The role of the gulose-mannose part of bleomycin in activation of iron-molecular oxygen complexes.
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ABSTRACT:
SUBMITTER: Kenani A
PROVIDER: S-EPMC1149325 | biostudies-other | 1988 Jul
REPOSITORIES: biostudies-other
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Project description:The reaction of nitroxyl radicals TEMPO (2,2',6,6'-tetramethylpiperidinyloxyl) and AZADO (2-azaadamantane-N-oxyl) with an iron(I) synthon affords iron(II)-nitroxido complexes (Ar L)Fe(?1 -TEMPO) and (Ar L)Fe(?2 -N,O-AZADO) (Ar L=1,9-(2,4,6-Ph3 C6 H2 )2 -5-mesityldipyrromethene). Both high-spin iron(II)-nitroxido species are stable in the absence of weak C-H bonds, but decay via N-O bond homolysis to ferrous or ferric iron hydroxides in the presence of 1,4-cyclohexadiene. Whereas (Ar L)Fe(?1 -TEMPO) reacts to give a diferrous hydroxide [(Ar L)Fe]2 (?-OH)2 , the reaction of four-coordinate (Ar L)Fe(?2 -N,O-AZADO) with hydrogen atom donors yields ferric hydroxide (Ar L)Fe(OH)(AZAD). Mechanistic experiments reveal saturation behavior in C-H substrate and are consistent with rate-determining hydrogen atom transfer.
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Project description:Dioxygen (O(2)) activation by iron enzymes is responsible for many metabolically important transformations in biology. Often a high-valent iron oxo oxidant is proposed to form upon O(2) activation at a mononuclear nonheme iron center, presumably via intervening iron superoxo and iron peroxo species. While iron(IV) oxo intermediates have been trapped and characterized in enzymes and models, less is known of the putative iron(III) superoxo species. Utilizing a synthetic model for the 2-oxoglutarate-dependent monoiron enzymes, [(Tp(iPr2))Fe(II)(O(2)CC(O)CH(3))], we have obtained indirect evidence for the formation of the putative iron(III) superoxo species, which can undergo one-electron reduction, hydrogen-atom transfer, or conversion to an iron(IV) oxo species, depending on the reaction conditions. These results demonstrate the various roles that the iron(III) superoxo species can play in the course of O(2) activation at a nonheme iron center.
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Project description:Cytochrome c oxidase (ox heart cytochrome aa3) is reduced on illumination in the presence of a photocatalyst system containing deazaflavin and EDTA. The photo-reduced enzyme reacts with oxygen at neutral pH to give a form of ferric enzyme, whereas a corresponding sample partially reduced by light in the absence of any photocatalyst reacts with oxygen to give an oxyferri species ('oxygenated' enzyme). Reduction by the photocatalyst system at an alkaline pH value (9.0) also gives rise to fully reduced oxidase (both haem groups ferrous). At these pH values the immediate product after oxygen addition is a species with a 605-606 nm absorption band, not identical with ferrous cytochrome a, but capable of oxidizing added cytochrome c. This intermediate, which is unstable at neutral pH, may be analogous to the 'compound B' obtained by Chance and co-workers [Chance, Saronio & Leigh (1975) J. Biol. Chem. 250, 9226-9237; Chance, Saronio & Leigh (1979) Biochem. J. 177, 931-941] at low temperatures.
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Project description:The new iron(II)-thiolate complexes [((iPr)BIP)Fe(II)(SPh)(Cl)] (1) and [((iPr)BIP)Fe(II)(SPh)(OTf)] (2) [BIP = bis(imino)pyridine] were prepared as models for cysteine dioxygenase (CDO), which converts Cys to Cys-SO(2)H at a (His)(3)Fe(II) center. Reaction of 1 and 2 with O(2) leads to Fe-oxygenation and S-oxygenation, respectively. For 1 + O(2), the spectroscopic and reactivity data, including (18)O isotope studies, are consistent with an assignment of an iron(IV)-oxo complex, [((iPr)BIP)Fe(IV)(O)(Cl)](+) (3), as the product of oxygenation. In contrast, 2 + O(2) results in direct S-oxygenation to give a sulfonato product, PhSO(3)(-). The positioning of the thiolate ligand in 1 versus 2 appears to play a critical role in determining the outcome of O(2) activation. The thiolate ligands in 1 and 2 are essential for O(2) reactivity and exhibit an important influence over the Fe(III)/Fe(II) redox potential.
