOD1 fibrillar structures2014In: Journal of Biological Inorganic Chemistry, ISSN 0949-8257, E-ISSN 1432-1327, Vol. 19, no 4-5, p. 659-666Article in journal (Refereed)
    Abstract [en]

    Copper-zinc superoxide dismutase 1 (SOD1) is present in the protein aggregates deposited in motor neurons of amyotrophic lateral sclerosis (ALS) patients. ALS is a neurodegenerative disease that can be either sporadic (ca. 90 %) or familial (fALS). The most widely studied forms of fALS are caused by mutations in the sequence of SOD1. Ex mortuo SOD1 aggregates are usually found to be amorphous. In vitro SOD1, in its immature reduced and apo state, forms fibrillar aggregates. Previous literature data have suggested that a monomeric SOD1 construct, lacking loops IV and VII, (apoSOD Delta IV-VII), shares the same fibrillization properties of apoSOD1, both proteins having the common structural feature of the central beta-barrel. In this work, we show that structural information can be obtained at a site-specific level from solid-state NMR. The residues that are sequentially assignable are found to be located at the putative nucleation site for fibrillar species formation in apoSOD, as detected by other experimental techniques.

  • 3.
    Bassan, Arianna
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Blomberg, Margareta R. A.
    Stockholm University, Faculty of Science, Department of Physics.
    Siegbahn, Per E. M.
    Stockholm University, Faculty of Science, Department of Physics.
    A Theoretical Study of the Cis-Dihydroxylation Mechanism in Naphthalene 1,2-dioxygenase2004In: Journal of Biological Inorganic Chemistry, ISSN 0949-8257, E-ISSN 1432-1327, Vol. 9, no 4, p. 439-452Article in journal (Refereed)
    Abstract [en]

    The catalytic mechanism of naphthalene 1,2-dioxygenase has been investigated by means of hybrid density functional theory. This Rieske-type enzyme, which contains an active site hosting a mononuclear non-heme iron(II) complex, uses dioxygen and two electrons provided by NADH to carry out the cis-dihydroxylation of naphthalene. Since a (hydro)peroxo-iron(III) moiety has been proposed to be involved in the catalytic cycle, it was probed whether and how this species is capable of cis-dihydroxylation of the aromatic substrate. Different oxidation and protonation states of the Fe–O2 complex were studied on the basis of the crystal structure of the enzyme with oxygen bound side-on to iron. It was found that feasible reaction pathways require a protonated peroxo ligand, FeIII–OOH; the deprotonated species, the peroxo-iron(III) complex, was found to be inert toward naphthalene. Among the different chemical patterns which have been explored, the most accessible one involves an epoxide intermediate, which may subsequently evolve toward an arene cation, and finally to the cis-diol. The possibility that an iron(V)-oxo species is formed prior to substrate hydroxylation was also examined, but found to implicate a rather high energy barrier. In contrast, a reasonably low barrier might lead to a high-valent iron-oxo species [i.e. iron(IV)-oxo] if a second external electron is supplied to the mononuclear iron center before dioxygenation.

  • 4. Berggren, Gustav
    et al.
    Sahlin, Margareta
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Crona, Mikael
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Swedish Orphan Biovitrum AB, Sweden.
    Tholander, Fredrik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Sjöberg, Britt-Marie
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Compounds with capacity to quench the tyrosyl radical in Pseudomonas aeruginosa ribonucleotide reductase2019In: Journal of Biological Inorganic Chemistry, ISSN 0949-8257, E-ISSN 1432-1327, Vol. 24, no 6, p. 841-848Article in journal (Refereed)
    Abstract [en]

    Ribonucleotide reductase (RNR) has been extensively probed as a target enzyme in the search for selective antibiotics. Here we report on the mechanism of inhibition of nine compounds, serving as representative examples of three different inhibitor classes previously identified by us to efficiently inhibit RNR. The interaction between the inhibitors and Pseudomonas aeruginosa RNR was elucidated using a combination of electron paramagnetic resonance spectroscopy and thermal shift analysis. All nine inhibitors were found to efficiently quench the tyrosyl radical present in RNR, required for catalysis. Three different mechanisms of radical quenching were identified, and shown to depend on reduction potential of the assay solution and quaternary structure of the protein complex. These results form a good foundation for further development of P. aeruginosa selective antibiotics. Moreover, this study underscores the complex nature of RNR inhibition and the need for detailed spectroscopic studies to unravel the mechanism of RNR inhibitors.

