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FEMS Microbiology Reviews Jun 2003Iron is essential to virtually all organisms, but poses problems of toxicity and poor solubility. Bacteria have evolved various mechanisms to counter the problems... (Review)
Review
Iron is essential to virtually all organisms, but poses problems of toxicity and poor solubility. Bacteria have evolved various mechanisms to counter the problems imposed by their iron dependence, allowing them to achieve effective iron homeostasis under a range of iron regimes. Highly efficient iron acquisition systems are used to scavenge iron from the environment under iron-restricted conditions. In many cases, this involves the secretion and internalisation of extracellular ferric chelators called siderophores. Ferrous iron can also be directly imported by the G protein-like transporter, FeoB. For pathogens, host-iron complexes (transferrin, lactoferrin, haem, haemoglobin) are directly used as iron sources. Bacterial iron storage proteins (ferritin, bacterioferritin) provide intracellular iron reserves for use when external supplies are restricted, and iron detoxification proteins (Dps) are employed to protect the chromosome from iron-induced free radical damage. There is evidence that bacteria control their iron requirements in response to iron availability by down-regulating the expression of iron proteins during iron-restricted growth. And finally, the expression of the iron homeostatic machinery is subject to iron-dependent global control ensuring that iron acquisition, storage and consumption are geared to iron availability and that intracellular levels of free iron do not reach toxic levels.
Topics: Bacteria; Bacterial Proteins; DNA-Binding Proteins; Escherichia coli; Gene Expression Regulation, Bacterial; Heme; Homeostasis; Iron; Models, Genetic; Protein Structure, Tertiary; Siderophores
PubMed: 12829269
DOI: 10.1016/S0168-6445(03)00055-X -
Current Opinion in Structural Biology Dec 2019Mechanisms for making and breaking the heme b cofactor (heme) are more diverse than previously expected. Biosynthetic pathways have diverged at least twice along... (Review)
Review
Mechanisms for making and breaking the heme b cofactor (heme) are more diverse than previously expected. Biosynthetic pathways have diverged at least twice along taxonomic lines, reflecting differences in membrane organization and O utilization among major groups of organisms. At least three families of heme degradases are now known, again differing in whether and how O is used by the organism and possibly the purpose for turning over the tetrapyrrole. Understanding these enzymes and pathways offers a handle for antimicrobial development and for monitoring heme use in organismal and ecological systems.
Topics: Binding Sites; Catalytic Domain; Heme; Metabolic Networks and Pathways; Models, Molecular; Molecular Conformation; Molecular Structure; Oxidation-Reduction; Protein Binding; Quantitative Structure-Activity Relationship; Sensitivity and Specificity
PubMed: 30802830
DOI: 10.1016/j.sbi.2019.01.006 -
The Journal of Biological Chemistry Sep 2015
Topics: Cytochrome P-450 Enzyme System; Heme; History, 20th Century; History, 21st Century; Mexico; United States
PubMed: 26195628
DOI: 10.1074/jbc.X115.680066 -
Journal of Molecular Biology Aug 2016Bacterial pathogens require the iron-containing cofactor heme to cause disease. Heme is essential to the function of hemoproteins, which are involved in energy... (Review)
Review
Bacterial pathogens require the iron-containing cofactor heme to cause disease. Heme is essential to the function of hemoproteins, which are involved in energy generation by the electron transport chain, detoxification of host immune effectors, and other processes. During infection, bacterial pathogens must synthesize heme or acquire heme from the host; however, host heme is sequestered in high-affinity hemoproteins. Pathogens have evolved elaborate strategies to acquire heme from host sources, particularly hemoglobin, and both heme acquisition and synthesis are important for pathogenesis. Paradoxically, excess heme is toxic to bacteria and pathogens must rely on heme detoxification strategies. Heme is a key nutrient in the struggle for survival between host and pathogen, and its study has offered significant insight into the molecular mechanisms of bacterial pathogenesis.