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Project description:Two recently discovered groups of prokaryotic di-metal carboxylate proteins harbor a heterodinuclear Mn/Fe cofactor. These are the class Ic ribonucleotide reductase R2 proteins and a group of oxidases that are found predominantly in pathogens and extremophiles, called R2-like ligand-binding oxidases (R2lox). We have recently shown that the Mn/Fe cofactor of R2lox self-assembles from Mn(II) and Fe(II) in vitro and catalyzes formation of a tyrosine-valine ether cross-link in the protein scaffold (Griese, J. J., Roos, K., Cox, N., Shafaat, H. S., Branca, R. M., Lehtiö, J., Gräslund, A., Lubitz, W., Siegbahn, P. E., and Högbom, M. (2013) Proc. Natl. Acad. Sci. U.S.A. 110, 17189-17194). Here, we present a detailed structural analysis of R2lox in the nonactivated, reduced, and oxidized resting Mn/Fe- and Fe/Fe-bound states, as well as the nonactivated Mn/Mn-bound state. X-ray crystallography and x-ray absorption spectroscopy demonstrate that the active site ligand configuration of R2lox is essentially the same regardless of cofactor composition. Both the Mn/Fe and the diiron cofactor activate oxygen and catalyze formation of the ether cross-link, whereas the dimanganese cluster does not. The structures delineate likely routes for gated oxygen and substrate access to the active site that are controlled by the redox state of the cofactor. These results suggest that oxygen activation proceeds via similar mechanisms at the Mn/Fe and Fe/Fe center and that R2lox proteins might utilize either cofactor in vivo based on metal availability.
| S-EPMC4646176 | biostudies-literature
Project description:The prevalence of pulmonary fibrosis is increasing with an aging population and its burden is likely to increase following COVID-19, with large financial and medical implications. As approved therapies in pulmonary fibrosis only slow disease progression, there is a significant unmet medical need. Hyperbaric oxygen (HBO) is the inhaling of pure oxygen, under the pressure of greater than one atmosphere absolute, and it has been reported to improve pulmonary function in patients with pulmonary fibrosis. Our recent study suggested that repetitive HBO exposure may affect biological processes in mice lungs such as response to wounding and extracellular matrix. To extend these findings, a bleomycin-induced pulmonary fibrosis mouse model was used to evaluate the effect of repetitive HBO exposure on pulmonary fibrosis. Building on our previous findings, we provide evidence that HBO exposure attenuates bleomycin-induced pulmonary fibrosis in mice. In vitro, HBO exposure could reverse, at least partially, transforming growth factor (TGF)-β-induced fibroblast activation, and this effect may be mediated by downregulating TGF-β-induced expression of hypoxia inducible factor (HIF)-1α. These findings support HBO as a potentially life-changing therapy for patients with pulmonary fibrosis, although further research is needed to fully evaluate this.
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Project description:Idiopathic pulmonary fibrosis (IPF) is a pernicious lung disease characterized by alveolar epithelial apoptosis, dysregulated repair of epithelial injury, scar formation, and respiratory failure. In this study, we identified phospholipase D (PLD)-generated phosphatidic acid (PA) signaling in the development of pulmonary fibrosis (PF). Of the PLD isoenzymes, the protein expression of PLD2, but not PLD1, was upregulated in lung tissues from IPF patients and bleomycin challenged mice. Both PLD1 (Pld1-/-)- and PLD2 (Pld2-/-)-deficient mice were protected against bleomycin-induced lung inflammation and fibrosis, thereby establishing the role of PLD in fibrogenesis. The role of PLD1 and PLD2 in bleomycin-induced lung epithelial injury was investigated by infecting bronchial airway epithelial cells (Beas2B) with catalytically inactive mutants of PLD (hPLD1-K898R or mPld2-K758R) or downregulation of expression of PLD1 or PLD2 with siRNA. Bleomycin stimulated mitochondrial (mt) superoxide production, mtDNA damage, and apoptosis in Beas2B cells, which was attenuated by the catalytically inactive mutants of PLD or PLD2 siRNA. These results show a role for PLD1 and PLD2 in bleomycin-induced generation of mt reactive oxygen species, mt DNA damage, and apoptosis of lung epithelial cells in mice. Thus, PLD may be a novel therapeutic target in ameliorating experimental PF in mice.
