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Rozman Grinberg, I., Berglund, S., Hasan, M., Lundin, D., Ho, F. M., Magnuson, A., . . . Berggren, G. (2019). Class Id ribonucleotide reductase utilizes a Mn2(IV,III) cofactor and undergoes large conformational changes on metal loading. Journal of Biological Inorganic Chemistry, 24(6), 863-877
Open this publication in new window or tab >>Class Id ribonucleotide reductase utilizes a Mn2(IV,III) cofactor and undergoes large conformational changes on metal loading
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2019 (English)In: Journal of Biological Inorganic Chemistry, ISSN 0949-8257, E-ISSN 1432-1327, Vol. 24, no 6, p. 863-877Article in journal (Refereed) Published
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 Mn2(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 Mn2(IV,III) cofactor in class Id NrdB from Facklamia ignava. Once formed, the Mn2(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 (O 2 ·− ). Considering the observed differences in the efficiency of these two activating reagents, we propose that the physiologically relevant mechanism involves superoxide.

Keywords
Ribonucleotide reductase, Dimanganese cofactor, Radicals, Electron paramagnetic resonance, X-ray crystallography, Phylogeny
National Category
Biophysics
Identifiers
urn:nbn:se:uu:diva-392170 (URN)10.1007/s00775-019-01697-8 (DOI)000487094500011 ()31414238 (PubMedID)
Funder
EU, European Research Council, 714102Swedish Research Council, 621-2014-5670Swedish Research Council, 2016-04855Swedish Research Council, 2016-01920Swedish Cancer Society, 2018/820Magnus Bergvall FoundationWenner-Gren Foundations
Available from: 2019-08-30 Created: 2019-08-30 Last updated: 2019-10-30Bibliographically approved
Berggren, G., Sahlin, M., Crona, M., Tholander, F. & Sjöberg, B.-M. (2019). Compounds with capacity to quench the tyrosyl radical in Pseudomonas aeruginosa ribonucleotide reductase. Journal of Biological Inorganic Chemistry, 24(6), 841-848
Open this publication in new window or tab >>Compounds with capacity to quench the tyrosyl radical in Pseudomonas aeruginosa ribonucleotide reductase
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2019 (English)In: Journal of Biological Inorganic Chemistry, ISSN 0949-8257, E-ISSN 1432-1327, Vol. 24, no 6, p. 841-848Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
SPRINGER, 2019
Keywords
Diferric-oxo center, Radicals, Inhibitors, Ribonucleotide reductase, Thermal shift analysis, EPR
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-395703 (URN)10.1007/s00775-019-01679-w (DOI)000487094500009 ()31218442 (PubMedID)
Funder
Swedish Research Council, 621-2014-5670Swedish Research Council, 2016-01,920Wenner-Gren Foundations
Available from: 2019-10-23 Created: 2019-10-23 Last updated: 2019-10-23Bibliographically approved
Shylin, S. I., Pavliuk, M. V., D'Amario, L., Mamedov, F., Sá, J., Berggren, G. & Fritsky, I. O. (2019). Efficient visible light-driven water oxidation catalysed by an iron(IV) clathrochelate complex. Chemical Communications, 55(23), 3335-3338
Open this publication in new window or tab >>Efficient visible light-driven water oxidation catalysed by an iron(IV) clathrochelate complex
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2019 (English)In: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 55, no 23, p. 3335-3338Article in journal (Refereed) Published
Abstract [en]

A water-stable FeIV clathrochelate complex catalyzes fast and homogeneous photochemical oxidation of water to dioxygen with a turnover frequency of 2.27 s−1 and a maximum turnover number of 365. An FeV intermediate generated under catalytic conditions is trapped and characterised using EPR and Mössbauer spectroscopy.

Keywords
Artificial photosynthesis, water oxidation, iron catalyst, photochemical water oxidation, electrochemical water oxidation
National Category
Physical Chemistry
Research subject
Chemistry with specialization in Physical Chemistry
Identifiers
urn:nbn:se:uu:diva-379606 (URN)10.1039/C9CC00229D (DOI)000461397500002 ()30801592 (PubMedID)
Funder
EU, Horizon 2020, 778245Swedish Institute
Available from: 2019-03-18 Created: 2019-03-18 Last updated: 2019-04-12Bibliographically approved
Aster, A., Wang, S., Mirmohades, M., Esmieu, C., Berggren, G., Hammarström, L. & Lomoth, R. (2019). Metal vs. ligand protonation and the alleged proton-shuttling role of the azadithiolate ligand in catalytic H-2 formation with FeFe hydrogenase model complexes. Chemical Science, 10(21), 5582-5588
Open this publication in new window or tab >>Metal vs. ligand protonation and the alleged proton-shuttling role of the azadithiolate ligand in catalytic H-2 formation with FeFe hydrogenase model complexes
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2019 (English)In: Chemical Science, ISSN 2041-6520, E-ISSN 2041-6539, Vol. 10, no 21, p. 5582-5588Article in journal (Refereed) Published
Abstract [en]