Topics: Bacteria; Heme; Host-Pathogen Interactions; Metabolic Networks and Pathways
PubMed: 27019298
DOI: 10.1016/j.jmb.2016.03.018 -
Critical Reviews in Biochemistry and... Feb 2022Heme is an essential biomolecule and cofactor involved in a myriad of biological processes. In this review, we focus on how heme binding to heme regulatory motifs... (Review)
Review
Heme is an essential biomolecule and cofactor involved in a myriad of biological processes. In this review, we focus on how heme binding to heme regulatory motifs (HRMs), catalytic sites, and gas signaling molecules as well as how changes in the heme redox state regulate protein structure, function, and degradation. We also relate these heme-dependent changes to the affected metabolic processes. We center our discussion on two HRM-containing proteins: human heme oxygenase-2, a protein that binds and degrades heme (releasing Fe and CO) in its catalytic core and binds Fe-heme at HRMs located within an unstructured region of the enzyme, and the transcriptional regulator Rev-erbβ, a protein that binds Fe-heme at an HRM and is involved in CO sensing. We will discuss these and other proteins as they relate to cellular heme composition, homeostasis, and trafficking. In addition, we will discuss the HRM-containing family of proteins and how the stability and activity of these proteins are regulated in a dependent manner through the HRMs. Then, after reviewing CO-mediated protein regulation of heme proteins, we turn our attention to the involvement of heme, HRMs, and CO in circadian rhythms. In sum, we stress the importance of understanding the various roles of heme and the distribution of the different heme pools as they relate to the heme redox state, CO, and heme binding affinities.
Topics: Heme; Humans; Oxidation-Reduction; Protein Binding; Receptors, Cytoplasmic and Nuclear; Repressor Proteins
PubMed: 34517731
DOI: 10.1080/10409238.2021.1961674 -
Archives of Biochemistry and Biophysics Feb 2014Heme degradation through the action of heme oxygenase (HO) is unusual in that it utilizes heme as both a substrate and cofactor for its own degradation. HO catalyzes the... (Review)
Review
Heme degradation through the action of heme oxygenase (HO) is unusual in that it utilizes heme as both a substrate and cofactor for its own degradation. HO catalyzes the oxygen-dependent degradation of heme to biliverdin with the release of CO and "free" iron. The characterization of HO enzymes from humans to bacteria reveals a similar overall structural fold that contributes to the unique reaction manifold. The heme oxygenases share a similar heme-dependent activation of O2 to the ferric hydroperoxide as that of the cytochrome P450s and peroxidases. However, whereas the P450s promote cleavage of the ferric hydroperoxide OO bond to the oxoferryl species the HOs stabilize the ferric hydroperoxide promoting hydroxylation at the heme edge. The alternate reaction pathway in HO is achieved through the conformational flexibility and extensive hydrogen bond network within the heme binding site priming the heme for hydroxylation. Until recently it was believed that all heme degrading enzymes converted heme to biliverdin and iron, with the release of carbon monoxide (CO). However, the recent discovery of the bacterial IsdG-like heme degrading proteins of Staphylococcus aureus, Bacillus anthracis and Mycobacterium tuberculosis has expanded the reaction manifold of heme oxidation. Characterization of the heme degradation products in the IsdG-like reaction suggests a mechanism distinct from the classical HOs. In the following review we will discuss the structure-function of the canonical HOs as it relates to the emerging alternate reaction manifold of the IsdG-like proteins.
Topics: Animals; Bacteria; Heme; Heme Oxygenase (Decyclizing); Humans; Hydroxylation; Models, Molecular; Oxidation-Reduction
PubMed: 24161941
DOI: 10.1016/j.abb.2013.10.013 -
Cells Feb 2020Heme is a ubiquitous and essential iron containing metallo-organic cofactor required for virtually all aerobic life. Heme synthesis is initiated and completed in... (Review)
Review
Heme is a ubiquitous and essential iron containing metallo-organic cofactor required for virtually all aerobic life. Heme synthesis is initiated and completed in mitochondria, followed by certain covalent modifications and/or its delivery to apo-hemoproteins residing throughout the cell. While the biochemical aspects of heme biosynthetic reactions are well understood, the trafficking of newly synthesized heme-a highly reactive and inherently toxic compound-and its subsequent delivery to target proteins remain far from clear. In this review, we summarize current knowledge about heme biosynthesis and trafficking within and outside of the mitochondria.
