Anti-leukemia Activity of 7-hydroxy-2-substituted-methyl-5 H -oxazolo[3,2- a] pyrimidin-5-one Derivatives

The synthesis of new 7-hydroxy-2-substituted-methyl-5 H -oxazolo[3,2- a] pyrimidin-5-ones derivatives, designed as structural bicyclic analogues of the iron chelator deferiprone, is described. They were tested for their ability to inhibit proliferation in human Bcr-Abl + leukemia cells.     

Acyclonucleoside Iron Chelators of 1‐(2‐Hydroxyethoxy)methyl‐2‐alkyl‐3‐hydroxy‐4‐pyridinones: Potential Oral Iron Chelation Therapeutics

The method of synthesizing acyclonucleoside iron chelators is both convenient and cost effective compared to that of synthesizing ribonucleoside iron chelators. The X‐ray crystal structural analysis shows that the 2‐hydroxyethoxymethyl group does not affect the geometry of the iron chelating sites. Therefore, the iron binding and removal properties of the acyclonucleoside iron chelators should remain similar to the ribonucleoside iron chelators, which is confirmed by the titration and competition reaction of the acyclonucleoside chelators with iron and ferritin, respectively. The acyclonucleoside iron chelators are more lipophilic with measured n‐octanol and Tris buffer distribution coefficients than ribonucleoside iron chelators.     

Post-transfusional iron overload in the haemoglobinopathies

In this report, we review the recent advances in evaluation and treatment of transfusional iron overload (IO). Results of the French thalassaemia registry are described. According to the disease, thalassaemia major or sickle cell anaemia, mechanisms and toxicity of iron overload, knowledge about IO long-term outcome and chelation treatment results, respective value of IO markers, differ. The recent tools evaluating organ specific IO and the diversification of iron chelator agents make possible to individualize chelation therapy in clinical practice. The severity of IO and the level of transfusional iron intake, the preferential localization of IO (heart/liver) as well as the tolerance and adherence profiles of the patient can now be taken into account. Introduction of cardiac magnetic resonance imaging for the quantification of myocardial iron and use of oral chelators have already been reported as decreasing the cardiac mortality rate related to IO in thalassaemia major patients. Long-term observation of patients under oral chelators will show if morbidity is also improving via a more continuous control of toxic iron and/or a better accessibility to cellular iron pools.     

Calcium and iron as key drivers of brown moss composition through differential effects on phosphorus availability

Brown moss-dominated rich fens are characterized by minerotrophic conditions, in which calcium (Ca) and iron (Fe) concentrations show large variations. We examined the relative importance of Ca and Fe in relation to the occurrence of three typical brown moss species: Scorpidium scorpioides, Scorpidium cossonii, and Hamatocaulis vernicosus. Peat chemistry was examined in 24 stands of brown moss-dominated rich fens: 12 in the Netherlands and 12 in central Sweden. Ca and Fe turned out to be important drivers of brown moss composition. Fens dominated by Scorpidium scorpioides or Scorpidium cossonii were characterized by high pore water Ca-concentrations and total soil Ca-contents, but low P-availability. In these Ca-rich, but Fe-poor fens, foliar N:P ratios of vascular vegetation exceeded 20?g?g^?1, indicating phosphorus (P)-limitation due to Ca-P precipitation or low P-sorption capacity due to low Fe-levels. In contrast, fens dominated by Hamatocaulis vernicosus were characterized by high pore water Fe-concentrations and total soil Fe-contents, but also relatively high P-availability. N:P ratios in these fens were below 13.5?g?g^?1, indicating potential nitrogen (N)-limitation. We conclude that the relative roles of Ca and Fe, as related to the geohydrological conditions present, strongly determine the brown moss composition in rich fens through their differential effects on plant P-availability.     