  • 5. Borowski, Tomasz
    et al.
    Wojcik, Anna
    Milaczewska, Anna
    Georgiev, Valentin
    Blomberg, Margareta R. A.
    Stockholm University, Faculty of Science, Department of Physics. Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Siegbahn, Per E. M.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Faculty of Science, Department of Physics.
    The alkenyl migration mechanism catalyzed by extradiol dioxygenases: a hybrid dft study2012In: Journal of Biological Inorganic Chemistry, ISSN 0949-8257, E-ISSN 1432-1327, Vol. 17, no 6, p. 881-890Article in journal (Refereed)
    Abstract [en]

    6-Hydroxymethyl-6-methylcyclohexa-2,4-dienone is a mechanistic probe which when incubated with an extradiol dioxygenase yields a 2-tropolone product. This observation was originally interpreted as evidence supporting a direct heterolytic 1,2-alkenyl migration mechanism for a ring expansion reaction catalyzed by this class of Fe(II)-dependent nonheme enzymes (Xin and Bugg in J Am Chem Soc 130:10422-10430, 2008). In the work reported in this contribution we used quantum chemical methods to test whether such a mechanism is energetically possible and we found that it is not, neither for the mechanistic probe nor for the native catalytic cycle intermediate. Models of increasing complexity were used to calculate energy barriers to the heterolytic 1,2-alkenyl migration and alternative radical mechanisms. It was found that the former involves substantially higher barriers than the latter. A tentative radical mechanism that accounts for the transformation of the probe substrate to 2-tropolone was also proposed, and it involves acceptable barriers.

  • 6. Ertem, Mehmed Z.
    et al.
    Cramer, Christopher J.
    Himo, Fahmi
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Siegbahn, Per E. M.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    N-O bond cleavage mechanism(s) in nitrous oxide reductase2012In: Journal of Biological Inorganic Chemistry, ISSN 0949-8257, E-ISSN 1432-1327, Vol. 17, no 5, p. 687-698Article in journal (Refereed)
    Abstract [en]

    Quantum chemical calculations of active-site models of nitrous oxide reductase (N2OR) have been undertaken to elucidate the mechanism of N-O bond cleavage mediated by the supported tetranuclear Cu4S core (Cu-Z) found in the enzymatic active site. Using either a minimal model previously employed by Gorelsky et al. (J. Am. Chem. Soc. 128:278-290, 2006) or a more extended model including key residue side chains in the active-site second shell, we found two distinct mechanisms. In the first model, N2O binds to the fully reduced Cu-Z in a bent mu-(1,3)-O,N bridging fashion between the Cu-I and Cu-IV centers and subsequently extrudes N-2 while generating the corresponding bridged mu-oxo species. In the second model, substrate N2O binds loosely to one of the coppers of Cu-Z in a terminal fashion, i.e., using only the oxygen atom; loss of N-2 generates the same mu-oxo copper core. The free energies of activation predicted for these two alternative pathways are sufficiently close to one another that theory does not provide decisive support for one over the other, posing an interesting problem with respect to experiments that might be designed to distinguish between the two. Effects of nearby residues and active-site water molecules are also explored.

  • 7.
    Georgiev, Valentin
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Borowski, Tomasz
    Polish Academy of Sciences.
    Blomberg, Margareta R.A.
    Stockholm University, Faculty of Science, Department of Physics.
    Siegbahn, Per E.M.
    A comparison of the reaction mechanisms of iron- and manganese-containing 2,3-HPCD: an important spin transition for manganese2008In: Journal of Biological Inorganic Chemistry, ISSN 0949-8257, E-ISSN 1432-1327, Vol. 13, no 6, p. 929-40Article in journal (Refereed)
    Abstract [en]

    Homoprotocatechuate (HPCA) dioxygenases are enzymes that take part in the catabolism of aromatic compounds in the environment. They use molecular oxygen to perform the ring cleavage of ortho-dihydroxylated aromatic compounds. A theoretical investigation of the catalytic cycle for HPCA 2,3-dioxygenase isolated from Brevibacterium fuscum (Bf 2,3-HPCD) was performed using hybrid DFT with the B3LYP functional, and a reaction mechanism is suggested. Models of different sizes were built from the crystal structure of the enzyme and were used in the search for intermediates and transition states. It was found that the enzyme follows a reaction pathway similar to that for other non-heme iron dioxygenases, and for the manganese-dependent analog MndD, although with different energetics. The computational results suggest that the rate-limiting step for the whole reaction of Bf 2,3-HPCD is the protonation of the activated oxygen, with an energy barrier of 17.4 kcal/mol, in good agreement with the experimental value of 16 kcal/mol obtained from the overall rate of the reaction. Surprisingly, a very low barrier was found for the O-O bond cleavage step, 11.3 kcal/mol, as compared to 21.8 kcal/mol for MndD (sextet spin state). This result motivated additional studies of the manganese-dependent enzyme. Different spin coupling between the unpaired electrons on the metal and on the evolving substrate radical was observed for the two enzymes, and therefore the quartet spin state potential energy surface of the MndD reaction was studied. The calculations show a crossing between the sextet and the quartet surfaces, and it was concluded that a spin transition occurs and determines a barrier of 14.4 kcal/mol for the O-O bond cleavage, which is found to be the rate-limiting step in MndD. Thus the two 83% identical enzymes, using different metal ions as co-factors, were found to have similar activation energies (in agreement with experiment), but different rate-limiting steps.

