| 1. |
- Aureliano, M., et al.
(författare)
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Decavanadate in vitro and in vivo effects : facts and opinions
- 2014
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Ingår i: Journal of Inorganic Biochemistry. - : Elsevier BV. - 0162-0134 .- 1873-3344. ; 137, s. 123-130
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Tidskriftsartikel (refereegranskat)abstract
- This review covers recent advances in the understanding of the in vitro and in vivo effects of decavanadate, (V10O28)(6-), particularly in mitochondria. In vivo toxicological studies involving vanadium rarely account for the fact that under physiological conditions some vanadium may be present in the form of the decavanadate ion, which may behave differently from ortho- and metavanadates. It has for example been demonstrated that vanadium levels in heart or liver mitochondria are increased upon decavanadate exposure. Additionally, in vitro studies have shown that mitochondrial depolarization (IC50, 40 nM) and oxygen consumption (IC50, 99 nM) are strongly affected by decavanadate, which causes reduction of cytochrome b (complex III). We review these recent findings which together suggest that the observed cellular targets, metabolic pathway and toxicological effects differ according to the species of vanadium present. Finally, the toxicological effects of decavanadate depend on several factors such as the mode of administration, exposure time and type of tissue. (C) 2014 Elsevier Inc. All rights reserved.
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| 2. |
- Das, Biswanath, et al.
(författare)
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A dinuclear zinc(II) complex of a new unsymmetric ligand with an N(5)0(2) donor set; A structural and functional model for the active site of zinc phosphoesterases
- 2014
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Ingår i: Journal of Inorganic Biochemistry. - : Elsevier BV. - 0162-0134 .- 1873-3344. ; 132, s. 6-17
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Tidskriftsartikel (refereegranskat)abstract
- The dinuclear complex [Zn-2(DPCPMP)(pivalate)](C10(4)), where DPCPMP is the new unsymmetrical ligand [2-(N-(3-((bis((pyridin-2-yl)methyl)amino)methyl)-2-hydroxy-5-methylbenzyl)-N-((pyridin2-y1)methyl)amino)acetic acid], has been synthesized and characterized. The complex is a functional model for zinc phosphoesterases with dinuclear active sites. The hydrolytic efficacy of the complex has been investigated using bis-(2,4-dinitrophenyl)phosphate(BDNPP), a DNA analog, as substrate. Speciation studies using potentiometric titrations have been performed for both the ligand and the corresponding dizinc complex to elucidate the formation of the active hydrolysis catalyst; they reveals that the dinuclear zinc(II) complexes, [Zn-2(DPCPMP)](2) and [Zn-2(DPCPMP)(OH)1 predominate the solution above pH 4. The relatively high pKa of 8.38 for water deprotonation suggests that a terminal hydroxide complex is formed. Kinetic investigations of BDNPP hydrolysis over the pH range 5.5-11.0 and with varying metal to ligand ratio (metal salt:ligand = 0.5:1 to 3:1) have been performed. Variable temperature studies gave the activation parameters triangle H double dagger = 95.6 kJ mol(-1), triangle S double dagger = 44.8 J mo1(-1) K-1, and 6,triangle G double dagger = 108.0 kJ mo1-1. The cumulative results indicate the hydroxido-bridged dinuclear Zn(II) complex [Zn-2(DPCPMP)(mu-OH)] (+) as the effective catalyst. The mechanism of hydrolysis has been probed by computational modeling using density functional theory (DFF). Calculations show that the reaction goes through one concerted step (S(N)2 type) in which the bridging hydroxide in the transition state becomes terminal and performs a nucleophilic attack on the BDNPP phosphorus; the leaving group dissociates simultaneously in an overall inner sphere type activation. The calculated free energy barrier is in good agreement with the experimentally determined activation parameters.
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| 3. |
- Das, Biswanath, et al.
(författare)
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A dinuclear zinc(II) complex of a new unsymmetric ligand with an N5O2 donor set; A structural and functional model for the active site of zinc phosphoesterases.
