Sideroforo: differenze tra le versioni

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{{T|inglese|biologia|gennaio 2016}}
Con il nome di '''sideroforo''' si indica una piccola molecola con elevata affinità per il [[ferro]] e in grado di [[Chelazione|chelarlo]] efficacemente, prodotta generalmente da [[Microrganismo|microrganismi]], [[Fungi|funghi]] e [[Poaceae|graminacee]].
Con il nome di '''sideroforo''' si indica una piccola molecola con elevata affinità per il [[ferro]] e in grado di [[Chelazione|chelarlo]] efficacemente, prodotta generalmente da [[Microrganismo|microrganismi]], [[Fungi|funghi]] e [[Poaceae|graminacee]].<ref name="Neilands1">{{cite journal | author = J. B. Neilands | title = A Crystalline Organo-iron Pigment from a Rust Fungus (Ustilago sphaerogena) | journal = [[J. Am. Chem. Soc]] | year = 1952 | volume = 74 | pages = 4846–4847 | doi = 10.1021/ja01139a033 | issue = 19}}</ref><ref name="J. B. Neilands">{{cite journal | author = J. B. Neilands | title = Siderophores: Structure and Function of Microbial Iron Transport Compounds | journal = [[J. Biol. Chem.]] | year = 1995 | volume = 270 | pages = 26723–26726 | pmid=7592901 | doi=10.1074/jbc.270.45.26723 | issue = 45}}</ref><ref name="R. C. Hider">{{cite journal | author = R. C. Hider and X. Kong | title = Chemistry and biology of siderophores | journal = [[Nat. Prod. Rep.]] | year = 2010 | volume = 27 | pages = 637–657 | doi=10.1039/b906679a}}</ref><ref name="J. H. Crosa">{{cite book | author = J. H. Crosa, A. R. Mey, S. M. Payne (editor) | year = 2004 | title = Iron Transport in Bacteria | publisher=[[ASM Press]] | isbn= 1-55581-292-9}}</ref><ref name= CornelisP>{{cite book |author= Cornelis, P; Andrews, SC (editor)| year=2010 |title=Iron Uptake and Homeostasis in Microorganisms| publisher=[[Caister Academic Press]] | isbn= 978-1-904455-65-3}}</ref><ref name="Miller">Miller, Marvin J. Siderophores (microbial iron chelators) and siderophore-drug conjugates (new methods for microbially selective drug delivery). University of Notre Dame, 4/21/2008 http://www.nd.edu/~mmiller1/page2.html</ref>
I siderofori sono tra i più forti agenti chelanti del Fe<sup>3+</sup> conosciuti.
I siderofori sono tra i più forti agenti chelanti del Fe<sup>3+</sup> conosciuti.

== La scarsità di ferro solubile ==

Il ferro è essenziale per quasi tutta la vita per processi come la [[respirazione cellulare]] e la [[sintesi del DNA]]. Nonostante sia uno degli elementi più abbondanti nella crosta terrestre, la [[biodisponibilità]] di ferro in molti ambienti, come il suolo o il mare è limitato dalla bassissima [[solubilità]] del [[ferro]]. Questo è lo stato predominante del ferro in ambienti acquosi, non acidi e ossigenati. Si accumula in fasi minerali comuni come gli ossidi e idrossidi di ferro (i minerali che sono responsabili per il colore rosso e giallo del suolo), quindi, non può essere facilmente utilizzato dagli organismi.<ref name="Kraemer">{{cite journal | author = Kraemer, Stephan M. | title = Iron oxide dissolution and solubility in the presence of siderophores | journal = [[Aquatic Sciences]] | year = 2005 | volume = 66 | pages = 3–18 | doi = 10.1007/s00027-003-0690-5}}</ref> I microbi rilasciano i siderofori utilizzando il ferro da questi minerali formando complessi Fe<sup>3+</sup> che possono essere accettati dai meccanismi di [[trasporto attivo]]. Molti siderofori sono [[peptide non ribosomiale|peptidi non ribosomiali]],<ref name="R. C. Hider" /><ref name="Miethke">{{cite journal | author = Miethke, M.; Marahiel, M.| title = Siderophore-Based Iron Acquisition and Pathogen Control| journal = Microbiology and Molecular Biology Reviews | year = 2007 | volume = 71 | pages = 413–451 | doi = 10.1128/MMBR.00012-07 | pmid = 17804665 | issue = 3 | pmc = 2168645}}</ref> anche se molti sono biosintetizzati indipendentemente.<ref>{{cite journal | author = Challis, G. L. | title = A widely distributed bacterial pathway for siderophore biosynthesis independent of nonribosomal peptide synthetases | journal = [[ChemBioChem]] | year = 2005 | volume = 6 | pages = 601–611 | doi = 10.1002/cbic.200400283 | pmid = 15719346 | issue = 4}}</ref>