  • 8.
    Georgiev, Valentin
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Borowski, Tomasz
    Stockholm University, Faculty of Science, Department of Physics.
    Siegbahn, Per E.M.
    Stockholm University, Faculty of Science, Department of Physics.
    Theoretical study of the catalytic reaction mechanism of MndD2006In: Journal of Biological Inorganic Chemistry, ISSN 0949-8257, E-ISSN 1432-1327, Vol. 11, no 5, p. 571-85Article in journal (Refereed)
    Abstract [en]

    Manganese-dependent homoprotocatechuate 2,3-dioxygenase (MndD) is an enzyme taking part in the catabolism of aromatic compounds in the environment. It uses molecular oxygen to perform an extradiol cleavage of the ring of the ortho-dihydroxylated aromatic compound homoprotocatechuate. A theoretical investigation of the reaction path for MndD was performed using hybrid density functional theory with the B3LYP functional, and a catalytic mechanism has been suggested. Models of different size were built from the crystal structure of the enzyme and were used in the search for intermediates and transition states. It was found that the substrate first binds at the active site as a monoanion. Next the dioxygen is bound, forming a hydroperoxo intermediate. The O-O bond, activated in this way undergoes homolytic cleavage leading to an oxyl and then to an extra epoxide radical with subsequent opening of the aromatic ring. The lactone ring is then hydrolyzed by the Mn-bound OH group, and the final product is obtained in the last reaction steps. Alternative reaction paths were considered, and their calculated barriers were found to be higher than for the suggested mechanism. The selectivity between the extra- and intra-cleavage pathways was found to be determined by the barriers for the decay of the radical state.

  • 9.
    Griese, Julia J.
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Uppsala University, Sweden.
    Branca, Rui M. M.
    Srinivas, Vivek
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Högbom, Martin
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Ether cross-link formation in the R2-like ligand-binding oxidase2018In: Journal of Biological Inorganic Chemistry, ISSN 0949-8257, E-ISSN 1432-1327, Vol. 23, no 6, p. 879-886Article in journal (Refereed)
    Abstract [en]

    R2-like ligand-binding oxidases contain a dinuclear metal cofactor which can consist either of two iron ions or one manganese and one iron ion, but the heterodinuclear Mn/Fe cofactor is the preferred assembly in the presence of Mn-II and Fe-II in vitro. We have previously shown that both types of cofactor are capable of catalyzing formation of a tyrosine-valine ether cross-link in the protein scaffold. Here we demonstrate that Mn/Fe centers catalyze cross-link formation more efficiently than Fe/Fe centers, indicating that the heterodinuclear cofactor is the biologically relevant one. We further explore the chemical potential of the Mn/Fe cofactor by introducing mutations at the cross-linking valine residue. We find that cross-link formation is possible also to the tertiary beta-carbon in an isoleucine, but not to the secondary beta-carbon or tertiary gamma-carbon in a leucine, nor to the primary beta-carbon of an alanine. These results illustrate that the reactivity of the cofactor is highly specific and directed.

  • 10.
    Griese, Julia J.
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Uppsala University, Sweden.
    Kositzki, Ramona
    Haumann, Michael
    Högbom, Martin
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Assembly of a heterodinuclear Mn/Fe cofactor is coupled to tyrosine-valine ether cross-link formation in the R2-like ligand-binding oxidase2019In: Journal of Biological Inorganic Chemistry, ISSN 0949-8257, E-ISSN 1432-1327, Vol. 24, no 2, p. 211-221Article in journal (Refereed)
    Abstract [en]

