| 1. |
- Czapla-Masztafiak, Joanna, et al.
(författare)
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Mechanism of hydrolysis of a platinum(IV) complex discovered by atomic telemetry
- 2018
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Ingår i: Journal of Inorganic Biochemistry. - : ELSEVIER SCIENCE INC. - 0162-0134 .- 1873-3344. ; 187, s. 56-61
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Tidskriftsartikel (refereegranskat)abstract
- Herein we report on the hydrolysis mechanism of [Pt{N(p-HC6F4)CH2}(2)(NC5H5)(2)(OH)(2)], a platinum(IV) complex that exhibits anti-cancer properties. Atomic telemetry, an in situ technique based on electron structure sensitive X-ray spectroscopy, revealed that hydrolysis preceded any reduction of the metal center. The obtained results are complemented with F-19 NMR measurements and theoretical calculations and support the observation that this Pt-II complex does not reduce spontaneously to Ptll in HEPES buffer solution at pH 7.4 and after 24 h incubation. These results are of importance for the design of novel Pt-based coordination complexes as well as understanding their behavior under physiological conditions.
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| 2. |
- Hakobyan, Shoghik, et al.
(författare)
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Influence of Chelation Strength and Bacterial Uptake of Gallium Salicylidene Acylhydrazide on Biofilm Formation and Virulence by Pseudomonas aeruginosa
- 2016
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Ingår i: Journal of Inorganic Biochemistry. - : Elsevier. - 0162-0134 .- 1873-3344. ; 160, s. 24-32
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Tidskriftsartikel (refereegranskat)abstract
- Development of antibiotic resistance in bacteria causes major challenges for our society and has prompted a great need for new and alternative treatment methods for infection. One promising approach is to target bacterial virulence using for example salicylidene acylhydrazides (hydrazones). Hydrazones coordinate metal ions such as Fe(III) and Ga(III) through a five-membered and a six-membered chelation ring. One suggested mode of action is via restricting bacterial Fe uptake. Thus, it was hypothesized that the chelating strength of these substances could be used to predict their biological activity on bacterial cells. This was investigated by comparing Ga chelation strength of two hydrazone complexes, as well as bacterial Ga uptake, biofilm formation, and virulence in the form of production and secretion of a toxin (ExoS) by Pseudomonas aeruginosa. Equilibrium constants for deprotonation and Ga(III) binding of the hydrazone N′-(5-chloro-2-hydroxy-3-methylbenzylidene)-2,4-dihydroxybenzhydrazide (ME0329), with anti-virulence effect against P. aeruginosa, were determined and compared to bacterial siderophores and the previously described Ga(III) 2-oxo-2-[N-(2,4,6-trihydroxy-benzylidene)-hydrazino]-acetamide (Ga-ME0163) and Ga-citrate complexes. In comparison with these two complexes, it was shown that the uptake of Ga(III) was higher from the Ga-ME0329 complex. The results further show that the Ga-ME0329 complex reduced ExoS expression and secretion to a higher extent than Ga-citrate, Ga-ME0163 or the non-coordinated hydrazone. However, the effect against biofilm formation by P. aeruginosa, by the ME0329 complex, was similar to Ga-citrate and lower than what has been reported for Ga-ME0163.
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| 3. |
- Kutin, Yuri, et al.
(författare)
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Divergent assembly mechanisms of the manganese/iron cofactors in R2lox and R2c proteins
- 2016
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Ingår i: Journal of Inorganic Biochemistry. - : Elsevier BV. - 0162-0134 .- 1873-3344. ; 162, s. 164-177
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Tidskriftsartikel (refereegranskat)abstract
- A manganese/iron cofactor which performs multi-electron oxidative chemistry is found in two classes of ferritin-like proteins, the small subunit (R2) of dass Ic ribonucleotide reductase (R2c) and the R2-like ligand-binding oxidase (R2lox). It is undear how a heterodimeric Mn/Fe metallocofactor is assembled in these two related proteins as opposed to a homodimeric Fe/Fe cofactor, especially considering the structural similarity and proximity of the two metal-binding sites in both protein scaffolds and the similar first coordination sphere ligand preferences of Mn-II and Fe-II. Using EPR and Mfissbauer spectroscopies as well as X-ray anomalous dispersion, we examined metal loading and cofactor activation of both proteins in vitro (in solution). We find divergent cofactor assembly mechanisms for the two systems. In both cases, excess Mn-II promotes heterobimetallic cofactor assembly. In the absence of Fe-II, R2c cooperatively binds Mn-II at both metal sites, whereas R2lox does not readily bind Mn-II at either site. Heterometallic cofactor assembly is favored at substoichiometric Feu concentrations in R2lox. Fe-II and Mn-II likely bind to the protein in a stepwise fashion, with Feu binding to site 2 initiating cofactor assembly. In R2c, however, heterometallic assembly is presumably achieved by the displacement of Mn-II by Fe-II at site 2. The divergent metal loading mechanisms are correlated with the putative in vivo functions of R2c and R2lox, and most likely with the intracellular Mn-II/Fe-II concentrations in the host organisms from which they were isolated.
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| 4. |
- Moa, Sara, et al.
