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Frontiers in Molecular Biosciences 2022Hemerythrin is an oxygen-binding protein originally found in certain marine invertebrates. Oxygen reversibly binds at its non-heme diiron center, which consists of two... (Review)
Review
Hemerythrin is an oxygen-binding protein originally found in certain marine invertebrates. Oxygen reversibly binds at its non-heme diiron center, which consists of two oxo-bridged iron atoms bound to a characteristic conserved set of five His residues, one Glu residue, and one Asp residue. It was recently discovered that several bacteria utilize hemerythrin as an oxygen- and redox-sensing domain in responding to changes in cellular oxygen concentration or redox status, and immediately adapt to these environmental changes in order to maintain important physiological processes, including chemotaxis and c-di-GMP synthesis and degradation. This Mini Review focuses on the recent progress made on structural and functional aspects of these emerging bacterial hemerythrin domain-containing oxygen and redox sensors, revealing characteristic features of this family of proteins.
PubMed: 35992274
DOI: 10.3389/fmolb.2022.967059 -
Protein Science : a Publication of the... Apr 2018Hemerythrin-like proteins have generally been studied for their ability to reversibly bind oxygen through their binuclear nonheme iron centers. However, in recent years,...
Hemerythrin-like proteins have generally been studied for their ability to reversibly bind oxygen through their binuclear nonheme iron centers. However, in recent years, it has become increasingly evident that some members of the hemerythrin-like superfamily also participate in many other biological processes. For instance, the binuclear nonheme iron site of YtfE, a hemerythrin-like protein involved in the repair of iron centers in Escherichia coli, catalyzes the reduction of nitric oxide to nitrous oxide, and the human F-box/LRR-repeat protein 5, which contains a hemerythrin-like domain, is involved in intracellular iron homeostasis. Furthermore, structural data on hemerythrin-like domains from two proteins of unknown function, PF0695 from Pyrococcus furiosus and NMB1532 from Neisseria meningitidis, show that the cation-binding sites, typical of hemerythrin, can be absent or be occupied by metal ions other than iron. To systematically investigate this functional and structural diversity of the hemerythrin-like superfamily, we have collected hemerythrin-like sequences from a database comprising fully sequenced proteomes and generated a cluster map based on their all-against-all pairwise sequence similarity. Our results show that the hemerythrin-like superfamily comprises a large number of protein families which can be classified into three broad groups on the basis of their cation-coordinating residues: (a) signal-transduction and oxygen-carrier hemerythrins (H-HxxxE-HxxxH-HxxxxD); (b) hemerythrin-like (H-HxxxE-H-HxxxE); and, (c) metazoan F-box proteins (H-HExxE-H-HxxxE). Interestingly, all but two hemerythrin-like families exhibit internal sequence and structural symmetry, suggesting that a duplication event may have led to the origin of the hemerythrin domain.
Topics: Amino Acid Motifs; Cluster Analysis; Evolution, Molecular; Hemerythrin; Nonheme Iron Proteins; Oxygen; Phylogeny; Protein Domains; Structural Homology, Protein
PubMed: 29330894
DOI: 10.1002/pro.3374 -
Molecules (Basel, Switzerland) Jun 2022Repair of Iron Center proteins (RIC) form a family of di-iron proteins that are widely spread in the microbial world. RICs contain a binuclear nonheme iron site in a... (Review)
Review
Repair of Iron Center proteins (RIC) form a family of di-iron proteins that are widely spread in the microbial world. RICs contain a binuclear nonheme iron site in a four-helix bundle fold, two basic features of hemerythrin-like proteins. In this work, we review the data on microbial RICs including how their genes are regulated and contribute to the survival of pathogenic bacteria. We gathered the currently available biochemical, spectroscopic and structural data on RICs with a particular focus on RIC (also known as YtfE), which remains the best-studied protein with extensive biochemical characterization. Additionally, we present novel structural data for YtfE harboring a di-manganese site and the protein's affinity for this metal. The networking of protein interactions involving YtfE is also described and integrated into the proposed physiological role as an iron donor for reassembling of stress-damaged iron-sulfur centers.
