Chemistry and biology of siderophores.

Iron is an essential element for most organisms, including bacteria. The oxidized form is insoluble, and the reduced form is highly toxic for most macromolecules and, in biological systems, is generally sequestrated by iron- and heme-carrier proteins. Thus, despite its abundance on earth, there is practically no free iron available for bacteria whatever biotope they colonize. To fulfill their iron needs, bacteria have multiple iron acquisition systems, reflecting the diversity of their potential biotopes. The iron/heme acquisition systems in bacteria have one of two general mechanisms. The first involves direct contact between the bacterium and the exogenous iron/heme sources. The second mechanism relies on molecules (siderophores and hemophores) synthesized and released by bacteria into the extracellular medium; these molecules scavenge iron or heme from various sources. Recent genetic, biochemical, and crystallographic studies have allowed substantial progress in describing molecular mechanisms of siderophore and hemophore interactions with the outer membrane receptors, transport through the inner membrane, iron storage, and regulation of genes encoding biosynthesis and uptake proteins.

Bacterial Iron Sources: From Siderophores to Hemophores

Iron (Fe) is an essential micronutrient for marine organisms, and it is now well established that low Fe availability controls phytoplankton productivity, community structure, and ecosystem functioning in vast regions of the global ocean. The biogeochemical cycle of Fe involves complex interactions between lithogenic inputs (atmospheric, continental, or hydrothermal), dissolution, precipitation, scavenging, biological uptake, remineralization, and sedimentation processes. Each of these aspects of Fe biogeochemical cycling is likely influenced by organic Fe-binding ligands, which complex more than 99% of dissolved Fe. In this review we consider recent advances in our knowledge of Fe complexation in the marine environment and their implications for the biogeochemistry of Fe in the ocean. We also highlight the importance of constraining the dissolved Fe concentration value used in interpreting voltammetric titration data for the determination of Fe speciation. Within the published Fe speciation data, there appear to be important temporal and spatial variations in Fe-binding ligand concentrations and their conditional stability constants in the marine environment. Excess ligand concentrations, particularly in the truly soluble size fraction, seem to be consistently higher in the upper water column, and especially in Fe-limited, but productive, waters. Evidence is accumulating for an association of Fe with both small, well-defined ligands, such as siderophores, as well as with larger, macromolecular complexes like humic substances, exopolymeric substances, and transparent exopolymers. The diverse size spectrum and chemical nature of Fe ligand complexes corresponds to a change in kinetic inertness which will have a consequent impact on biological availability. However, much work is still to be done in coupling voltammetry, mass spectrometry techniques, and process studies to better characterize the nature and cycling of Fe-binding ligands in the marine environment.

https://digitalcommons.usf.edu/cgi/viewcontent.cgi?article=1611&context=msc_facpub

The Organic Complexation of Iron in the Marine Environment: A Review

Preface 1 Solution Chemistry of Iron in Biological Media 11 Aqueous Solution Chemistry of Iron 12 Biomineralisation References 2 The Importance of Iron for Biological Systems 21 Introduction 22 Physical Techniques for the Study of Iron in Biological Systems 23 Haemoproteins 24 Iron-Sulfur Proteins 25 Other Iron Containing Proteins 3 Microbial Iron Transport and Metabolism 31 Introduction 32 Siderophores 33 Intracellular Iron Metabolism 34 Control of Gene Expression by Iron 4 Iron Uptake by Plants and Fungi 41 Iron Acquisition by Plants 42 Iron Acquisition by Yeast References 5 Cellular Iron Uptake and Export in Mammals 51 The Transferrins 52 Structure of Transferrins 53 Transferrin Iron Binding and Release 54 Iron Uptake by Mammalian Cells - Uptake of Transferrin Bound Iron 55 Cellular Iron Uptake and Export 56 Uptake of Iron from Other Sources than Transferrin 57 Nontransferrin Bound Iron 58 Ferritin Bound Iron 59 Haptoglobin and Haemopexin as Iron Transporters References 6 Intracellular Iron Storage and Biomineralisation 61 Intracellular Iron Storage 62 Biomineralisation 7 Intracellular Iron Metabolism and Cellular Iron Homeostasis 71 Intracellular Iron Metabolism 72 Cellular Iron Homeostasis References 8 Iron Absorption in Mammals, with Particular Reference to Man, and Regulation of Systemic Iron Balance 81 Iron Metabolism in Man: An Overview 82 Sources of Dietary Iron in Man and the Importance of Luminal Factors 83 Iron Losses and Requirements for Absorbed Iron 84 Molecular Mechanisms of Mucosal Iron Absorption 85 Regulation of Iron Uptake by the Enterocyte 86 Regulation of Systemic Iron Balance References 9 Pathophysiology of Iron Deficiency and Iron Overload in Man 91 Introduction: Acquired and Genetic Disorders of Iron Metabolism 92 Homeostatic Control of the Internal Milieu and Consequences of Its Disruption 93 Iron Overload Syndromes 94 Primary Iron Overload, Hereditary Haemochromatosis (HH) 95 Secondary Iron Overload 96 Iron Deficiency and IDA 97 Anaemia of Chronic Disease 98 Conclusions References 10 Iron and Oxidative Stress 101 Introduction to Free Radicals 102 Reactive Oxygen Species (ROS) 103 Cytoprotective Enzymes and Antioxidants 104 Ageing and Cytoprotection 105 Oxidative Stress 106 Cyclin Dependent Kinases 107 Deregulation of Calcium Homeostasis and Oxidative Stress 108 Nitric Oxide and Cyclic Guaylate Cyclase 109 Activation of cAMP Dependent PKA 1010 Importance of Iron, ROS and RNS in Phagocytic Cells 11 Brain Iron Homeostasis and Its Perturbation in Various Neurodegenerative Diseases 111 Introduction 112 Mechanisms for Iron Transport into Brain 113 Importance of Iron in the Developing Foetus 114 Iron Uptake and Turnover Within the Brain 115 Importance of IRPs in Brain Iron Homeostasis 116 Brain Iron Speciation 117 Neurodegenerative Diseases References 12 Interactions Between Iron and Other Metals 121 Introduction 122 Interactions Between Iron and Essential Metals 123 Iron and Toxic Metals References Concluding Remarks Index