- 2014
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Ingår i: Journal of Inorganic Biochemistry. - : Elsevier BV. - 1873-3344 .- 0162-0134. ; 132:Online 13 August 2013, s. 6-17
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Tidskriftsartikel (refereegranskat)abstract
- The dinuclear complex [Zn2(DPCPMP)(pivalate)](ClO4), where DPCPMP is the new unsymmetrical ligand [2-(N-(3-((bis((pyridin-2-yl)methyl)amino)methyl)-2-hydroxy-5-methylbenzyl)-N-((pyridin-2-yl)methyl)amino)acetic acid], has been synthesized and characterized. The complex is a functional model for zinc phosphoesterases with dinuclear active sites. The hydrolytic efficacy of the complex has been investigated using bis-(2,4-dinitrophenyl)phosphate (BDNPP), a DNA analog, as substrate. Speciation studies using potentiometric titrations have been performed for both the ligand and the corresponding dizinc complex to elucidate the formation of the active hydrolysis catalyst; they reveals that the dinuclear zinc(II) complexes, [Zn2(DPCPMP)](2+) and [Zn2(DPCPMP)(OH)](+) predominate the solution above pH4. The relatively high pKa of 8.38 for water deprotonation suggests that a terminal hydroxide complex is formed. Kinetic investigations of BDNPP hydrolysis over the pH range 5.5-11.0 and with varying metal to ligand ratio (metal salt:ligand=0.5:1 to 3:1) have been performed. Variable temperature studies gave the activation parameters ΔH(‡)=95.6kJmol(-1), ΔS(‡)=-44.8Jmol(-1)K(-1), and ΔG(‡)=108.0kJmol(-1). The cumulative results indicate the hydroxido-bridged dinuclear Zn(II) complex [Zn2(DPCPMP)(μ-OH)](+) as the effective catalyst. The mechanism of hydrolysis has been probed by computational modeling using density functional theory (DFT). Calculations show that the reaction goes through one concerted step (SN2 type) in which the bridging hydroxide in the transition state becomes terminal and performs a nucleophilic attack on the BDNPP phosphorus; the leaving group dissociates simultaneously in an overall inner sphere type activation. The calculated free energy barrier is in good agreement with the experimentally determined activation parameters.
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| 4. |
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| 5. |
- Fraqueza, Gil, et al.
(författare)
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Sarcoplasmic reticulum calcium ATPase interactions with decaniobate, decavanadate, vanadate, tungstate and molybdate
- 2012
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Ingår i: Journal of Inorganic Biochemistry. - : Elsevier BV. - 0162-0134 .- 1873-3344. ; 107:1, s. 82-89
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Tidskriftsartikel (refereegranskat)abstract
- Over the last few decades there has been increasing interest in oxometalate and polyoxometalate applications to medicine and pharmacology. This interest arose, at least in part, due to the properties of these classes of compounds as anti-cancer, anti-diabetic agents, and also for treatment of neurodegenerative diseases, among others. However, our understanding of the mechanism of action would be improved if biological models could be used to clarify potential toxicological effects in main cellular processes. Sarcoplasmic reticulum (SR) vesicles, containing a large amount of Ca(2+)-ATPase, an enzyme that accumulates calcium by active transport using ATP, have been suggested as a useful model to study the effects of oxometalates on calcium homeostasis. In the present article, it is shown that decavanadate, decaniobate, vanadate, tungstate and molybdate, all inhibited SR Ca(2+)-ATPase, with the following IC(50) values: 15, 35, 50, 400 mu M and 45 mM, respectively. Decaniobate (Nb(10)), is the strongest P-type enzyme inhibitor, after decavanadate (V(10)). Atomic-absorption spectroscopy (AAS) analysis, indicates that decavanadate binds to the protein with a 1:1 decavanadate:Ca(2+)-ATPase stoichiometry. Furthermore, V10 binds with similar extension to all the protein conformations, which occur during calcium translocation by active transport, namely El, El P, E2 and E2P, as analysed by MS. In contrast, it was confirmed that the binding of monomeric vanadate (H(2)VO(4)(2-):V(1)) to the calcium pump is favoured only for the E2 and E2P conformations of the ATPase, whereas no significant amount of vanadate is bound to the E1 and E1P conformations. Scatchard plot analysis, confirmed a 1:1 ratio for decavanadate-Ca(2+)-ATPase, with a dissociation constant, k(d) of 1 mu M(-1). The interaction of decavanadate V(10)O(28)(6-) (V(10)) with Ca(2+)-ATPase is prevented by the isostructural and isoelectronic decaniobate Nb(10)O(28)(6-) (Nb(10)), whereas no significant effects were detected with ATP or with heparin, a known competitive ATP binding molecule, suggesting that V(10) binds non-competitively, with respect to ATP, to the protein. Finally, it was shown that decaniobate inhibits SR Ca(2+)-ATPase activity in a non competitive type of inhibition, with respect to ATP. Taken together, these data demonstrate that decameric niobate and vanadate species are stronger inhibitors of the SR calcium ATPase than simple monomeric vanadate, tungstate and molybdate oxometalates, thus affecting calcium homeostasis, cell signalling and cell bioenergetics, as well many other cellular processes. The ability of these oxometalates to act either as phosphate analogues, as a transition-state analogue in enzyme-catalysed phosphoryl group transfer processes and as potentially nucleotide-dependent enzymes modulators or inhibitors, suggests that different oxometalates may reveal different mechanistic preferences in these classes of enzymes. (C) 2011 Elsevier Inc. All rights reserved.