    R2-like ligand-binding oxidases (R2lox) assemble a heterodinuclear Mn/Fe cofactor which performs reductive dioxygen (O-2) activation, catalyzes formation of a tyrosine-valine ether cross-link in the protein scaffold, and binds a fatty acid in a putative substrate channel. We have previously shown that the N-terminal metal binding site 1 is unspecific for manganese or iron in the absence of O-2, but prefers manganese in the presence of O-2, whereas the C-terminal site 2 is specific for iron. Here, we analyze the effects of amino acid exchanges in the cofactor environment on cofactor assembly and metalation specificity using X-ray crystallography, X-ray absorption spectroscopy, and metal quantification. We find that exchange of either the cross-linking tyrosine or the valine, regardless of whether the mutation still allows cross-link formation or not, results in unspecific manganese or iron binding at site 1 both in the absence or presence of O-2, while site 2 still prefers iron as in the wild-type. In contrast, a mutation that blocks binding of the fatty acid does not affect the metal specificity of either site under anoxic or aerobic conditions, and cross-link formation is still observed. All variants assemble a dinuclear trivalent metal cofactor in the aerobic resting state, independently of cross-link formation. These findings imply that the cross-link residues are required to achieve the preference for manganese in site 1 in the presence of O-2. The metalation specificity, therefore, appears to be established during the redox reactions leading to cross-link formation.

  • 11.
    Griese, Julia J.
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Srinivas, Vivek
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Högbom, Martin
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Assembly of nonheme Mn/Fe active sites in heterodinuclear metalloproteins2014In: Journal of Biological Inorganic Chemistry, ISSN 0949-8257, E-ISSN 1432-1327, Vol. 19, no 6, p. 759-774Article, review/survey (Refereed)
    Abstract [en]

    The ferritin superfamily contains several protein groups that share a common fold and metal coordinating ligands. The different groups utilize different dinuclear cofactors to perform a diverse set of reactions. Several groups use an oxygen-activating di-iron cluster, while others use di-manganese or heterodinuclear Mn/Fe cofactors. Given the similar primary ligand preferences of Mn and Fe as well as the similarities between the binding sites, the basis for metal specificity in these systems remains enigmatic. Recent data for the heterodinuclear cluster show that the protein scaffold per se is capable of discriminating between Mn and Fe and can assemble the Mn/Fe center in the absence of any potential assembly machineries or metal chaperones. Here we review the current understanding of the assembly of the heterodinuclear cofactor in the two different protein groups in which it has been identified, ribonucleotide reductase R2c proteins and R2-like ligand-binding oxidases. Interestingly, although the two groups form the same metal cluster they appear to employ partly different mechanisms to assemble it. In addition, it seems that both the thermodynamics of metal binding and the kinetics of oxygen activation play a role in achieving metal specificity.

  • 12.
    Grāve, Kristīne
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Larnbert, Wietske
    Berggren, Gustav
    Griese, Julia J.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Uppsala University, Sweden.
    Bennett, Matthew D.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Logan, Derek
    Högbom, Martin
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Redox-induced structural changes in the di-iron and di-manganese forms of Bacillus anthracis ribonucleotide reductase subunit NrdF suggest a mechanism for gating of radical access2019In: Journal of Biological Inorganic Chemistry, ISSN 0949-8257, E-ISSN 1432-1327, Vol. 24, no 6, p. 849-861Article in journal (Refereed)
    Abstract [en]

    Class Ib ribonucleotide reductases (RNR) utilize a di-nuclear manganese or iron cofactor for reduction of superoxide or molecular oxygen, respectively. This generates a stable tyrosyl radical (Y center dot) in the R2 subunit (NrdF), which is further used for ribonucleotide reduction in the R1 subunit of RNR. Here, we report high-resolution crystal structures of Bacillus anthracis NrdF in the metal-free form (1.51 angstrom) and in complex with manganese (Mn-II/Mn-II, 1.30 angstrom). We also report three structures of the protein in complex with iron, either prepared anaerobically (Fe-II/Fe-II form, 1.32 angstrom), or prepared aerobically in the photo-reduced Fe-II/Fe-II form (1.63 angstrom) and with the partially oxidized metallo-cofactor (1.46 angstrom). The structures reveal significant conformational dynamics, likely to be associated with the generation, stabilization, and transfer of the radical to the R1 subunit. Based on observed redox-dependent structural changes, we propose that the passage for the superoxide, linking the FMN cofactor of NrdI and the metal site in NrdF, is closed upon metal oxidation, blocking access to the metal and radical sites. In addition, we describe the structural mechanics likely to be involved in this process.