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Project description:Nutrient iron entering the blood binds transferrin (TFN)d, which delivers iron to cells in the body. In healthy individuals, ?30% of TFN is iron-bound while the remainder is unbound (apo-TFN). TFN saturates the plasma of individuals with iron-overload diseases such as hereditary hemochromatosis, prompting release of a poorly-defined low-molecular-mass (LMM) iron species called non-transferrin-bound iron (NTBI). An experiment was devised to directly detect NTBI in plasma of iron-deficient pigs and to assess the role of the liver which is known to bind NTBI. Catheters were surgically installed in the portal vein (PV) and either the caudal vena cava or the cranial vena cava. After the animals recovered, 57Fe II ascorbate was injected into the stomach via a feeding tube. Blood was removed through the catheters before and after injection; plasma became 57Fe-enriched after injection. 57Fe-enriched plasma was passed through a 10 kDa cutoff membrane and the flow-through solution (FTS) was subjected to size-exclusion liquid chromatography (LC). The eluent flowed into an ICP-MS where 56Fe and 57Fe were detected. Low-intensity iron peaks with masses of 400-1600 Da were observed, but none became enriched in 57Fe after injection. Rather, the injected 57Fe bound to apo-TFN. Viewed naively, this implies that nutrient-derived 57Fe in healthy mammals passes from the intestines to apo-TFN without first entering the blood as a LMM intermediate. In this case, nutrient iron exported from intestinal enterocytes of healthy individuals may quickly bind apo-TFN such that LMM iron species do not accumulate in blood plasma. Some 57Fe from the FTS may have adsorbed onto the column. In any event, the LMM iron species in plasma that eluted from the column must have originated from iron stored within the body, perhaps in macrophages - not directly from nutrient iron absorption. The liver absorbed and released LMM iron species, but the effect was modest, consistent with its role as a dynamic iron buffer. Passage through the liver also altered the distribution of different forms of TFN present in the PV.
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Project description:A series of tetranuclear iron complexes displaying a site-differentiated metal center was synthesized. Three of the metal centers are coordinated to our previously reported ligand, based on a 1,3,5-triarylbenzene motif with nitrogen and oxygen donors. The fourth (apical) iron center is coordinatively unsaturated and appended to the trinuclear core through three bridging pyrazolates and an interstitial ?4-oxide moiety. Electrochemical studies of complex [LFe3(PhPz)3OFe][OTf]2 revealed three reversible redox events assigned to the Fe(II)4/Fe(II)3Fe(III) (-1.733 V), Fe(II)3Fe(III)/Fe(II)2Fe(III)2 (-0.727 V), and Fe(II)2Fe(III)2/Fe(II)Fe(III)3 (0.018 V) redox couples. Combined Mössbauer and crystallographic studies indicate that the change in oxidation state is exclusively localized at the triiron core, without changing the oxidation state of the apical metal center. This phenomenon is assigned to differences in the coordination environment of the two metal sites and provides a strategy for storing electron and hole equivalents without affecting the oxidation state of the coordinatively unsaturated metal. The presence of a ligand-binding site allowed the effect of redox modulation on nitric oxide activation by an Fe(II) metal center to be studied. Treatment of the clusters with nitric oxide resulted in binding of NO to the apical iron center, generating a {FeNO}(7) moiety. As with the NO-free precursors, the three reversible redox events are localized at the iron centers distal from the NO ligand. Altering the redox state of the triiron core resulted in significant change in the NO stretching frequency, by as much as 100 cm(-1). The increased activation of NO is attributed to structural changes within the clusters, in particular, those related to the interaction of the metal centers with the interstitial atom. The differences in NO activation were further shown to lead to differential reactivity, with NO disproportionation and N2O formation performed by the more electron-rich cluster.
| S-EPMC4871614 | biostudies-literature
Project description:SARS-CoV-2 infection is characterized by a protean clinical picture that can range from asymptomatic patients to life-threatening conditions. Severe COVID-19 patients often display a severe pulmonary involvement and develop neutrophilia, lymphopenia, and strikingly elevated levels of IL-6. There is an over-exuberant cytokine release with hyperferritinemia leading to the idea that COVID-19 is part of the hyperferritinemic syndrome spectrum. Indeed, very high levels of ferritin can occur in other diseases including hemophagocytic lymphohistiocytosis, macrophage activation syndrome, adult-onset Still's disease, catastrophic antiphospholipid syndrome and septic shock. Numerous studies have demonstrated the immunomodulatory effects of ferritin and its association with mortality and sustained inflammatory process. High levels of free iron are harmful in tissues, especially through the redox damage that can lead to fibrosis. Iron chelation represents a pillar in the treatment of iron overload. In addition, it was proven to have an anti-viral and anti-fibrotic activity. Herein, we analyse the pathogenic role of ferritin and iron during SARS-CoV-2 infection and propose iron depletion therapy as a novel therapeutic approach in the COVID-19 pandemic.
| S-EPMC7366458 | biostudies-literature