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| 6. |
- Glans, Lotta, et al.
(författare)
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Synthesis, characterization and antimalarial activity of new chromium arene-quinoline half sandwich complexes.
- 2011
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Ingår i: Journal of Inorganic Biochemistry. - : Elsevier BV. - 1873-3344 .- 0162-0134. ; 105:7, s. 985-990
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Tidskriftsartikel (refereegranskat)abstract
- Organometallic analogs of chloroquine (CQ) are of interest as drug candidates that may be able to overcome the widespread chloroquine resistance developed by malaria parasites. Two new chromium arene CQ-analogs: [η(6)-N-(7-chloroquinolin-4-yl)-N'-(2-dimethylamino-methylbenzyl)-ethane-1,2-diamine]tricarbonylchromium 4 and [η(6)-N-(7-chloroquinolin-4-yl)-N'-(2-dimethylaminobenzyl)-ethane-1,2-diamine]tricarbonylchromium 9 have been synthesized and characterized. In addition, X-ray crystal structures of the intermediates (η(6)-benzyldimethylamine)tricarbonylchromium 2, [η(6)-2-((dimethylamino)methyl) benzaldehyde]tricarbonylchromium 3 and p-(η(6)-dimethylaminobenzaldehyde)tricarbonyl chromium 8 are reported. Compound 4 was more active than chloroquine against both CQ-sensitive and CQ-resistant strains of Plasmodium falciparum when antimalarial activity was tested in vitro. The activity of 4 against the CQ-resistant parasite strain was twice as high as for the organic ligand alone (IC(50) values of 33.9nM versus 63.1nM).
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| 7. |
- Hakobyan, Shoghik, et al.
(författare)
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Proton and gallium(III) binding properties of a biologically active salicylidene acylhydrazide
- 2014
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Ingår i: Journal of Inorganic Biochemistry. - : Elsevier. - 0162-0134 .- 1873-3344. ; 138, s. 9-15
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Tidskriftsartikel (refereegranskat)abstract
- Bacterial biofilm formation causes a range of problems in our society, especially in health care. Salicylidene acylhydrazides (hydrazones) are promising antivirulence drugs targeting secretion systems used during bacterial infection of host cells. When mixed with the gallium ion they become especially potent as bacterial and biofilm growth-suppressing agents, although the mechanisms through which this occurs are not fully understood. At the base of this uncertainty lies the nature of hydrazone-metal interactions. This study addresses this issue by resolving the equilibrium speciation of hydrazone-gallium aqueous solutions. The protonation constants of the target 2-oxo-2-[N-(2,4,6-trihydroxy-benzylidene)-hydrazino]-acetamide (ME0163) hydrazone species and of its 2,4,6-trihydroxybenzaldehyde and oxamic acid hydrazide building blocks were determined by UV-visible spectrophotometry to achieve this goal. These studies show that the hydrazone is an excessively strong complexing agent for gallium and that its antivirulence properties are predominantly ascribed to monomeric 1:1Ga-ME0163 complexes of various Ga hydrolysis and ME0163 protonation states. The chelation of Ga(III) to the hydrazone also increased the stability of the compounds against acid-induced hydrolysis, making this group of compounds very interesting for biological applications where the Fe-antagonist action of both Ga(III) and the hydrazone can be combined for enhanced biological effect.
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| 8. |
- Liao, Rong-Zhen, 1983-, et al.