  • 13.
    Guell, Mireia
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Luis, Josep M.
    Siegbahn, Per E. M.
    Stockholm University, Faculty of Science, Department of Physics.
    Sola, Miquel
    Theoretical study of the hydroxylation of phenols mediated by an end-on bound superoxo-copper(II) complex2009In: Journal of Biological Inorganic Chemistry, ISSN 0949-8257, E-ISSN 1432-1327, Vol. 14, no 2, p. 273-285Article in journal (Refereed)
    Abstract [en]

    Peptidylglycine alpha-amidating monooxygenase and dopamine beta-monooxygenase are copper-containing proteins which catalyze essential hydroxylation reactions in biological systems. There are several possible mechanisms for the reductive O-2-activation at their mononuclear copper active site. Recently, Karlin and coworkers reported on the reactivity of a copper(II)-superoxo complex which is capable of inducing the hydroxylation of phenols with incorporated oxygen atoms derived from the Cu(II)-O-2(-) moiety. In the present work the reaction mechanism for the abovementioned superoxo complex with phenols is studied. The pathways found are analyzed with the aim of providing some insight into the nature of the chemical and biological copper-promoted oxidative processes with 1:1 Cu(I)/O-2-derived species.

  • 14.
    Guell, Mireia
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Luis, Josep M.
    Sola, Miquel
    Siegbahn, Per E. M.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Theoretical study of the hydroxylation of phenolates by the Cu2O2(N,N '-dimethylethylenediamine)(2)(2+) complex2009In: Journal of Biological Inorganic Chemistry, ISSN 0949-8257, E-ISSN 1432-1327, Vol. 14, no 2, p. 229-242Article in journal (Refereed)
    Abstract [en]

    Tyrosinase catalyzes the ortho hydroxylation of monophenols and the subsequent oxidation of the diphenolic products to the resulting quinones. In efforts to create biomimetic copper complexes that can oxidize C-H bonds, Stack and coworkers recently reported a synthetic mu-eta(2):eta(2)-peroxodicopper(II)(DBED)(2) complex ( DBED is N,N'-di-tert-butylethylenediamine), which rapidly hydroxylates phenolates. A reactive intermediate consistent with a bis-mu-oxo-dicopper(III)-phenolate complex, with the O-O bond fully cleaved, is observed experimentally. Overall, the evidence for sequential O-O bond cleavage and C-O bond formation in this synthetic complex suggests an alternative mechanism to the concerted or late-stage O-O bond scission generally accepted for the phenol hydroxylation reaction performed by tyrosinase. In this work, the reaction mechanism of this peroxodicopper(II) complex was studied with hybrid density functional methods by replacing DBED in the mu-eta(2):eta(2)-peroxodicopper(II)(DBED)(2) complex by N,N'-dimethylethylenediamine ligands to reduce the computational costs. The reaction mechanism obtained is compared with the existing proposals for the catalytic ortho hydroxylation of monophenol and the subsequent oxidation of the diphenolic product to the resulting quinone with the aim of gaining some understanding about the copper-promoted oxidation processes mediated by 2: 1 Cu(I)O-2-derived species.

  • 15. Guell, Mireia
    et al.
    Siegbahn, Per E. M.
    Stockholm University, Faculty of Science, Department of Physics.
    Theoretical study of the catalytic mechanism of catechol oxidase2007In: Journal of Biological Inorganic Chemistry, ISSN 0949-8257, E-ISSN 1432-1327, Vol. 12, no 8, p. 1251-1264Article in journal (Refereed)
    Abstract [en]

    The mechanism for the oxidation of catechol by catechol oxidase has been studied using B3LYP hybrid density functional theory. On the basis of the X-ray structure of the enzyme, the molecular system investigated includes the first-shell protein ligands of the two metal centers as well as the second-shell ligand Cys92. The cycle starts out with the oxidized, open-shell singlet complex with oxidation states Cu-2(II,II) with a mu-eta(2) :eta(2) bridging peroxide, as suggested experimentally, which is obtained from the oxidation of Cu-2(I,I) by dioxygen. The substrate of each half-reaction is a catechol molecule approaching the dicopper complex: the first half-reaction involves Cu(I) oxidation by peroxide and the second one Cu(II) reduction. The quantitative potential energy profile of the reaction is discussed in connection with experimental data. Since no protons leave or enter the active site during the catalytic cycle, no external base is required. Unlike the previous density functional theory study, the dicopper complex has a charge of +2.

