Iron-containing Enzymes Research Articles

Yeast optimizes metal utilization based on metabolic network and enzyme kinetics

Metal ions are vital to metabolism, as they can act as cofactors on enzymes and thus modulate individual enzymatic reactions. Although many enzymes have been reported to interact with metal ions, the quantitative relationships between metal ions and metabolism are lacking. Here, we reconstructed a genome-scale metabolic model of the yeast Saccharomyces cerevisiae to account for proteome constraints and enzyme cofactors such as metal ions, named CofactorYeast. The model is able to estimate abundances of metal ions binding on enzymes in cells under various conditions, which are comparable to measured metal ion contents in biomass. In addition, the model predicts distinct metabolic flux distributions in response to reduced levels of various metal ions in the medium. Specifically, the model reproduces changes upon iron deficiency in metabolic and gene expression levels, which could be interpreted by optimization principles (i.e., yeast optimizes iron utilization based on metabolic network and enzyme kinetics rather than preferentially targeting iron to specific enzymes or pathways). At last, we show the potential of using the model for understanding cell factories that harbor heterologous iron-containing enzymes to synthesize high-value compounds such as p-coumaric acid. Overall, the model demonstrates the dependence of enzymes on metal ions and links metal ions to metabolism on a genome scale.

Research progress of the decarboxylation mechanisms of fatty acids to generate aliphatic hydrocarbons catalyzed by iron-containing enzymes

With the progress of human society, the consumption of energy materials is increasing in particularly the fossil fuels, which accounts for 84.7% of the total global consumption in 2018. Thus, excessive exploitation of fossil fuels not only brings about an increasingly serious energy crisis, but also leads to a series of environmental problems, such as the air quality deterioration and soil acidification, which are not conducive to the sustainable development of society. Since the 21st Annual Conference of the China Association for Science and Technology in 2019, “renewable synthetic fuels” has become one of the focuses of attention, and it also puts forward higher requirements for the research and development of renewable energy. About 60 years ago, many plants, insects, microorganisms and microalgae were found to metabolize hydrocarbons. In 2010, Schirmer’s groups recognized the alkane biosynthesis pathways of marine chlorobacteria, which aroused great interest in hydrocarbon biosynthesis. Recently, more proteases to catalyze the synthesis of hydrocarbons have been successively discovered, such as aldehyde deformylase (ADO, CYP4G and CER), fatty acid decarboxylase (UndA, UndB and OleT), polyketone synthase (Ols) and thiolytic enzyme complex system (OleABCD). In the past decades, many studies have been conducted to explore the biosynthesis of hydrocarbon, and useful information regarding the reaction mechanism has been obtained, including the kinetic rate constants and the crystal structures of the enzymes. In addition, on the basis of crystal structure, quantum chemistry method (QM) and molecular dynamics simulations (MD) were also used to explore the reaction mechanism of fatty acid decarboxylation. Since most enzymes involved in the hydrocarbon biosynthesis are iron-containing enzymes, which employ the Fe-coordinate dioxygen to trigger the reaction. In general, the whole reaction cycle contains the binding of substrates and dioxygen, and decarboxylation usually involves the hydrogen atom abstraction and breaking of C−C bond. During the reaction, complex electron transfer takes place among the Fe center, O2 and substrate, and many factors were found to affect the catalytic activity. According to the previous experimental and theoretical studies, different enzymes show different activity and substrate scope. In general, the catalytic efficiency is still very low for most enzymes, and thus, understanding the mechanism of these catalytic reactions is undoubtedly an important basis for engineering optimization and all applications, and can also provide ideas for the design and synthesis of biomimetic catalysts. In this paper, we review the research progress of five representative iron enzymes that catalyze the biosynthesis of aliphatic hydrocarbon, including OleT, UndA, UndB, ADO and CYP4G, and discuss the future development and application of enzyme catalysis in renewable synthetic fuels. This paper may offer some ideas and guidelines for sustainable energy supply in the future.