(författare)
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Quantum chemical study of mechanism and stereoselectivity of secondary alcohol dehydrogenase
- 2017
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Ingår i: Journal of Inorganic Biochemistry. - : Elsevier BV. - 0162-0134 .- 1873-3344. ; 175, s. 259-266
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Tidskriftsartikel (refereegranskat)abstract
- Secondary alcohol dehydrogenase from Thermoanaerobacter brockii (TbSADH) is a Zn- and NADP-dependent enzyme that catalyses the reversible transformation of secondary alcohols into ketones. It is of potential biocatalytic interest as it can be used in the synthesis of chiral alcohols by asymmetric reduction of ketones. In this paper, density functional theory calculations are employed to elucidate the origins of the enantioselectivity of TbSADH using a large model of the active site and considering two different substrates, 2-butanol and 3-hexanol. For these two substrates the enzyme has experimentally been shown to have the opposite enantioselectivity. The energy profiles for the reactions are calculated and the stationary points along the reaction path are characterised. The calculations first confirm that the general mechanism proposed for other alcohol dehydrogenases is energetically viable. In this mechanism, a proton is first transferred from the substrate to a histidine residue at the surface, followed by a hydride transfer to the NADP cofactor. The calculated overall energy barrier is consistent with the measured rate constant. Very importantly, the calculations are able to reproduce and rationalise the enantioselectivity of the enzyme for both substrates. The detailed characterisation of the energies and geometries of the involved transition states will be valuable in the rational engineering of TbSADH to expand its utility in biocatalysis.
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| 5. |
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| 6. |
- Raleiras, Patrícia, et al.
(författare)
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Photoinduced reduction of the medial FeS center in the hydrogenase small subunit HupS from Nostoc punctiforme
- 2015
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Ingår i: Journal of Inorganic Biochemistry. - : Elsevier BV. - 0162-0134 .- 1873-3344. ; 148, s. 57-61
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Tidskriftsartikel (refereegranskat)abstract
- The small subunit from the NiFe uptake hydrogenase, HupSL, in the cyanobacterium Nostoc punctiforme ATCC 29133, has been isolated in the absence of the large subunit (P. Raleiras, P. Kellers, P. Lindblad, S. Styring, A. Magnuson, J. Biol. Chem. 288 (2013) 18,345-18,352). Here, we have used flash photolysis to reduce the iron-sulfur clusters in the isolated small subunit, HupS. We used ascorbate as electron donor to the photogenerated excited state of Ru(II)-trisbipyridine (Ru(bpy)3), to generate Ru(I)(bpy)3 as reducing agent. Our results show that the isolated small subunit can be reduced by the Ru(I)(bpy)3 generated through flash photolysis.
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| 7. |
- Dong, Geng, et al.
(författare)
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Effect of the protein ligand in DMSO reductase studied by computational methods
- 2017
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Ingår i: Journal of Inorganic Biochemistry. - : Elsevier BV. - 0162-0134. ; 171, s. 45-51
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Tidskriftsartikel (refereegranskat)abstract
- The DMSO reductase family is the largest and most diverse family of mononuclear molybdenum oxygen-atom-transfer proteins. Their active sites contain a Mo ion coordinated to two molybdopterin ligands, one oxo group in the oxidised state, and one additional, often protein-derived ligand. We have used density-functional theory to evaluate how the fourth ligand (serine, cysteine, selenocysteine, OH−, O2–, SH−, or S2–) affects the geometries, reaction mechanism, reaction energies, and reduction potentials of intermediates in the DMSO reductase reaction. Our results show that there are only small changes in the geometries of the reactant and product states, except from the elongation of the Mo[sbnd]X bond as the ionic radius of X[dbnd]O, S, Se increases. The five ligands with a single negative charge gave an identical two-step reaction mechanism, in which DMSO first binds to the reduced active site, after which the S[sbnd]O bond is cleaved, concomitantly with the transfer of two electrons from Mo in a rate-determining second transition state. The five models gave similar activation energies of 69–85 kJ/mol, with SH− giving the lowest barrier. In contrast, the O2– and S2– ligands gave much higher activation energies (212 and 168 kJ/mol) and differing mechanisms (a more symmetric intermediate for O2– and a one-step reaction without any intermediate for S2–). The high activation energies are caused by a less exothermic reaction energy, 13–25 kJ/mol, and by a more stable reactant state owing to the strong Mo[sbnd]O2– or Mo[sbnd]S2– bonds.
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| 8. |
- Stringer, Tameryn, et al.
(författare)
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Evaluation of PTA-derived ruthenium(II) and iridium(III) quinoline complexes against chloroquine-sensitive and resistant strains of the Plasmodium falciparum malaria parasite
- 2019
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Ingår i: Journal of Inorganic Biochemistry. - : Elsevier BV. - 0162-0134. ; 191, s. 164-173
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Tidskriftsartikel (refereegranskat)abstract
- Cationic 1,3,5‑triaza‑phosphaadamantane (PTA) quinoline ruthenium(II) and iridium(III) complexes were successfully synthesized and characterized using standard spectroscopic and analytical techniques. The complexes were evaluated for their in vitro antiplasmodial activities against the chloroquine-sensitive (CQS) NF54 and chloroquine-resistant (CQR) K1 strains of the Plasmodium falciparum species of the malaria parasite and were found to exhibit good activities in the sensitive strain but moderate activities in the resistant strain, suggesting a resistance mechanism similar to chloroquine (CQ). Selected samples were screened for their ability to inhibit synthetic haemozoin formation and were found to be inhibitors with similar activity to CQ. The complexes also exhibit moderate to low cytotoxicity when evaluated against the Chinese Hamster Ovarian (CHO) cell-line in vitro, suggesting selectivity towards the malaria parasite rather than mammalian cells.
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