  • 16.
    Hammerstad, Marta
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. University of Oslo, Norway.
    Rohr, Asmund K.
    Andersen, Niels H.
    Gräslund, Astrid
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Högbom, Martin
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Andersson, K. Kristoffer
    The class Ib ribonucleotide reductase from Mycobacterium tuberculosis has two active R2F subunits2014In: Journal of Biological Inorganic Chemistry, ISSN 0949-8257, E-ISSN 1432-1327, Vol. 19, no 6, p. 893-902Article in journal (Refereed)
    Abstract [en]

    Ribonucleotide reductases (RNRs) catalyze the reduction of ribonucleotides to their corresponding deoxyribonucleotides, playing a crucial role in DNA repair and replication in all living organisms. Class Ib RNRs require either a diiron-tyrosyl radical (Y center dot) or a dimanganese-Y center dot cofactor in their R2F subunit to initiate ribonucleotide reduction in the R1 subunit. Mycobacterium tuberculosis, the causative agent of tuberculosis, contains two genes, nrdF1 and nrdF2, encoding the small subunits R2F-1 and R2F-2, respectively, where the latter has been thought to serve as the only active small subunit in the M. tuberculosis class Ib RNR. Here, we present evidence for the presence of an active Fe (2) (III) -Y center dot cofactor in the M. tuberculosis RNR R2F-1 small subunit, supported and characterized by UV-vis, X-band electron paramagnetic resonance, and resonance Raman spectroscopy, showing features similar to those for the M. tuberculosis R2F-2-Fe (2) (III) -Y center dot cofactor. We also report enzymatic activity of Fe (2) (III) -R2F-1 when assayed with R1, and suggest that the active M. tuberculosis class Ib RNR can use two different small subunits, R2F-1 and R2F-2, with similar activity.

  • 17.
    Högbom, Martin
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    The manganese/iron-carboxylate proteins: what is what, where are they, and what can the sequences tell us?2010In: Journal of Biological Inorganic Chemistry, ISSN 0949-8257, E-ISSN 1432-1327, Vol. 15, no 3, p. 339-349Article in journal (Refereed)
    Abstract [en]

    The manganese/iron-carboxylate proteins make up a recently discovered group of proteins that contain a heterodinuclear Mn/Fe redox cofactor. The chemical potential of the heterodinuclear metal site is just starting to be characterized, but available data suggest that it may have capabilities for similarly versatile chemistry as the extensively studied diiron-carboxylate cofactor. The presently identified members of the manganese/iron-carboxylate proteins are all sequence homologues of the radical-generating R2 subunit of class I ribonucleotide reductase, canonically a diiron protein. They are also commonly misannotated as such in databases. In spite of the sequence similarity, the manganese/iron-carboxylate proteins form at least two functionally distinct groups, radical-generating ribonucleotide reductase subunits and ligand-binding Mn/Fe proteins. Here, the presently available sequences for the manganese/iron-carboxylate proteins are gathered, grouped, and analyzed. The analysis provides sequence determinants that allow group identification of new sequences on the single-protein level. Key differences between the groups are mapped on the known representative structures, providing clues to the structural prerequisites for metal specificity, cofactor formation, and difference in function. The organisms that encode manganese/iron-carboxylate proteins are briefly discussed; their environmental preference suggests that the Mn/Fe heterodinuclear cofactor is preferred by extremophiles and pathogens with a particularly high relative presence in Archaea.

  • 18.
    Noack, Holger
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Siegbahn, Per E. M.
    Stockholm University, Faculty of Science, Department of Physics.
    Theoretical investigation on the oxidative chlorination performed by a biomimetic non-heme iron catalyst2007In: Journal of Biological Inorganic Chemistry, ISSN 0949-8257, E-ISSN 1432-1327, Vol. 12, p. 1151-1162Article in journal (Refereed)
    Abstract [en]

    The present study is a part of an effort to understand the mechanism of the oxidative chlorination, as performed by a biomimetic non-heme iron complex. This catalytically active complex is generated from a peroxide and [(TPA)FeIIICl2]+ [TPA is tris(2-pyridylmethyl)amine]. The reaction catalyzed by [(TPA)FeCl2]+/ROOH involves either [(TPA)ClFeV=O]2+ or [(TPA)ClFeIV=O]+ as an intermediate. On the basis of density functional theory the reaction of these two possible catalysts with cyclohexane is investigated. A question addressed is how the competing hydroxylation of the substrate is avoided. It is demon- strated that the high-valent iron complex [(TPA)Cl– FeV=O]2+ is capable of stereospecific alkane chlorination, based on an ionic rather than on a radical pathway. In contrast, the results found for [(TPA)ClFeIV=O]+ cannot explain the experimental findings. In this case the transition states for chlorination and hydroxylation are energetically too close. The exclusive chlorination of the substrate by Cl–FeIV=O may be explained by an indirect or a direct effect, altering the position of the competing rebound barriers.