Biodegradation of aromatic pollutants by metalloenzymes: A structural-functional-environmental perspective

• Biodegradation of environmental pollutants has been favored for decades. • Significant progress has been made in the biodegradation of aromatic pollutants by metalloenzymes. • Both native and artificial metalloenzymes have been applied for biodegradation. • The progress sheds light on the structure-function relationship of metalloenzymes. • The progress provides clues for applications of metalloenzymes in environmental protection. Environmental security is closely related to public health. Aromatic pollutants constitute a class of hazardous environmental chemicals, such as halophenols and polycyclic aromatic hydrocarbons. Biodegradation of environmental pollutants has been favored for decades. As reviewed herein, significant progress has been made in biodegradation of aromatic pollutants by native metalloenzymes, including heme enzymes (peroxidases and cytochrome P450s), non-heme iron-containing enzymes (Rieske dioxygenases), and copper-containing enzymes (catechol oxidase, tyrosinase, and laccase), and artificial metalloenzymes, including engineered myoglobins, designed manganese peroxidase and de novo designed metalloenzymes, such as those in helical bundles and peptide assemblies, as well as synthetic structural and functional models of natural enzymes. These advances shed light on the structure–function relationship of metalloenzymes, providing clues for potential applications in environmental protection. Future directions for making full use of native and artificial metalloenzymes in environmental science are also prospected.

Iron Complexes of Flavonoids-Antioxidant Capacity and Beyond.

Flavonoids are common plant natural products able to suppress ROS-related damage and alleviate oxidative stress. One of key mechanisms, involved in this phenomenon is chelation of transition metal ions. From a physiological perspective, iron is the most significant transition metal, because of its abundance in living organisms and ubiquitous involvement in redox processes. The chemical, pharmaceutical, and biological properties of flavonoids can be significantly affected by their interaction with transition metal ions, mainly iron. In this review, we explain the interaction of various flavonoid structures with Fe(II) and Fe(III) ions and critically discuss the influence of chelated ions on the flavonoid biochemical properties. In addition, specific biological effects of their iron metallocomplexes, such as the inhibition of iron-containing enzymes, have been included in this review.

Low iron-induced small RNA BrrF regulates central metabolism and oxidative stress responses in Burkholderia cenocepacia.

Regulatory small RNAs play an essential role in maintaining cell homeostasis in bacteria in response to environmental stresses such as iron starvation. Prokaryotes generally encode a large number of RNA regulators, yet their identification and characterisation is still in its infancy for most bacterial species. Burkholderia cenocepacia is an opportunistic pathogen with high innate antimicrobial resistance, which can cause the often fatal cepacia syndrome in individuals with cystic fibrosis. In this study we characterise a small RNA which is involved in the response to iron starvation, a condition that pathogenic bacteria are likely to encounter in the host. BrrF is a small RNA highly upregulated in Burkholderia cenocepacia under conditions of iron depletion and with a genome context consistent with Fur regulation. Its computationally predicted targets include iron-containing enzymes of the tricarboxylic acid (TCA) cycle such as aconitase and succinate dehydrogenase, as well as iron-containing enzymes responsible for the oxidative stress response, such as superoxide dismutase and catalase. Phenotypic and gene expression analysis of BrrF deletion and overexpression mutants show that the regulation of these genes is BrrF-dependent. Expression of acnA, fumA, sdhA and sdhC was downregulated during iron depletion in the wild type strain, but not in a BrrF deletion mutant. TCA cycle genes not predicted as target for BrrF were not affected in the same manner by iron depletion. Likewise, expression of sodB and katB was dowregulated during iron depletion in the wild type strain, but not in a BrrF deletion mutant. BrrF overexpression reduced aconitase and superoxide dismutase activities and increased sensitivity to hydrogen peroxide. All phenotypes and gene expression changes of the BrrF deletion mutant could be complemented by overexpressing BrrF in trans. Overall, BrrF acts as a regulator of central metabolism and oxidative stress response, possibly as an iron-sparing measure to maintain iron homeostasis under conditions of iron starvation.