Electron and proton transfer reactions of diiron complexes [Fe(2)adt(CO)(6)] (1) and [Fe(2)adt(CO)(4)(PMe3)(2)] (4), with the biomimetic azadithiolate (adt) bridging ligand, have been investigated by real-time IR- and UV-vis-spectroscopic observation to elucidate the role of the adt-N as a potential proton shuttle in catalytic H-2 formation. Protonation of the one-electron reduced complex, 1(-), occurs on the adt-N yielding 1H and the same species is obtained by one-electron reduction of 1H(+). The preference for ligand vs. metal protonation in the Fe-2(i,0) state is presumably kinetic but no evidence for tautomerization of 1H to the hydride 1Hy was observed. This shows that the adt ligand does not work as a proton relay in the formation of hydride intermediates in the reduced catalyst. A hydride intermediate 1HHy(+) is formed only by protonation of 1H with stronger acid. Adt protonation results in reduction of the catalyst at much less negative potential, but subsequent protonation of the metal centers is not slowed down, as would be expected according to the decrease in basicity. Thus, the adtH(+) complex retains a high turnover frequency at the lowered overpotential. Instead of proton shuttling, we propose that this gain in catalytic performance compared to the propyldithiolate analogue might be rationalized in terms of lower reorganization energy for hydride formation with bulk acid upon adt protonation.

Place, publisher, year, edition, pages
Royal Society of Chemistry, 2019
National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-390686 (URN)10.1039/c9sc00876d (DOI)000474412700015 ()31293742 (PubMedID)
Funder
Swedish Research Council, 621-2014-5670Swedish Research Council, 2016-04271Swedish Research Council Formas, 213-2014-880
Available from: 2019-08-16 Created: 2019-08-16 Last updated: 2019-08-16Bibliographically approved
Nemeth, B., Esmieu, C., Redman, H. J. & Berggren, G. (2019). Monitoring H-cluster assembly using a semi-synthetic HydF protein. Dalton Transactions, 48(18), 5978-5986
Open this publication in new window or tab >>Monitoring H-cluster assembly using a semi-synthetic HydF protein
2019 (English)In: Dalton Transactions, ISSN 1477-9226, E-ISSN 1477-9234, Vol. 48, no 18, p. 5978-5986Article in journal (Refereed) Published
Abstract [en]

The [FeFe] hydrogenase enzyme interconverts protons and molecular hydrogen with remarkable efficiency. The reaction is catalysed by a unique metallo-cofactor denoted as the H-cluster containing an organometallic dinuclear Fe component, the [2Fe] subsite. The HydF protein delivers a precursor of the [2Fe] subsite to the apo-[FeFe] hydrogenase, thus completing the H-cluster and activating the enzyme. Herein we generate a semi-synthetic form of HydF by loading it with a synthetic low valent dinuclear Fe complex. We show that this semi-synthetic protein is practically indistinguishable from the native protein, and utilize this form of HydF to explore the mechanism of H-cluster assembly. More specifically, we show that transfer of the precatalyst from HydF to the hydrogenase enzyme results in the release of CO, underscoring that the pre-catalyst is a four CO species when bound to HydF. Moreover, we propose that an electron transfer reaction occurs during H-cluster assembly, resulting in an oxidation of the [2Fe] subsite with concomitant reduction of the [4Fe4S] cluster present on the HydF protein.

Place, publisher, year, edition, pages
ROYAL SOC CHEMISTRY, 2019
National Category
Theoretical Chemistry Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-390520 (URN)10.1039/c8dt04294b (DOI)000472449300013 ()30632592 (PubMedID)
Funder
Swedish Research Council, 621-2014-5670Swedish Research Council Formas, 213-2014-880EU, European Research Council, 714102
Available from: 2019-08-14 Created: 2019-08-14 Last updated: 2019-09-18Bibliographically approved
Shylin, S. I., Pavliuk, M. V., D'Amario, L., Fritsky, I. O. & Berggren, G. (2019). Photoinduced hole transfer from tris(bipyridine)ruthenium dye to a high-valent iron-based water oxidation catalyst. Faraday discussions (Online), 215, 162-174
Open this publication in new window or tab >>Photoinduced hole transfer from tris(bipyridine)ruthenium dye to a high-valent iron-based water oxidation catalyst
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2019 (English)In: Faraday discussions (Online), ISSN 1359-6640, E-ISSN 1364-5498, Vol. 215, p. 162-174Article in journal (Refereed) Published
Abstract [en]