(författare)
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Dipeptide hydrolysis by the dinuclear zinc enzyme human renal dipeptidase: Mechanistic insights from DFT calculations
- 2010
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Ingår i: Journal of Inorganic Biochemistry. - : Elsevier BV. - 0162-0134 .- 1873-3344. ; 104:1, s. 37-46
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Tidskriftsartikel (refereegranskat)abstract
- The reaction mechanism of the dinuclear zinc enzyme human renal dipeptidase is investigated using hybrid density functional theory. This enzyme catalyzes the hydrolysis of dipeptides and beta-lactam antibiotics. Two different protonation states in which the important active site residue Asp288 is either neutral or ionized were considered. In both cases, the bridging hydroxide is shown to be capable of performing the nucleophilic attack on the substrate carbonyl carbon from its bridging position, resulting in the formation of a tetrahedral intermediate. This step is followed by protonation of the dipeptide nitrogen, coupled with C-N bond cleavage. The calculations establish that both cases have quite feasible energy barriers. When the Asp288 is neutral, the hydrolytic reaction occurs with a large exothermicity. However, the reaction becomes very close to thermoneutral with an ionized Asp288. The two zinc ions are shown to play different roles in the reaction. Zn1 binds the amino group of the substrate, and Zn2 interacts with the carboxylate group of the substrate, helping in orienting it for the nucleophilic attack. In addition, Zn2 stabilizes the oxyanion of the tetrahedral intermediate, thereby facilitating the nucleophilic attack
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| 9. |
- Liao, Rong-Zhen, 1983-, et al.
(författare)
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Tungsten-dependent formaldehyde ferredoxin oxidoreductase : Reaction mechanism from quantum chemical calculations
- 2011
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Ingår i: Journal of Inorganic Biochemistry. - : Elsevier BV. - 0162-0134 .- 1873-3344. ; 105:7, s. 927-936
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Tidskriftsartikel (refereegranskat)abstract
- Formaldehyde ferredoxin oxidoreductase from Pyrococcus furiosus is a tungsten-dependent enzyme thatcatalyzes the oxidation of formaldehyde to formic acid. In the present study, quantum chemical calculationsare used to elucidate the reaction mechanism of this enzyme. Several possible mechanistic scenarios areinvestigated with a large model of the active site designed on the basis of the X-ray crystal structure of thenative enzyme. Based on the calculations, we propose a new mechanism in which the formaldehyde substratebinds directly to the tungsten ion.WVI=O then performs a nucleophilic attack on the formaldehyde carbon toform a tetrahedral intermediate. In the second step, which is calculated to be rate limiting, a proton istransferred to the second-shell Glu308 residue, coupled with a two-electron reduction of the tungsten ion.The calculated barriers for the mechanism are energetically very feasible and in relatively good agreementwith experimental rate constants. Three other second-shell mechanisms, including one previously proposedbased on experimental findings, are considered but ruled out because of their high barriers.
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| 10. |
- Lindgren, Joel, et al.
(författare)
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Engineered non-fluorescent Affibody molecules facilitate studies of the amyloid-beta (A beta) peptide in monomeric form : Low pH was found to reduce A beta/Cu(II) binding affinity
- 2013
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Ingår i: Journal of Inorganic Biochemistry. - : Elsevier BV. - 0162-0134 .- 1873-3344. ; 120, s. 18-23
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Tidskriftsartikel (refereegranskat)abstract
- Aggregation of amyloid-beta (A beta) peptides into oligomers and amyloid plaques in the human brain is considered a causative factor in Alzheimer's disease (AD). As metal ions are over-represented in AD patient brains, and as distinct A beta aggregation pathways in presence of Cu(II) have been demonstrated, metal binding to A beta likely affects AD progression. A beta aggregation is moreover pH-dependent, and AD appears to involve inflammatory conditions leading to physiological acidosis. Although metal binding specificity to A beta varies at different pH's, metal binding affinity to A beta has so far not been quantitatively investigated at sub-neutral pH levels. This may be explained by the difficulties involved in studying monomeric peptide properties under aggregation-promoting conditions. We have recently devised a modified Affibody molecule, Z(A beta 3)(12-58), that binds A beta with sub-nanomolar affinity, thereby locking the peptide in monomeric form without affecting the N-terminal region where metal ions bind. Here, we introduce non-fluorescent A beta-binding Affibody variants that keep A beta monomeric while only slightly affecting the A beta peptide's metal binding properties. Using fluorescence spectroscopy, we demonstrate that Cu(II)/A beta(1-40) binding is almost two orders of magnitude weaker at pH 5.0 (apparent K-D = 51 mu M) than at pH 7.3 (apparent K-D = 0.86 mu M). This effect is arguably caused by protonation of the histidines involved in the metal ligandation. Our results indicate that engineered variants of Affibody molecules are useful for studying metal-binding and other properties of monomeric A beta under various physiological conditions, which will improve our understanding of the molecular mechanisms involved in AD.
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