I siderofori sono anche importanti per alcuni batteri patogeni per la loro acquisizione di ferro.<ref name="R. C. Hider" /><ref name="J. H. Crosa" /><ref name="Miller" /> Nei mammiferi, il ferro è strettamente legato alle proteine come [[emoglobina]], [[transferrina]], [[lattoferrina]] e [[ferritina]]. La rigida [[omeostasi]] del ferro porta ad una concentrazione libera di circa 10<sup>−24</sup> mol L<sup>−1</sup>,<ref name="Raymond">{{cite journal | author = Raymond, K. N.; Dertz, E. A.; Kim, S. S.| title = Enterobactin: An archetype for microbial iron transport| journal = [[PNAS]] | year = 2003 | volume = 100 | pages = 3584–3588 | doi = 10.1073/pnas.0630018100 | pmid = 12655062 | issue = 7 | pmc = 152965}}</ref> quindi non ci sono grandi pressioni evolutive su batteri patogeni per ottenere questo metallo. Ad esempio, l’agente patogeno [[antrace]] ''[[Bacillus anthracis]] '' rilascia due siderofori, [[bacillibactina]] e [[petrobactina]], per rimuovere il ferro ferrico dalle proteine. Mentre bacillibactina ha dimostrato di legarsi alla proteina del sistema immunitario [[siderocalina]],<ref name="Raymond2">{{cite journal | author = Rebecca J. Abergel, Melissa K. Wilson, Jean E. L. Arceneaux, Trisha M. Hoette, Roland K. Strong, B. Rowe Byers, and Kenneth N. Raymond| title = Anthrax pathogen evades the mammalian immune system through stealth siderophore production| journal = [[PNAS]] | year = 2006 | volume = 103 | pages = 18499–18503 | doi = 10.1073/pnas.0607055103 | pmid = 17132740 | issue = 49 | pmc = 1693691}}</ref> petrobactina si presume che eluda il sistema immunitario e ha dimostrato di essere importante per la virulenza nei topi.<ref>{{cite journal | author = Cendrowski, S., W. MacArthur, and P. Hanna.| title = Bacillus anthracis requires siderophore biosynthesis for growth in macrophages and mouse virulence|journal = [[Molecular Microbiology (journal)|Molecular Microbiology]] | year = 2004 | volume = 51 | pages = 407–417 | doi = 10.1046/j.1365-2958.2003.03861.x | pmid = 14756782 | issue = 2}}</ref>

I siderofori sono tra i più forti leganti di Fe<sup>3+</sup> conosciuti, e l'[[enterobactina]] uno di essi.<ref name="Raymond"/> A causa di questa proprietà, hanno attirato l'interesse della scienza medica nella [[terapia chelante]] metallica con il sideroforo [[deferoxamina]] B, guadagnando ampio utilizzo nei trattamenti per l'[[avvelenamento da ferro]] e per la [[talassemia]].<ref name="T. Zhou">{{cite journal | author = T. Zhou, Y. Ma, X. Kong and R. C. Hider | title = Design of iron chelators with therapeutic application.| journal = [[Dalton. Trans.]] | year = 2012 | volume = 41 | pages = 6371–6389 | doi = 10.1039/c2dt12159j | pmid = 22391807 | issue = 21}}</ref>