Topics: Bacterial Proteins; Escherichia coli; Escherichia coli Proteins; Hemerythrin; Iron; Iron-Sulfur Proteins; Sulfur
PubMed: 35807291
DOI: 10.3390/molecules27134051 -
Cellular and Molecular Life Sciences :... Jan 2017It is now well documented that peptides with enhanced or alternative functionality (termed cryptides) can be liberated from larger, and sometimes inactive, proteins. A... (Review)
Review
It is now well documented that peptides with enhanced or alternative functionality (termed cryptides) can be liberated from larger, and sometimes inactive, proteins. A primary example of this phenomenon is the oxygen-transport protein hemoglobin. Aside from respiration, hemoglobin and hemoglobin-derived peptides have been associated with immune modulation, hematopoiesis, signal transduction and microbicidal activities in metazoans. Likewise, the functional equivalents to hemoglobin in invertebrates, namely hemocyanin and hemerythrin, act as potent immune effectors under certain physiological conditions. The purpose of this review is to evaluate the true extent of oxygen-transport protein dynamics in innate immunity, and to impress upon the reader the multi-functionality of these ancient proteins on the basis of their structures. In this context, erythrocyte-pathogen antibiosis and the immune competences of various erythroid cells are compared across diverse taxa.
Topics: Animals; Biological Transport; Hemerythrin; Hemocyanins; Hemoglobins; Humans; Immunity, Innate; Oxygen
PubMed: 27518203
DOI: 10.1007/s00018-016-2326-7 -
Archives of Biochemistry and Biophysics Jul 2021Oxo-bridged diiron proteins are a distinct class of non-heme iron proteins. Their active sites are composed of two irons that are coordinated by amino acid side chains,... (Review)
Review
Oxo-bridged diiron proteins are a distinct class of non-heme iron proteins. Their active sites are composed of two irons that are coordinated by amino acid side chains, and a bridging oxygen that interacts with each iron. These proteins are members of the ferritin superfamily and share the structural feature of a four α-helix bundle that provides the residues that coordinate the irons. The different proteins also display a wide range of structures and functions. A prototype of this family is hemerythrin, which functions as an oxygen transporter. Several other hemerythrin-like proteins have been described with a diversity of functions including oxygen and iron sensing, and catalytic activities. Rubrerythrins react with hydrogen peroxide and rubrerythrin-like proteins possess a rubredoxin domain, in addition to the oxo-bridged diiron center. Other redox enzymes with oxo-bridged irons include flavodiiron proteins that act as O or NO reductases, ribonucleotide reductase and methane monooxygenase. Ferritins have an oxo-bridged diiron in the ferroxidase center of the protein, which plays a role in the iron storage function of these proteins. There are also bacterial ferritins that exhibit catalytic activities. The structures and functions of this broad class of oxo-bridged diiron proteins are described and compared in this review.
Topics: Hemeproteins; Iron; Models, Molecular; Oxygen; Protein Conformation
PubMed: 33991497
DOI: 10.1016/j.abb.2021.108917 -
Frontiers in Plant Science 2019Iron (Fe) is an essential nutrient for plants, but at the same time its redox properties can make it a dangerous toxin inside living cells. Homeostasis between uptake,... (Review)
Review
Iron (Fe) is an essential nutrient for plants, but at the same time its redox properties can make it a dangerous toxin inside living cells. Homeostasis between uptake, use and storage of Fe must be maintained at all times. A small family of unique hemerythrin E3 ubiquitin ligases found in green algae and plants play an important role in avoiding toxic Fe overload, acting as negative regulators of Fe homeostasis. Protein interaction data showed that they target specific transcription factors for degradation by the 26S proteasome. It is thought that the activity of the E3 ubiquitin ligases is controlled by Fe binding to the N-terminal hemerythrin motifs. Here, we discuss what we have learned so far from studies on the HRZ (Hemerythrin RING Zinc finger) proteins in rice, the homologous BTS (BRUTUS) and root-specific BTSL (BRUTUS-LIKE) in Arabidopsis. A mechanistic model is proposed to help focus future research questions towards a full understanding of the regulatory role of these proteins in Fe homeostasis in plants.