An efficient water oxidation system is a prerequisite for developing solar energy conversion devices. Using advanced time-resolved spectroscopy, we study the initial catalytic relevant electron transfer events in the light-driven water oxidation system utilizing [Ru(bpy)(3)](2+) (bpy = 2,2 '-bipyridine) as a light harvester, persulfate as a sacrificial electron acceptor, and a high-valent iron clathrochelate complex as a catalyst. Upon irradiation by visible light, the excited state of the ruthenium dye is quenched by persulfate to afford a [Ru(bpy)(3)](3+)/SO4- pair, showing a cage escape yield up to 75%. This is followed by the subsequent fast hole transfer from [Ru(bpy)(3)](3+) to the Fe-IV catalyst to give the long-lived Fe-V intermediate in aqueous solution. In the presence of excess photosensitizer, this process exhibits pseudo-first order kinetics with respect to the catalyst with a rate constant of 3.2(1) x 10(10) s(-1). Consequently, efficient hole scavenging activity of the high-valent iron complex is proposed to explain its high catalytic performance for water oxidation.

Place, publisher, year, edition, pages
ROYAL SOC CHEMISTRY, 2019
National Category
Physical Chemistry
Identifiers
urn:nbn:se:uu:diva-392589 (URN)10.1039/c8fd00167g (DOI)000477683600011 ()30951052 (PubMedID)
Funder
EU, Horizon 2020, 778245Swedish Institute, 23913/2017
Available from: 2019-09-06 Created: 2019-09-06 Last updated: 2019-09-06Bibliographically approved
Grāve, K., Lambert, W., Berggren, G., Griese, J. J., Bennett, M. D., Logan, D. T. & Högbom, M. (2019). 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 access. Journal of Biological Inorganic Chemistry, 24(6), 849-861
Open this publication in new window or tab >>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 access
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2019 (English)In: Journal of Biological Inorganic Chemistry, ISSN 0949-8257, E-ISSN 1432-1327, Vol. 24, no 6, p. 849-861Article in journal (Refereed) Published
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·) 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 Å) and in complex with manganese (MnII/MnII, 1.30 Å). We also report three structures of the protein in complex with iron, either prepared anaerobically (FeII/FeII form, 1.32 Å), or prepared aerobically in the photo-reduced FeII/FeII form (1.63 Å) and with the partially oxidized metallo-cofactor (1.46 Å). 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.

Keywords
Oxidoreductase, Metalloprotein, Carboxylate shift, X-ray crystallography, Ferritin superfamily
National Category
Structural Biology
Identifiers
urn:nbn:se:uu:diva-390928 (URN)10.1007/s00775-019-01703-z (DOI)000487094500010 ()31410573 (PubMedID)
Funder
Knut and Alice Wallenberg Foundation, 2017.0275EU, European Research Council, HIGH-GEAR, 724394Swedish Research Council, 2017-04018EU, FP7, Seventh Framework Programme, 283570
Available from: 2019-08-15 Created: 2019-08-15 Last updated: 2019-10-31Bibliographically approved
Esmieu, C., Guo, M., Redman, H. J., Lundberg, M. & Berggren, G. (2019). Synthesis of a miniaturized [FeFe] hydrogenase model system. Dalton Transactions, 48(7), 2280-2284
Open this publication in new window or tab >>Synthesis of a miniaturized [FeFe] hydrogenase model system
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2019 (English)In: Dalton Transactions, ISSN 1477-9226, E-ISSN 1477-9234, Vol. 48, no 7, p. 2280-2284Article in journal (Refereed) Published
Abstract [en]

The reaction occurring during artificial maturation of [FeFe] hydrogenase has been recreated using molecular systems. The formation of a miniaturized [FeFe] hydrogenase model system, generated through the combination of a [4Fe4S] cluster binding oligopeptide and an organometallic Fe complex, has been monitored by a range of spectroscopic techniques. A structure of the final assembly is suggested based on EPR and FTIR spectroscopy in combination with DFT calculations. The capacity of this novel H-cluster model to catalyze H-2 production in aqueous media at mild potentials is verified in chemical assays.