Meeting reports

This investigation documents the formation of Green Rust (GR) and immobilization of Ni 2+ in response to bacterial reduction of hydrous ferric oxide (HFO). In the absence of Ni 2+ , 79% of the total Fe(III) present as HFO was reduced; at 10 -3 and 10 -4 M Ni 2+ , 36% of the total Fe(III) was reduced, whereas 45 to 50% of the total Fe(III) was reduced at 10 -5 M Ni 2+ . The inhibitory effect of 10 -3 and 10 -4 M Ni 2+ on Fe(III)-reduction corresponded to a 50% decrease in number of viable cells relative to the Ni 2+ -free condition, and a 25% decrease at 10 -5 M Ni 2+ . A prominent GR peak at d = 10.9 nm was evident in X-ray diffraction patterns of postreduction residual solids from the cultures. Minor peaks arising for vivianite and magnetite were also present. In samples prepared for scanning electron microscopy, thin hexagonal plates of GR were easily distinguished as a solid phase transformation product of HFO. Small hexagonal sheets and fragments of larger GR plates were also observed in transmission electron microscopy whole mounts together with bacteria that were mineralized by surface precipitates of microcrystalline magnetite. Energy dispersive spectroscopy (EDS) confirmed that GR contained Fe and P, as well as Ni in those samples taken from the Ni 2+ -amended experiments. EDS detected neither P nor Ni in the magnetite precipitates associated with the bacterial cells. Dissolved Ni2 + concentrations decreased in an exponential fashion with respect to time in all experimental systems, corresponding to an overall first-order rate constant k of -0.030 day -1 . At the same time, a strong linear relationship (r 2 = 0.99) between the dissolved and solid phase Ni 2+ /Fe 2+ ratios over the entire period of the Fe(III)reduction experiments provided evidence that the solid-phase partitioning of Ni 2+ in GR extended from equilibrium solid-solution behavior.     

Geomicrobiology and Redox Geochemistry of the Karstified Miocene Gypsum Aquifer,Western Ukraine: The Study from Zoloushka Cave

The gypsum karst of the western Ukraine developed largely under artesian conditions. The Miocene aquifer is presently entrenched and dewatered over much of the territory, while it remains confined in the zone adjacent to the Carpathian Foredeep. The most prominent geochemical features of the Miocene aquifer system in the confined karst zone are: (1) the almost universal presence of a bioepigenetic calcite bed, enriched in the light carbon isotope, at the top of the gypsum (the "Ratynsky Limestone"), (2) the widespread sulfur mineralization associated with the above calcite bed (the region is one of the world's largest sulfur-bearing basins), and (3) high H 2 S and CO 2 in the groundwater. Intense microbial sulfate-reduction processes occur in the gypsum in this zone. Zoloushka Cave is the third longest (92 km) and the largest by volume (more than 7 2 10 5 m 3 ) gypsum cave in the world. It is a unique example of a young artesian cave that only during the Holocene became partly drained and during the last 50 years progressively dewatered due to a quarry operation. These rapid changes have induced a number of transitional geochemical processes, some of which appear to be bacterially mediated. Six groups of microorganisms have been identified in the cave. Our article discusses the aquifer geochemistry during the transitional stage in the light of the microbiological studies.     

Biomineralization of Poorly Crystalline Fe(III) Oxides by Dissimilatory Metal Reducing Bacteria (DMRB)