PubMed: 30815004
DOI: 10.3389/fpls.2019.00098 -
Molecular and Biochemical Parasitology 2016Amebiasis is an intestinal infection widespread throughout the world caused by the human pathogen Entamoeba histolytica. Metronidazole has been a drug of choice against... (Review)
Review
Amebiasis is an intestinal infection widespread throughout the world caused by the human pathogen Entamoeba histolytica. Metronidazole has been a drug of choice against amebiasis for decades despite its low efficacy against asymptomatic cyst carriers and emergence of resistance in other protozoa with similar anaerobic metabolism. Therefore, identification and characterization of specific targets is urgently needed to design new therapeutics for improved treatment against amebiasis. Toward this goal, thiol-dependent redox metabolism is of particular interest. The thiol-dependent redox metabolism in E. histolytica consists of proteins including peroxiredoxin, rubrerythrin, Fe-superoxide dismutase, flavodiiron proteins, NADPH: flavin oxidoreductase, and amino acids including l-cysteine, S-methyl-l-cysteine, and thioprolines (thiazolidine-4-carboxylic acids). E. histolytica completely lacks glutathione and its metabolism, and l-cysteine is the major intracellular low molecular mass thiol. Moreover, this parasite possesses a functional thioredoxin system consisting of thioredoxin and thioredoxin reductase, which is a ubiquitous oxidoreductase system with antioxidant and redox regulatory roles. In this review, we summarize and highlight the thiol-based redox metabolism and its control mechanisms in E. histolytica, in particular, the features of the system unique to E. histolytica, and its potential use for drug development against amebiasis.
Topics: Antiprotozoal Agents; Cysteine; Entamoeba histolytica; Entamoebiasis; Flavoproteins; Gene Expression Regulation; Hemerythrin; Humans; Molecular Targeted Therapy; Oxidation-Reduction; Peroxiredoxins; Protozoan Proteins; Rubredoxins; Superoxide Dismutase; Thiazolidines; Thioredoxin-Disulfide Reductase; Thioredoxins
PubMed: 26775086
DOI: 10.1016/j.molbiopara.2016.01.004 -
Journal of Experimental Botany Mar 2022Iron (Fe) is an essential transition metal. Based on its redox-active nature under biological conditions, various Fe compounds serve as cofactors in redox enzymes. In... (Review)
Review
Iron (Fe) is an essential transition metal. Based on its redox-active nature under biological conditions, various Fe compounds serve as cofactors in redox enzymes. In plants, the photosynthetic machinery has the highest demand for Fe. In consequence, the delivery and incorporation of Fe into cofactors of the photosynthetic apparatus is the focus of Fe metabolism in leaves. Disturbance of foliar Fe homeostasis leads to impaired biosynthesis of chlorophylls and composition of the photosynthetic machinery. Nevertheless, mitochondrial function also has a significant demand for Fe. The proper incorporation of Fe into proteins and cofactors as well as a balanced intracellular Fe status in leaf cells require the ability to sense Fe, but may also rely on indirect signals that report on the physiological processes connected to Fe homeostasis. Although multiple pieces of information have been gained on Fe signalling in roots, the regulation of Fe status in leaves has not yet been clarified in detail. In this review, we give an overview on current knowledge of foliar Fe homeostasis, from the chemical forms to the allocation and sensing of Fe in leaves.