<!--Besides siderophores, some pathogenic bacteria produce ''hemophores'' ([[heme]] binding scavenging proteins) or have receptors that bind directly to iron/heme proteins.<ref name="Vogel">{{cite journal | author = Krewulak, K. D.; Vogel, H. J.| title = Structural biology of bacterial iron uptake| journal = Biochim. Biophys. Acta. | year = 2008 | volume = 1778 | pages = 1781–1804 | doi = 10.1016/j.bbamem.2007.07.026 | pmid = 17916327 | issue = 9}}</ref> In eukaryotes, other strategies to enhance iron solubility and uptake are the acidification of the surroundings (e.g. used by plant roots) or the [[extracellular]] [[Reduction (chemistry)|reduction]] of [[iron|Fe<sup>3+</sup>]] into the more soluble [[iron|Fe<sup>2+</sup>]] ions.-->
==Struttura==
<!--[[File:Catecholate-Iron-Complex.png|thumb|right|Catecholate-iron complex]]
Siderophores usually form a stable, hexadentate, [[octahedral]] complex preferentially with Fe<sup>3+</sup> compared to other naturally occurring abundant metal ions, although if there are less than six donor atoms water can also coordinate. The most effective siderophores are those that have three bidentate [[ligand]]s per molecule, forming a hexadentate complex and causing a smaller entropic change than that caused by chelating a single ferric ion with separate ligands.<ref name="John M. Roosenberg">{{cite journal | author = John M. Roosenberg II, Yun-Ming Lin, Yong Lu and Marvin J. Miller | title = Studies and Syntheses of Siderophores, Microbial Iron Chelators, and Analogs as Potential Drug Delivery Agents | journal = [[Current Medicinal Chemistry]] | year = 2000 | volume = 7 | pages = 159–197 | pmid=10637361 | issue=2 | doi = 10.2174/0929867003375353}}</ref> A comprehensive list of siderophores is presented in.<ref name="Appendix(i)">{{cite journal | author = R. C. Hider and X. Kong | title = Chemistry and biology of siderophores (Appendix(i) List of siderophorestructures) | journal = [[Nat. Prod. Rep.]] | year = 2010 | volume = 27 | pages = 637–657 | doi = 10.1039/b906679a}}</ref>
Fe<sup>3+</sup> is a hard [[Lewis acid]], preferring hard [[Lewis bases]] such as anionic or neutral oxygen to coordinate with. Microbes usually release the iron from the siderophore by reduction to Fe<sup>2+</sup> which has little affinity to these ligands.<ref name="Miethke" />
-->
<!--Siderophores are usually classified by the ligands used to chelate the ferric iron. The major groups of siderophores include the [[catecholate]]s (phenolates), [[hydroxamic acid|hydroxamate]]s and [[carboxylate]]s (e.g. derivatives of [[citric acid]]).<ref name="R. C. Hider"/> Citric acid can also act as a siderophore.<ref>Winkelmann, G.; Drechsel, H., Biotechnology (2nd edition), Chapter 5: Microbial Siderophores. 1999.</ref> The wide variety of siderophores may be due to evolutionary pressures placed on microbes to produce structurally different siderophores which cannot be transported by other microbes' specific active transport systems, or in the case of pathogens deactivated by the host organism.<ref name="R. C. Hider" /><ref name="Miller"/>-->

==Varietà==
<!--Examples of siderophores produced by various [[bacterium|bacteria]] and [[fungi]]:
[[File:Ferrichrome.PNG|thumbnail|Ferrichrome, a hydroxamate siderophore]]
[[File:Deferoxamine-2D-skeletal.png|400px|thumb|[[deferoxamine|Desferrioxamine B]], a hydroxamate siderophore]]
[[Image:Enterobactin.svg|200px|thumb| [[Enterobactin]], a catecholate siderophore]]
[[File:Azotobactin.png|thumbnail|Azotobactin, a mixed-ligand siderophore]]
[[File:Pyoverdine.png|thumbnail|Pyoverdine, a mixed-ligand siderophore]]
[[File:Yersiniabactin.svg|thumbnail|Yersiniabactin, a mixed-ligand siderophore]]-->