Detoxification of Cyanide Wastewater by Cyanotrophic Organisms: the case of Phanerochaete chrysosporium

Abstract
 Cyanide, a carbon-nitrogen radical, is a major building block in many industries including pharmaceuticals, petrochemical and gold processing. In the gold extraction industry, cyanide has been the universal lixiviant for over a century due to better understood process chemistry, among others. Industries that discharge cyanide-laden effluents are mandated to keep concentrations below 0.2 mg/L to prevent death by cyanide-intoxification, which occurs when cyanide binds to key iron-containing enzymes and prevent them from supplying oxygen-containing blood to the tissues. Techniques used to attenuate cyanide in wastewater can broadly be grouped into chemical, physical and biological methods. In recent times, attention has been placed on biotechnological methods, which make use of cyanotrophic microorganisms to clean up cyanide-contaminated environments. This paper reports on studies set out to assess the ability of Phanerochaete chrysosporium to degrade cyanide under different conditions including changes in cyanide concentration, culture mass, time, closed system and open system. At the end of 24-hour contact in an open agitated system with initial pH of 11.5, a control experiment using 100 mg/L cyanide revealed a natural attenuation of 15% with pH decreasing to 9.88, while the best myco-detoxification of 85% was achieved by contacting 100 mg/L cyanide with 0.5 g culture mass, translating into degradation capacity of 17.2 mg/g (milligram of cyanide per gram of culture) with pH reducing to 8.4 in 24 hours. The degradation could be based on a number of mechanisms including hydrolysis to HCN, oxidation to cyanyl radical and cyanate due to natural attenuation through atmospheric contact, and secretion of organic acid, oxidative enzymes, and hydrogen peroxide by the fungus.
 
 Keywords: Cyanotrophic Organism, Myco-Detoxification, Cyanide-Laden Effluents, pH

Role of Superoxide Reductase FA796 in Oxidative Stress Resistance in Filifactor alocis

Filifactor alocis, a Gram-positive anaerobic bacterium, is now a proposed diagnostic indicator of periodontal disease. Because the stress response of this bacterium to the oxidative environment of the periodontal pocket may impact its pathogenicity, an understanding of its oxidative stress resistance strategy is vital. Interrogation of the F. alocis genome identified the HMPREF0389_00796 gene that encodes for a putative superoxide reductase (SOR) enzyme. SORs are non-heme, iron-containing enzymes that can catalyze the reduction of superoxide radicals to hydrogen peroxide and are important in the protection against oxidative stress. In this study, we have functionally characterized the putative SOR (FA796) from F. alocis ATCC 35896. The recombinant FA796 protein, which is predicted to be a homotetramer of the 1Fe-SOR class, can reduce superoxide radicals. F. alocis FLL141 (∆FA796::ermF) was significantly more sensitive to oxygen/air exposure compared to the parent strain. Sensitivity correlated with the level of intracellular superoxide radicals. Additionally, the FA796-defective mutant had increased sensitivity to hydrogen peroxide-induced stress, was inhibited in its ability to form biofilm and had reduced survival in epithelial cells. Collectively, these results suggest that the F. alocis SOR protein is a key enzymatic scavenger of superoxide radicals and protects the bacterium from oxidative stress conditions.

Purification of Soluble Membrane-Bound Ambystoma mexicanum Epidermal Lipoxygenase from E. coli and Its Growth Effect on Human Fetal Foreskin Fibroblast.