Topics: Homeostasis; Iron; Iron-Sulfur Proteins; Photosynthesis; Plant Leaves
PubMed: 35104334
DOI: 10.1093/jxb/erac030 -
Frontiers in Pharmacology 2014Glutathione transferases (GSTs) represent a widespread multigenic enzyme family able to modify a broad range of molecules. These notably include secondary metabolites... (Review)
Review
Glutathione transferases (GSTs) represent a widespread multigenic enzyme family able to modify a broad range of molecules. These notably include secondary metabolites and exogenous substrates often referred to as xenobiotics, usually for their detoxification, subsequent transport or export. To achieve this, these enzymes can bind non-substrate ligands (ligandin function) and/or catalyze the conjugation of glutathione onto the targeted molecules, the latter activity being exhibited by GSTs having a serine or a tyrosine as catalytic residues. Besides, other GST members possess a catalytic cysteine residue, a substitution that radically changes enzyme properties. Instead of promoting GSH-conjugation reactions, cysteine-containing GSTs (Cys-GSTs) are able to perform deglutathionylation reactions similarly to glutaredoxins but the targets are usually different since glutaredoxin substrates are mostly oxidized proteins and Cys-GST substrates are metabolites. The Cys-GSTs are found in most organisms and form several classes. While Beta and Omega GSTs and chloride intracellular channel proteins (CLICs) are not found in plants, these organisms possess microsomal ProstaGlandin E-Synthase type 2, glutathionyl hydroquinone reductases, Lambda, Iota and Hemerythrin GSTs and dehydroascorbate reductases (DHARs); the four last classes being restricted to the green lineage. In plants, whereas the role of DHARs is clearly associated to the reduction of dehydroascorbate to ascorbate, the physiological roles of other Cys-GSTs remain largely unknown. In this context, a genomic and phylogenetic analysis of Cys-GSTs in photosynthetic organisms provides an updated classification that is discussed in the light of the recent literature about the functional and structural properties of Cys-GSTs. Considering the antioxidant potencies of phenolic compounds and more generally of secondary metabolites, the connection of GSTs with secondary metabolism may be interesting from a pharmacological perspective.
PubMed: 25191271
DOI: 10.3389/fphar.2014.00192 -
Journal of Inorganic Biochemistry Apr 2014The ability to sense and adapt to changes in pO2 is crucial for basic metabolism in most organisms, leading to elaborate pathways for sensing hypoxia (low pO2). This... (Review)
Review
The ability to sense and adapt to changes in pO2 is crucial for basic metabolism in most organisms, leading to elaborate pathways for sensing hypoxia (low pO2). This review focuses on the mechanisms utilized by mammals and bacteria to sense hypoxia. While responses to acute hypoxia in mammalian tissues lead to altered vascular tension, the molecular mechanism of signal transduction is not well understood. In contrast, chronic hypoxia evokes cellular responses that lead to transcriptional changes mediated by the hypoxia inducible factor (HIF), which is directly controlled by post-translational hydroxylation of HIF by the non-heme Fe(II)/αKG-dependent enzymes FIH and PHD2. Research on PHD2 and FIH is focused on developing inhibitors and understanding the links between HIF binding and the O2 reaction in these enzymes. Sulfur speciation is a putative mechanism for acute O2-sensing, with special focus on the role of H2S. This sulfur-centered model is discussed, as are some of the directions for further refinement of this model. In contrast to mammals, bacterial O2-sensing relies on protein cofactors that either bind O2 or oxidatively decompose. The sensing modality for bacterial O2-sensors is either via altered DNA binding affinity of the sensory protein, or else due to the actions of a two-component signaling cascade. Emerging data suggests that proteins containing a hemerythrin-domain, such as FBXL5, may serve to connect iron sensing to O2-sensing in both bacteria and humans. As specific molecular machinery becomes identified, these hypoxia sensing pathways present therapeutic targets for diseases including ischemia, cancer, or bacterial infection.
Topics: Animals; Bacteria; Heme; Humans; Hypoxia; Hypoxia-Inducible Factor 1; Hypoxia-Inducible Factor-Proline Dioxygenases; Mammals; Oxygen; Signal Transduction
PubMed: 24468676
DOI: 10.1016/j.jinorgbio.2013.12.010