  • 19.
    Roos, Katarina
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Siegbahn, Per E. M.
    Stockholm University, Faculty of Science, Department of Physics.
    A comparison of two-electron chemistry performed by the manganese and iron heterodimer and homodimers2012In: Journal of Biological Inorganic Chemistry, ISSN 0949-8257, E-ISSN 1432-1327, Vol. 17, no 3, p. 363-373Article in journal (Refereed)
    Abstract [en]

    Two-electron chemistry with an iron dimer, a manganese dimer, and a manganese-iron dimer as a catalyst has been modeled using B3LYP* hybrid density functional theory. The recently discovered MnFe proteins form (at least) two functionally distinct groups, performing radical generation (class Ic ribonucleotide reductase subunit II) and substrate oxidations (subunit II-like ligand-binding oxidases, R2lox), respectively. Proteins from the latter group appear to be functionally similar to the diiron carboxylate proteins that perform two-electron oxidations of substrates, such as methane monooxygenase. To qualitatively determine the potential role of a MnFe center in R2lox, methane hydroxylation with the MnFe heterodimer and with the FeFe and MnMn homodimers is studied. The redox potential of the active state of the Mn(IV)Fe(IV) heterodimer is about 7 kcal mol(-1) lower than that of the active state of the Fe(IV)Fe(IV) homodimer, leading to a high barrier for the rate-limiting hydrogen abstraction with the MnFe site. If the entropy loss is not included, the barriers are lower, and the MnFe heterodimer can therefore have a role in R2lox as an oxidase for larger substrates exergonically bound to the protein. A MnMn center has a high barrier both with and without entropy loss. The higher stability of Fe(IV) in the presence of Mn(IV) in the other site compared with a second Fe(IV) suggests an explanation for the presence of the MnFe site in R2lox: to provide a metal center that is capable of two-electron chemistry, and which is more stable and less sensitive to external reductants than an Fe(IV)Fe(IV) site.

  • 20.
    Roos, Katarina
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Siegbahn, Per E. M.
    Stockholm University, Faculty of Science, Department of Physics.
    Oxygen cleavage with manganese and iron in ribonucleotide reductase from Chlamydia trachomatis2011In: Journal of Biological Inorganic Chemistry, ISSN 0949-8257, E-ISSN 1432-1327, Vol. 16, no 4, p. 553-565Article in journal (Refereed)
    Abstract [en]

    The oxygen cleavage in Chlamydia trachomatis ribonucleotide reductase (RNR) has been studied using B3LYP* hybrid density functional theory. Class Ic C. trachomatis RNR lacks the radical-bearing tyrosine, crucial for activity in conventional class I (subclass a and b) RNR. Instead of the Fe(III)Fe(III)-Tyr(rad) active state, C. trachomatis RNR has a mixed Mn(IV)Fe(III) metal center in subunit II (R2). A mixed MnFe metal center has never been observed as a radical cofactor before. The active state is generated by reductive oxygen cleavage at the metal site. On the basis of calculated barriers for oxygen cleavage in C. trachomatis R2 and R2 from Escherichia coli with a diiron, a mixed manganese iron, and a dimanganese center, conclusions can be drawn about the effect of changing metals in R2. The oxygen cleavage is found to be governed by two factors: the redox potentials of the metals and the relative stability of the different peroxides. Mn(IV) has higher stability than Fe(IV), and the barrier is therefore lower with a mixed metal center than with a diiron center. With a dimanganese center, an asymmetric peroxide is more stable than the symmetric peroxide, and the barrier therefore becomes too high. Calculated proton-coupled redox potentials are compared to identify three possible R2 active states, the Fe(III)-Fe(III)-Tyr(rad) state, the Mn(IV)Fe(III) state, and. the Mn(IV)Mn(IV) state. A tentative energy profile of the thermodynamics of the radical transfer from R2 to subunit I is constructed to illustrate how the stability of the active states can be understood from a thermodynamical point of view.

  • 21.
    Rozman Grinberg, Inna
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Berglund, Sigrid
    Hasan, Mahmudul
    Lundin, Daniel
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Ho, Felix M.
    Magnuson, Ann
    Logan, Derek T.
    Sjöberg, Britt-Marie
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Berggren, Gustav
    Class Id ribonucleotide reductase utilizes a Mn-2(IV,III) cofactor and undergoes large conformational changes on metal loading2019In: Journal of Biological Inorganic Chemistry, ISSN 0949-8257, E-ISSN 1432-1327, Vol. 24, no 6, p. 863-877Article in journal (Refereed)
    Abstract [en]