Iron Metabolism: From Molecular Mechanisms to Clinical Consequences

Siderophores from Neighboring Organisms Promote the Growth of Uncultured Bacteria

Iron concentrations in the ocean are low enough to limit the growth of marine microorganisms, which raises questions about the molecular mechanisms these organisms use to acquire iron. Marine bacteria have been shown to produce siderophores to facilitate iron(III) uptake. We describe the structures of a suite of amphiphilic siderophores, named the amphibactins, which are produced by a nearshore isolate, γ Proteobacterium, Vibrio sp. R-10. Each amphibactin has the same Tris-hydroxamate-containing peptidic headgroup composed of three ornithine residues and one serine residue but differs in the acyl appendage, which ranges from C-14 to C-18 and varies in the degree of saturation and hydroxylation. Although amphiphilic siderophores are relatively rare, cell-associated amphiphilic siderophores are even less common. We find that the amphibactins are cell-associated siderophores. As a result of the variation in the nature of the fatty acid appendage and the cellular location of the amphibactins, the membrane partitioning of these siderophores was investigated. The physiological mixture of amphibactins had a range of membrane affinities (3.8 × 103 to 8.3 × 102 M−1) that are larger overall than other amphiphilic siderophores, likely accounting for their cell association. This cell association is likely an important defense against siderophore diffusion in the oceanic environment. The phylogenetic affiliation of Vibrio sp. R-10 is discussed, as well as the observed predominance of amphiphilic siderophores produced by marine bacteria in contrast to those produced by terrestrial bacteria.

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Structure and membrane affinity of a suite of amphiphilic siderophores produced by a marine bacterium.

The coastal α-proteobacterium Ochrobactrum sp. SP18 produces a suite of three citrate-derived, cell-associated amphiphilic siderophores, ochrobactins A–C. The ochrobactins are composed of a citric acid backbone amide-linked to two lysine residues. Each e-amine of lysine is hydroxylated and acylated forming two hydroxamic acid moieties. One of the acylated appendages of each ochrobactin is (E)-2-decenoic acid. The other acylated appendages for ochrobactins A–C are (E)-2-octenoic acid, octanoic acid and (E)-2-decenoic acid, respectively. The ferric ochrobactin complexes are photoreactive in UV light, producing an oxidized ligand with loss of 46 mass units that can still coordinate Fe(III). The relative partitioning of the apo-ochrobactins, Fe(III) ochrobactins and Fe(III) photoproducts into 1,2-dimyristoyl-sn-glycero-3-phosphocholine vesicles is presented. The ochrobactins are the first example of aerobactin-based siderophores with two fatty acid appendages produced in a suite with varying acyl appendage lengths.

Jessica D. Martin

Papers

Structure and membrane affinity of a suite of amphiphilic siderophores produced by a marine bacterium.

Structure and membrane affinity of new amphiphilic siderophores produced by Ochrobactrum sp. SP18

Vanadium bromoperoxidase from Delisea pulchra: enzyme-catalyzed formation of bromofuranone and attendant disruption of quorum sensing

The marine biogeochemistry of iron.