Lipoxygenases are non-heme iron-containing lipid dioxygenases enzymes that catalyze the hydroperoxidation of lipids. The Mexican axolotl (Ambystoma mexicanum) is a prominent source of the enzyme with a regeneration capacity in limbs. It has been shown that transfected human osteosarcoma and keratinocyte cells with epidermal lipoxygenase (LOXe) have an increased rate of cell migration. In the present study, LOXe, a peripheral membrane protein, was produced in Escherichia coli. The enzyme was purified using different detergents, anionic solutions, and gel filtration chromatography. Kinetic assay of the enzyme activity was carried out by the spectroscopy method using arachidonic acid as a substrate. Finally, the enzyme was characterized and its growth effect on human fibroblast cells was examined by MTT viability assay. Enzyme kinetic parameters including Km of 90.4µM and Vmax of 2.63IU were determined for LOXe. The enzyme with 0.1nM end concentration promoted the growth of 5000 cells/well human fibroblast cells up to 11% (P < 0.01). In the present study, we introduce an E. coli expression system to produce an excessive amount of soluble LOXe and the efficient purification method to provide a soluble and active form of LOXe that is effective in stimulating human fibroblast cell proliferation.

Reclassifying Hepatic Cell Death during Liver Damage: Ferroptosis-A Novel Form of Non-Apoptotic Cell Death?

Ferroptosis has emerged as a new type of cell death in different pathological conditions, including neurological and kidney diseases and, especially, in different types of cancer. The hallmark of this regulated cell death is the presence of iron-driven lipid peroxidation; the activation of key genes related to this process such as glutathione peroxidase-4 (gpx4), acyl-CoA synthetase long-chain family member-4 (acsl4), carbonyl reductase [NADPH] 3 (cbr3), and prostaglandin peroxidase synthase-2 (ptgs2); and morphological changes including shrunken and electron-dense mitochondria. Iron overload in the liver has long been recognized as both a major trigger of liver damage in different diseases, and it is also associated with liver fibrosis. New evidence suggests that ferroptosis might be a novel type of non-apoptotic cell death in several liver diseases including non-alcoholic steatohepatitis (NASH), alcoholic liver disease (ALD), drug-induced liver injury (DILI), viral hepatitis, and hemochromatosis. The interaction between iron-related lipid peroxidation, cellular stress signals, and antioxidant systems plays a pivotal role in the development of this novel type of cell death. In addition, integrated responses from lipidic mediators together with free iron from iron-containing enzymes are essential to understanding this process. The presence of ferroptosis and the exact mechanisms leading to this non-apoptotic type of cell death in the liver remain scarcely elucidated. Recognizing ferroptosis as a novel type of cell death in the liver could lead to the understanding of the complex interaction between different types of cell death, their role in progression of liver fibrosis, the development of new biomarkers, as well as the use of modulators of ferroptosis, allowing improved theranostic approaches in the clinic.

Ferroptosis: Final destination for cancer?

Ferroptosis is a recently defined, non‐apoptotic, regulated cell death (RCD) process that comprises abnormal metabolism of cellular lipid oxides catalysed by iron ions or iron‐containing enzymes. In this process, a variety of inducers destroy the cell redox balance and produce a large number of lipid peroxidation products, eventually triggering cell death. However, in terms of morphology, biochemistry and genetics, ferroptosis is quite different from apoptosis, necrosis, autophagy‐dependent cell death and other RCD processes. A growing number of studies suggest that the relationship between ferroptosis and cancer is extremely complicated and that ferroptosis promises to be a novel approach for the cancer treatment. This article primarily focuses on the mechanism of ferroptosis and discusses the potential application of ferroptosis in cancer therapy.

Second-Coordination Sphere Effects on Selectivity and Specificity of Heme and Nonheme Iron Enzymes.

Mononuclear iron-containing enzymes are highly versatile oxidants that often react stereospecifically and/or regioselectively with substrates. Combined experimental and computational studies on heme monooxygenases, nonheme iron dioxygenases and halogenases have revealed the intricate details of the second-coordination sphere, which determine this specificity and selectivity. These second-coordination sphere effects originate from the positioning of the substrate and oxidant, which involve the binding of the co-factors and substrate into the active site of the protein. In addition, some enzymes affect the selectivity and reactivity through charge-stabilization from nearby bound cations/anions, an induced electric field or through the positioning of salt bridges and hydrogen-bonding interactions to first-coordination sphere iron ligands and/or the substrate. Examples of all of these second-coordination sphere effects in iron-containing enzymes and how these influence structure and reactivity are given.