<!--'''Hydroxamate siderophores'''
{| class="wikitable" border="1"
|-
! Siderophore
! Organism
|-
| [[ferrichrome]]
| ''[[Ustilago]] sphaerogena''
|-
| Desferrioxamine B
([[Deferoxamine]])
| ''[[Streptomyces]] pilosus''
'' [[Streptomyces]] coelicolor''
|-
| Desferrioxamine E
| '' [[Streptomyces]] coelicolor''
|-
| [[fusarinine C]]
| ''[[Fusarium]] roseum''
|-
| ornibactin
| ''[[Burkholderia cepacia]]''
|-
| [[rhodotorulic acid]]
| ''[[Rhodotorula]] pilimanae''
|}

'''Catecholate siderophores'''
{| class="wikitable" border="1"
|-
! Siderophore
! Organism
|-
| [[enterobactin]]
| ''[[Escherichia coli]]''
enteric bacteria
|-
| bacillibactin
| ''[[Bacillus subtilis]] ''
'' [[Bacillus anthracis]] ''
|-
| vibriobactin
| ''[[Vibrio cholerae]]''
|}

'''Mixed ligands'''
{| class="wikitable" border="1"
|-
! Siderophore
! Organism
|-
| [[pyoverdine|azotobactin]]
| ''[[Azotobacter vinelandii]]''
|-
| [[pyoverdine]]
| ''[[Pseudomonas aeruginosa]]''
|-
| [[yersiniabactin]]
| ''[[Yersinia pestis]]''
|}

A comprehensive list of siderophore structures (over 250) is presented in Appendix 1 in reference.<ref name="R. C. Hider" />-->

<!--==Biological function==

===Bacteria and fungi===
In response to iron limitation in their environment, genes involved in microbe siderophore production and uptake are derepressed, leading to manufacture of siderophores and the appropriate uptake proteins. In bacteria, Fe<sup>2+</sup>-dependent repressors bind to DNA upstream to genes involved in siderophore production at high intracellular iron concentrations. At low concentrations, Fe<sup>2+</sup> dissociates from the repressor, which in turn dissociates from the DNA, leading to transcription of the genes. In gram-negative and AT-rich gram-positive bacteria, this is usually regulated by the ''Fur'' (ferric uptake regulator) repressor, whilst in GC-rich gram-positive bacteria (e.g. [[Actinobacteria]]) it is ''DtxR'' (diphtheria toxin repressor), so-called as the production of the dangerous [[diphtheria toxin]] by ''[[Corynebacterium diphtheriae]]'' is also regulated by this system.<ref name="Miethke" />