Dissimilatory metal reducing bacteria (DMRB) catalyze the reduction of Fe(III) to Fe(II) in anoxic soils, sediments, and groundwater. Two-line ferrihydrite is a bioavailable Fe(III) oxide form that is exploited by DMRB as a terminal electron acceptor. A wide variety of biomineralization products result from the interaction of DMRB with 2-line ferrihydrite. Here we describe the state of knowledge on the biotransformation of synthetic 2-line ferrihydrite by laboratory cultures of DMRB using select published data and new experimental results. A facultative DMRB is emphasized ( Shewanella putrefaciens ) upon which most of this work has been performed. Key factors controlling the identity of the secondary mineral suite are evaluated including medium composition, electron donor and acceptor concentrations, ferrihydrite aging/recrystallization status, sorbed ions, and co-associated crystalline Fe(III) oxides. It is shown that crystalline ferric (goethite, hematite, lepidocrocite), ferrous (siderite, vivianite), and mixed valence (magnetite, green rust) iron solids are formed in anoxic, circumneutral DMRB incubations. Some products are well rationalized based on thermodynamic considerations, but others appear to result from kinetic pathways driven by ions that inhibit interfacial electron transfer or the precipitation of select phases. The primary factor controlling the nature of the secondary mineral suite appears to be the Fe(II) supply rate and magnitude, and its surface reaction with the residual oxide and other sorbed ions. The common observation of end-product mineral mixtures that are not at global equilibrium indicates that microenvironments surrounding respiring DMRB cells or the reaction-path trajectory (over Eh-pH space) may influence the identity of the final biomineralization suite.     

Mechanism of Ferrous Iron Binding and Oxidation by Ferritin from a Pennate Diatom

A novel ferritin was recently found in Pseudo-nitzschia multiseries (PmFTN), a marine pennate diatom that plays a major role in global primary production and carbon sequestration into the deep ocean. Crystals of recombinant PmFTN were soaked in iron and zinc solutions, and the structures were solved to 1.65–2.2-Å resolution. Three distinct iron binding sites were identified as determined from anomalous dispersion data from aerobically grown ferrous soaked crystals. Sites A and B comprise the conserved ferroxidase active site, and site C forms a pathway leading toward the central cavity where iron storage occurs. In contrast, crystal structures derived from anaerobically grown and ferrous soaked crystals revealed only one ferrous iron in the active site occupying site A. In the presence of dioxygen, zinc is observed bound to all three sites. Iron oxidation experiments using stopped-flow absorbance spectroscopy revealed an extremely rapid phase corresponding to Fe(II) oxidation at the ferroxidase site, which is saturated after adding 48 ferrous iron to apo-PmFTN (two ferrous iron per subunit), and a much slower phase due to iron core formation. These results suggest an ordered stepwise binding of ferrous iron and dioxygen to the ferroxidase site in preparation for catalysis and a partial mobilization of iron from the site following oxidation.     

Structures of the Substrate-free and Product-bound Forms of HmuO,a Heme Oxygenase from Corynebacterium diphtheriae: X-RAY CRYSTALLOGRAPHY AND MOLECULAR DYNAMICS INVESTIGATION*?

Heme oxygenase catalyzes the degradation of heme to biliverdin, iron, and carbon monoxide. Here, we present crystal structures of the substrate-free, Fe³⁺-biliverdin-bound, and biliverdin-bound forms of HmuO, a heme oxygenase from Corynebacterium diphtheriae, refined to 1.80, 1.90, and 1.85 Å resolution, respectively. In the substrate-free structure, the proximal and distal helices, which tightly bracket the substrate heme in the substrate-bound heme complex, move apart, and the proximal helix is partially unwound. These features are supported by the molecular dynamic simulations. The structure implies that the heme binding fixes the enzyme active site structure, including the water hydrogen bond network critical for heme degradation. The biliverdin groups assume the helical conformation and are located in the heme pocket in the crystal structures of the Fe³⁺-biliverdin-bound and the biliverdin-bound HmuO, prepared by in situ heme oxygenase reaction from the heme complex crystals. The proximal His serves as the Fe³⁺-biliverdin axial ligand in the former complex and forms a hydrogen bond through a bridging water molecule with the biliverdin pyrrole nitrogen atoms in the latter complex. In both structures, salt bridges between one of the biliverdin propionate groups and the Arg and Lys residues further stabilize biliverdin at the HmuO heme pocket. Additionally, the crystal structure of a mixture of two intermediates between the Fe³⁺-biliverdin and biliverdin complexes has been determined at 1.70 Å resolution, implying a possible route for iron exit.