Comparative facilitation of activated carbon and goethite on methanogenesis from volatile fatty acids

To provide insight into direct interspecies electron transfer (DIET) via carbon-based materials and ferric oxides, the effects of three conductive materials (i.e. activated carbon (AC), iron modified activated carbon (FEAC) and goethite (FEOOH)), on methanogenesis from volatile fatty acids (VFAs) were evaluated. Under the acid stress (~4 g/L VFAs), the maximum methane yield of 266 mL/g-chemical oxygen demand (COD) was found in the FEOOH supplemented reactor, which was 48% higher than that of AC reactor. The reasons for the enhanced activity of the electron transport chain and extracellular electron transfer ability by FEOOH include: 1) the activation on iron-containing enzymes that involved in methanogenesis and acidogenesis; 2) selective enrichment on functional microorganism. The higher electron donating capacities (EDC) value of FEOOH may be a triggering factor on the growth of Syntrophomonadaceae, which perform DIET with methanogens (Methanosaeta and Methanosarcina) for the syntrophic degradation of VFAs.

Heterogeneity in respiratory electron transfer and adaptive iron utilization in a bacterial biofilm

In Bacillus subtilis, robust biofilm formation requires large quantities of ferric iron. Here we show that this process requires preferential production of a siderophore precursor, 2,3-dihydroxybenzoate, instead of the siderophore bacillibactin. A large proportion of iron is associated extracellularly with the biofilm matrix. The biofilms are conductive, with extracellular iron potentially acting as electron acceptor. A relatively small proportion of ferric iron is internalized and boosts production of iron-containing enzymes involved in respiratory electron transfer and establishing strong membrane potential, which is key to biofilm matrix production. Our study highlights metabolic diversity and versatile energy generation strategies within B. subtilis biofilms.

Dimeric structures of quinol-dependent nitric oxide reductases (qNORs) revealed by cryo-electron microscopy.

Quinol-dependent nitric oxide reductases (qNORs) are membrane-integrated, iron-containing enzymes of the denitrification pathway, which catalyze the reduction of nitric oxide (NO) to the major ozone destroying gas nitrous oxide (N2O). Cryo-electron microscopy structures of active qNOR from Alcaligenes xylosoxidans and an activity-enhancing mutant have been determined to be at local resolutions of 3.7 and 3.2 Å, respectively. They unexpectedly reveal a dimeric conformation (also confirmed for qNOR from Neisseria meningitidis) and define the active-site configuration, with a clear water channel from the cytoplasm. Structure-based mutagenesis has identified key residues involved in proton transport and substrate delivery to the active site of qNORs. The proton supply direction differs from cytochrome c-dependent NOR (cNOR), where water molecules from the cytoplasm serve as a proton source similar to those from cytochrome c oxidase.

The heme-sensitive regulator SbnI has a bifunctional role in staphyloferrin B production by Staphylococcus aureus

Staphylococcus aureus infection relies on iron acquisition from its host. S. aureus takes up iron through heme uptake by the iron-responsive surface determinant (Isd) system and by the production of iron-scavenging siderophores. Staphyloferrin B (SB) is a siderophore produced by the 9-gene sbn gene cluster for SB biosynthesis and efflux. Recently, the ninth gene product, SbnI, was determined to be a free l-serine kinase that produces O-phospho-l-serine (OPS), a substrate for SB biosynthesis. Previous studies have also characterized SbnI as a DNA-binding regulatory protein that senses heme to control sbn gene expression for SB synthesis. Here, we present crystal structures at 1.9-2.1 Å resolution of a SbnI homolog from Staphylococcus pseudintermedius (SpSbnI) in both apo form and in complex with ADP, a product of the kinase reaction; the latter confirmed the active-site location. The structures revealed that SpSbnI forms a dimer through C-terminal domain swapping and a dimer of dimers through intermolecular disulfide formation. Heme binding had only a modest effect on SbnI enzymatic activity, suggesting that its two functions are independent and structurally distinct. We identified a heme-binding site and observed catalytic heme transfer between a heme-degrading protein of the Isd system, IsdI, and SbnI. These findings support the notion that SbnI has a bifunctional role contributing precursor OPS to SB synthesis and directly sensing heme to control expression of the sbn locus. We propose that heme transfer from IsdI to SbnI enables S. aureus to control iron source preference according to the sources available in the environment.