Topics: Heme; Mitochondria
PubMed: 32121449
DOI: 10.3390/cells9030579 -
Applied Microbiology and Biotechnology Aug 2011Heme biosynthesis in fungal host strains has acquired considerable interest in relation to the production of secreted heme-containing peroxidases. Class II peroxidase... (Review)
Review
Heme biosynthesis in fungal host strains has acquired considerable interest in relation to the production of secreted heme-containing peroxidases. Class II peroxidase enzymes have been suggested as eco-friendly replacements of polluting chemical processes in industry. These peroxidases are naturally produced in small amounts by basidiomycetes. Filamentous fungi like Aspergillus sp. are considered as suitable hosts for protein production due to their high capacity of protein secretion. For the purpose of peroxidase production, heme is considered a putative limiting factor. However, heme addition is not appropriate in large-scale production processes due to its high hydrophobicity and cost price. The preferred situation in order to overcome the limiting effect of heme would be to increase intracellular heme levels. This requires a thorough insight into the biosynthetic pathway and its regulation. In this review, the heme biosynthetic pathway is discussed with regards to synthesis, regulation, and transport. Although the heme biosynthetic pathway is a highly conserved and tightly regulated pathway, the mode of regulation does not appear to be conserved among eukaryotes. However, common factors like feedback inhibition and regulation by heme, iron, and oxygen appear to be involved in regulation of the heme biosynthesis pathway in most organisms. Therefore, they are the initial targets to be investigated in Aspergillus niger.
Topics: Aspergillus niger; Coenzymes; Fungi; Heme; Peroxidases
PubMed: 21687966
DOI: 10.1007/s00253-011-3391-3 -
BioMed Research International 2015Heme is a prosthetic group comprising ferrous iron (Fe(2+)) and protoporphyrin IX and is an essential cofactor in various biological processes such as oxygen transport... (Review)
Review
Heme is a prosthetic group comprising ferrous iron (Fe(2+)) and protoporphyrin IX and is an essential cofactor in various biological processes such as oxygen transport (hemoglobin) and storage (myoglobin) and electron transfer (respiratory cytochromes) in addition to its role as a structural component of hemoproteins. Heme biosynthesis is induced during erythroid differentiation and is coordinated with the expression of genes involved in globin formation and iron acquisition/transport. However, erythroid and nonerythroid cells exhibit distinct differences in the heme biosynthetic pathway regulation. Defects of heme biosynthesis in developing erythroblasts can have profound medical implications, as represented by sideroblastic anemia. This review will focus on the biology of heme in mammalian erythroid cells, including the heme biosynthetic pathway as well as the regulatory role of heme and human disorders that arise from defective heme synthesis.
Topics: Anemia, Sideroblastic; Animals; Erythroid Cells; Heme; Humans; Mice; Porphyria, Erythropoietic
PubMed: 26557657
DOI: 10.1155/2015/278536 -
The mitochondrial heme metabolon: Insights into the complex(ity) of heme synthesis and distribution.Molecular Genetics and Metabolism Nov 2019Heme is an essential cofactor in metazoans that is also toxic in its free state. Heme is synthesized by most metazoans and must be delivered to all cellular compartments... (Review)
Review
Heme is an essential cofactor in metazoans that is also toxic in its free state. Heme is synthesized by most metazoans and must be delivered to all cellular compartments for incorporation into a variety of hemoproteins. The heme biosynthesis enzymes have been proposed to exist in a metabolon, a protein complex consisting of interacting enzymes in a metabolic pathway. Metabolons enhance the function of enzymatic pathways by creating favorable microenvironments for pathway enzymes and intermediates, facilitating substrate transport, and providing a scaffold for interactions with other pathways, signaling molecules, or organelles. Herein we detail growing evidence for a mitochondrial heme metabolon and discuss its implications for the study of heme biosynthesis and cellular heme homeostasis.
Topics: Animals; Heme; Homeostasis; Humans; Metabolic Networks and Pathways; Metabolome; Mice; Mitochondria
PubMed: 30709775
DOI: 10.1016/j.ymgme.2019.01.006