    Outside of the photosynthetic machinery, high-valent manganese cofactors are rare in biology. It was proposed that a recently discovered subclass of ribonucleotide reductase (RNR), class Id, is dependent on a Mn-2(IV,III) cofactor for catalysis. Class I RNRs consist of a substrate-binding component (NrdA) and a metal-containing radical-generating component (NrdB). Herein we utilize a combination of EPR spectroscopy and enzyme assays to underscore the enzymatic relevance of the Mn-2(IV,III) cofactor in class Id NrdB from Facklamia ignava. Once formed, the Mn-2(IV,III) cofactor confers enzyme activity that correlates well with cofactor quantity. Moreover, we present the X-ray structure of the apo- and aerobically Mn-loaded forms of the homologous class Id NrdB from Leeuwenhoekiella blandensis, revealing a dimanganese centre typical of the subclass, with a tyrosine residue maintained at distance from the metal centre and a lysine residue projected towards the metals. Structural comparison of the apo- and metal-loaded forms of the protein reveals a refolding of the loop containing the conserved lysine and an unusual shift in the orientation of helices within a monomer, leading to the opening of a channel towards the metal site. Such major conformational changes have not been observed in NrdB proteins before. Finally, in vitro reconstitution experiments reveal that the high-valent manganese cofactor is not formed spontaneously from oxygen, but can be generated from at least two different reduced oxygen species, i.e. H2O2 and superoxide (O2 center dot-). Considering the observed differences in the efficiency of these two activating reagents, we propose that the physiologically relevant mechanism involves superoxide.

  • 22.
    Siegbahn, Per E. M.
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Himo, Fahmi
    Recent developments of the quantum chemical cluster approach for modeling enzyme reactions2009In: Journal of Biological Inorganic Chemistry, ISSN 0949-8257, E-ISSN 1432-1327, Vol. 14, no 5, p. 643-651Article, review/survey (Refereed)
    Abstract [en]

    The quantum chemical cluster approach for modeling enzyme reactions is reviewed. Recent applications have used cluster models much larger than before which have given new modeling insights. One important and rather surprising feature is the fast convergence with cluster size of the energetics of the reactions. Even for reactions with significant charge separation it has in some cases been possible to obtain full convergence in the sense that dielectric cavity effects from outside the cluster do not contribute to any significant extent. Direct comparisons between quantum mechanics (QM)-only and QM/molecular mechanics (MM) calculations for quite large clusters in a case where the results differ significantly have shown that care has to be taken when using the QM/MM approach where there is strong charge polarization. Insights from the methods used, generally hybrid density functional methods, have also led to possibilities to give reasonable error limits for the results. Examples are finally given from the most extensive study using the cluster model, the one of oxygen formation at the oxygen-evolving complex in photosystem II.

  • 23. Yang, Xi-Xi
    et al.
    Mao, Qiu-Yun
    An, Xiao-Ting
    Li, Xi-Chen
    Siegbahn, Per E. M.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Chen, Guang-Ju
    Tan, Hong-Wei
    Theoretical study of the mechanism of the manganese catalase KatB2019In: Journal of Biological Inorganic Chemistry, ISSN 0949-8257, E-ISSN 1432-1327, Vol. 24, no 1, p. 103-115Article in journal (Refereed)
    Abstract [en]

    The mechanism of the H2O2 disproportionation catalyzed by the manganese catalase (MnCat) KatB was studied using the hybrid density functional theory B3LYP and the quantum chemical cluster approach. Compared to the previous mechanistic study at the molecular level for the Thermus thermophilus MnCat (TTC), more modern methodology was used and larger models of increasing sizes were employed with the help of the high-resolution X-ray structure. In the reaction pathway suggested for KatB using the Large chemical model, the O-O homolysis of the first substrate H2O2 occurs through a -(1):(1) coordination mode and requires a barrier of 10.9kcal/mol. In the intermediate state of the bond cleavage, two hydroxides form as terminal ligands of the dimanganese cluster at the Mn-2(III,III) oxidation state. One of the two Mn(III)-OH- moieties and a second-sphere tyrosine stabilize the second substrate H2O2 in the second-sphere of the active site via hydrogen bonding interactions. The H2O2, unbound to the metals, is first oxidized into HO2<bold> through a proton</bold>-coupled electron transfer (PCET) step with a barrier of 9.5kcal/mol. After the system switches to the triplet surface, the uncoordinated HO2<bold> replaces the product water terminally bound to the Mn</bold>(II) and is then oxidized into O-2 spontaneously. Transition states with structural similarities to those obtained for TTC, where -(2)-OH-/O2- groups play important roles, were found to be higher in energy.

1 - 23 of 23
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