Effects of repetitive magnetic stimulation on the growth of primarily cultured hippocampus neurons in vitro and their expression of iron-containing enzymes.

Background: The mechanism of action of repetitive transcranial magnetic stimulation (rTMS) involves the generation of neuronal and action potentials utilizing induced currents in time-varying magnetic fields. However, the long-lasting and effective biological impact of magnetic stimulation does not appear to be completely explained by the transient magnetic field pulses. In this context, we hypothesized magnetic stimulation may affect the expression of iron-containing enzymes in neurons, mediating the long-lasting biological effects associated with this stimulus. Methods: Primarily cultured hippocampus neurons from SD rats were used as the cell model in this study. These were randomly divided into control, sham, and magnetic stimulation groups to probe into the effect of the magnetic field directly. The latter group received 40%, 60%, and 100% maximal stimulator output Tesla (1.68, 2.52, and 4.2 T) with low-frequency rTMS (1 Hz). The expression of iron-containing enzymes (catalase and aconitase) and non-ferrous enzymes (protein kinase A) was measured with Western blotting and ELISA. Results: The survival rates of neurons in the 40%T and 60%T groups were significantly increased in comparison to the controls (P<0.05), while those in the 100%T group showed cell damage, with slightly disturbed neurite connections and decreased survival rate. Furthermore, catalase and aconitase expression was higher in all of the stimulated groups in comparison to controls (P<0.05). On the other hand, the expression of the iron-containing enzymes decreased in the 100%T group in comparison with the 40%T and 60%T groups (P<0.05). Meanwhile, the expression of protein kinase A was not significantly increased in the groups which underwent magnetic stimulation. Conclusion: rTMS may increase the expression of ferrous enzymes but does not have a strong effect on non-ferrous enzymes. Excessive intensity of magnetic stimulation may reduce neuronal survival rate and affect the expression of iron-containing enzymes. The mechanism underlying the lasting effect of rTMS may be related to the increase of ferriferous expression induced by magnetic stimulation, with a clear correlation with stimulation intensity.

Protective effects of alpha-ketoglutarate against aluminum toxicity in Drosophila melanogaster

In recent years, Drosophila melanogaster has emerged as a model for studies on aluminum toxicity. The current study aimed to disclose the mechanisms of aluminum toxicity in D. melanogaster at larval and adult stages and examined the potential protective effects of dietary alpha-ketoglutarate (AKG). Flies were reared on food containing 10 mM AlCl3, 10 mM AKG or both additives. Rearing on an AlCl3-containing diet induced behavioral defects, and decreased fecundity and long-term survival of female flies. The addition of dietary AKG did not ameliorate locomotor and taste behavior defects or the higher sensitivity to oxidative stress, but improved heat stress resistance, egg-laying capability and survival of females treated with AlCl3. Metabolic effects of AlCl3 exposure on flies included an imbalance of metal content, decreased glucose levels, increased free iron and storage triacylglyceride (TAG) levels, mitochondria dysfunction, and the development of oxidative stress. Dietary AKG did not prevent AlCl3 effects on glucose and TAG, but improved metal homeostasis, inhibited the increase in free Fe and restored the functional activity of iron-containing enzymes such as aconitase. In addition, AKG decreased the intensity of oxidative stress seen in AlCl3-reared adult flies, probably due to inhibition of iron mobilization. The results show that AKG is not a full antidote against Al toxicity but is able to relieve multiple metabolic effects of high aluminum. Furthermore, the modulating ability of AKG can clearly be helpful in exploring the molecular mechanisms of Al toxicity.