Place, publisher, year, edition, pages
ROYAL SOC CHEMISTRY, 2019
National Category
Inorganic Chemistry Theoretical Chemistry
Identifiers
urn:nbn:se:uu:diva-379261 (URN)10.1039/c8dt05085f (DOI)000459626400004 ()30667428 (PubMedID)
Funder
Swedish Research Council, 621-2014-5670Swedish Research Council Formas, 213-2014-880EU, European Research Council, 714102Wenner-Gren Foundations
Available from: 2019-03-15 Created: 2019-03-15 Last updated: 2019-03-15Bibliographically approved
Grinberg, I. R., Lundin, D., Sahlin, M., Crona, M., Berggren, G., Hofer, A. & Sjoberg, B.-M. (2018). A glutaredoxin domain fused to the radical-generating subunit of ribonucleotide reductase (RNR) functions as an efficient RNR reductant. Journal of Biological Chemistry, 293(41), 15889-15900
Open this publication in new window or tab >>A glutaredoxin domain fused to the radical-generating subunit of ribonucleotide reductase (RNR) functions as an efficient RNR reductant
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2018 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 293, no 41, p. 15889-15900Article in journal (Refereed) Published
Abstract [en]

Class I ribonucleotide reductase (RNR) consists of a catalytic subunit (NrdA) and a radical-generating subunit (NrdB) that together catalyze reduction of ribonucleotides to their corresponding deoxyribonucleotides. NrdB from the firmicute Facklamia ignava is a unique fusion protein with N-terminal addons of a glutaredoxin (Grx) domain followed by an ATP-binding domain, the ATP cone. Grx, usually encoded separately from the RNR operon, is a known RNR reductant. We show that the fused Grx domain functions as an efficient reductant of the F. ignava class I RNR via the common dithiol mechanism and, interestingly, also via a monothiol mechanism, although less efficiently. To our knowledge, a Grx that uses both of these two reaction mechanisms has not previously been observed with a native substrate. The ATP cone is in most RNRs an N-terminal domain of the catalytic subunit. It is an allosteric on/off switch promoting ribonucleotide reduction in the presence of ATP and inhibiting RNR activity in the presence of dATP. We found that dATP bound to the ATP cone of F. ignava NrdB promotes formation of tetramers that cannot form active complexes with NrdA. The ATP cone bound two dATP molecules but only one ATP molecule. F. ignava NrdB contains the recently identified radical-generating cofactor Mn-III/Mn-IV. We show that NrdA from F. ignava can form a catalytically competent RNR with the Mn-III/Mn-IV-containing NrdB from the flavobacterium Leeuwenhoekiella blandensis. In conclusion, F. ignava NrdB is fused with a Grx functioning as an RNR reductant and an ATP cone serving as an on/off switch.

Place, publisher, year, edition, pages
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2018
Keywords
ribonucleotide reductase, allosteric regulation, oxidation-reduction (redox), radical, manganese, ATP-cone, dATP inhibition, dithiol-monothiol, glutaredoxin, tetramers
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-369105 (URN)10.1074/jbc.RA118.004991 (DOI)000447256000013 ()30166338 (PubMedID)
Funder
Swedish Research Council, 2016-01920Swedish Research Council, 621-2014-5670Swedish Research Council Formas, 213-2014-880EU, European Research Council, 714102Swedish Cancer Society, CAN 2016/670Carl Tryggers foundation The Wenner-Gren Foundation
Available from: 2018-12-17 Created: 2018-12-17 Last updated: 2018-12-17Bibliographically approved
Esmieu, C., Raleiras, P. & Berggren, G. (2018). From protein engineering to artificial enzymes - biological and biomimetic approaches towards sustainable hydrogen production. SUSTAINABLE ENERGY & FUELS, 2(4), 724-750
Open this publication in new window or tab >>From protein engineering to artificial enzymes - biological and biomimetic approaches towards sustainable hydrogen production
2018 (English)In: SUSTAINABLE ENERGY & FUELS, ISSN 2398-4902, Vol. 2, no 4, p. 724-750Article, review/survey (Refereed) Published
Abstract [en]

Hydrogen gas is used extensively in industry today and is often put forward as a suitable energy carrier due its high energy density. Currently, the main source of molecular hydrogen is fossil fuels via steam reforming. Consequently, novel production methods are required to improve the sustainability of hydrogen gas for industrial processes, as well as paving the way for its implementation as a future solar fuel. Nature has already developed an elaborate hydrogen economy, where the production and consumption of hydrogen gas is catalysed by hydrogenase enzymes. In this review we summarize efforts on engineering and optimizing these enzymes for biological hydrogen gas production, with an emphasis on their inorganic cofactors. Moreover, we will describe how our understanding of these enzymes has been applied for the preparation of bio-inspired/-mimetic systems for efficient and sustainable hydrogen production.

Place, publisher, year, edition, pages
ROYAL SOC CHEMISTRY, 2018
National Category
Chemical Sciences
Identifiers
urn:nbn:se:uu:diva-357183 (URN)10.1039/c7se00582b (DOI)000428778800002 ()
Funder
Swedish Research Council, 621-2014-5670Swedish Research Council Formas, 213-2014-880EU, European Research Council, 714102
Available from: 2018-08-13 Created: 2018-08-13 Last updated: 2018-08-13Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0002-6717-6612

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