Probing Hydrogen Bonding Interactions to Iron-Oxido/Hydroxido Units by 57 Fe Nuclear Resonance Vibrational Spectroscopy.

Hydrogen bonds (H-bonds) have been shown to modulate the chemical reactivities of iron centers in iron-containing dioxygen-activating enzymes and model complexes. However, few examples are available that investigate how systematic changes in intramolecular H-bonds within the secondary coordination sphere influence specific properties of iron intermediates, such as iron-oxido/hydroxido species. Here, we used 57 Fe nuclear resonance vibrational spectroscopy (NRVS) to probe the Fe-O/OH vibrations in a series of FeIII -hydroxido and FeIV/III -oxido complexes with varying H-bonding networks but having similar trigonal bipyramidal primary coordination spheres. The data show that even subtle changes in the H-bonds to the Fe-O/OH units result in significant changes in their vibrational frequencies, thus demonstrating the utility of NRVS in studying the effect of the secondary coordination sphere to the reactivities of iron complexes.

Probing Hydrogen Bonding Interactions to Iron‐Oxido/Hydroxido Units by 57 Fe Nuclear Resonance Vibrational Spectroscopy

Hydrogen bonds (H-bonds) have been shown to modulate the chemical reactivities of iron centers in iron-containing dioxygen-activating enzymes and model complexes. However, few examples are available that investigate how systematic changes in intramolecular H-bonds within the secondary coordination sphere influence specific properties of iron intermediates, such as iron-oxido/hydroxido species. Here, we used 57Fe nuclear resonance vibrational spectroscopy (NRVS) to probe the Fe-O/OH vibrations in a series of FeIII-hydroxido and FeIV/III-oxido complexes with varying H-bonding networks but having similar trigonal bipyramidal primary coordination spheres. The data show that even subtle changes in the H-bonds to the Fe-O/OH units result in significant changes in their vibrational frequencies, thus demonstrating the utility of NRVS in studying the effect of the secondary coordination sphere to the reactivities of iron complexes.

Oxidative stress and neurodegeneration: the involvement of iron

Many evidences indicate that oxidative stress plays a significant role in a variety of human disease states, including neurodegenerative diseases. Iron is an essential metal for almost all living organisms due to its involvement in a large number of iron-containing proteins and enzymes, though it could be also toxic. Actually, free iron excess generates oxidative stress, particularly in brain, where anti-oxidative defences are relatively low. Its accumulation in specific regions is associated with pathogenesis in a variety of neurodegenerative diseases (i.e., Parkinson's disease, Alzheimer's disease, Huntington's chorea, Amyotrophic Lateral Sclerosis and Neurodegeneration with Brain Iron Accumulation). Anyway, the extent of toxicity is dictated, in part, by the localization of the iron complex within the cell (cytosolic, lysosomal and mitochondrial), its biochemical form, i.e., ferritin or hemosiderin, as well as the ability of the cell to prevent the generation and propagation of free radical by the wide range of antioxidants and cytoprotective enzymes in the cell. Particularly, ferrous iron can act as a catalyst in the Fenton reaction that potentiates oxygen toxicity by generating a wide range of free radical species, including hydroxyl radicals (·OH). The observation that patients with neurodegenerative diseases show a dramatic increase in their brain iron content, correlated with the production of reactive oxigen species in these areas of the brain, conceivably suggests that disturbances in brain iron homeostasis may contribute to the pathogenesis of these disorders. The aim of this review is to describe the chemical features of iron in human beings and iron induced toxicity in neurodegenerative diseases. Furthermore, the attention is focused on metal chelating drugs therapeutic strategies.