This is followed by excretion of the siderophore into the extracellular environment, where the siderophore acts to sequester and solubilize the iron.<ref name="R. C. Hider"/><ref name="Crowley">{{cite journal | author = Kraemer, Stephan M., Crowley, David, and Kretzschmar, Ruben | title = Siderophores in Plant Iron Acquisition: Geochemical Aspects | journal = [[Advances in Agronomy]] | year = 2006 | volume = 91 | pages = 1–46 | doi = 10.1016/S0065-2113(06)91001-3 | series = Advances in Agronomy | isbn = 978-0-12-000809-4}}</ref><ref name="Butler">{{cite journal | author = Kraemer, Stephan M., Butler, Allison, Borer, Paul, and Cervini-Silva, Javiera | title = Siderophores and the dissolution of iron bearing minerals in marine systems | journal = [[Reviews in Mineralogy and Geochemistry]] | year = 2005 | volume = 59 | pages = 53–76 | doi = 10.2138/rmg.2005.59.4}}</ref><ref name="Huyer">{{cite journal | author = Huyer, Marianne, and Page, William J. | title = Zn<sup>2+</sup> Increases Siderophore Production in Azotobacter vinelandii | journal = [[Applied and Environmental Microbiology]] | year = 1988 | volume = 54 | pages = 2625–2631}}</ref> Siderophores are then recognized by cell specific receptors on the outer membrane of the cell.<ref name="J. B. Neilands"/><ref name="R. C. Hider"/><ref name="A. del Olmo">{{cite journal | author = A. del Olmo, C. Caramelo, and C. SanJose | title = Fluorescent complex of pyoverdin with aluminum | journal = [[J. Inorg. Biochem.]] | year = 2003 | volume = 97 | pages = 384–387 | doi = 10.1016/S0162-0134(03)00316-7 | pmid=14568244 | issue = 4}}</ref> In fungi and other eukaryotes, the Fe-siderophore complex may be extracellularly reduced to Fe<sup>2+</sup>, while in many cases the whole Fe-siderophore complex is actively transported across the cell membrane. In gram-negative bacteria, these are transported into the periplasm via [[TonB-dependent receptors]], and are transferred into the cytoplasm by [[ABC transporters]].<ref name="R. C. Hider" /><ref name="Miethke" /><ref name="John M. Roosenberg" /><ref name="Cobessi">{{cite journal | author = David Cobessi, Ahmed Meksem, and Karl Brillet| title = Structure of the heme/hemoglobin outer membrane receptor ShuA from Shigella dysenteriae: Heme binding by an induced fit mechanism | journal = [[Proteins: Structure, Function, and Bioinformatics]] | year = 2010 | volume = 78 | issue = 2 | pages = 286–294 | doi = 10.1002/prot.22539 | pmid = 19731368}}</ref>

Once in the cytoplasm of the cell, the Fe<sup>3+</sup>-siderophore complex is usually reduced to Fe<sup>2+</sup> to release the iron, especially in the case of “weaker” siderophore ligands such as hydroxamates and carboxylates. Siderophore decomposition or other biological mechanisms can also release iron.,<ref name="John M. Roosenberg"/> especially in the case of catecholates such as ferric-enterobactin, whose reduction potential is too low for [[reducing agents]] such as [[flavin adenine dinucleotide]], hence enzymatic degradation is needed to release the iron.<ref name="Raymond" />

===Plants===
[[File:Deoxymugineic acid and nicotianamine.png|thumb|[[Deoxymugineic acid]], a phytosiderophore.]]
Although there is sufficient iron in most soils for plant growth, [[Iron deficiency (plant disorder)|plant iron deficiency]] is a problem in [[calcareous soil]], due to the low solubility of [[iron(III) hydroxide]]. Calcareous soil accounts for 30% of the world's farmland. Under such conditions [[poaceae|graminaceous]] plants (grasses, cereals and rice) secrete phytosiderophores into the soil,<ref name="Sugiura">{{cite journal | author = Y. Sugiura and K. Nomoto | title = Phytosiderophores structures and properties of mugineic acids and their metal complexes | journal = [[Structure and Bonding]] | year = 1984 | volume = 58 | pages = 107–135 | doi = 10.1007/BFb0111313 }}</ref> a typical example being [[deoxymugineic acid]]. Phytosiderophores have a different structure to those of fungal and bacterial siderophores having two α-aminocarboxylate binding centres, together with a single α-hydroxycarboxylate unit. This latter bidentate function provides phytosiderophores with a high selectivity for iron(III). When grown in an iron -deficient soil, roots of graminaceous plants secrete siderophores into the rhizosphere. On scavenging iron(III) the iron –phytosiderophore complex is transported across the cytoplasmic membrane using a proton [[symport]] mechanism.<ref name="Mori">{{cite book | author = S. Mori; Sigel, A. and Sigel, H. (editor)| year=1998 |title=Iron transport in graminaceous plants.| publisher=[[Metal Ions in Biological Systems]] | pages = 216–238}}</ref> The iron(III) complex is then reduced to iron(II) and the iron is transferred to [[nicotianamine]], which although very similar to the phytosiderophores is selective for iron(II) and is not secreted by the roots.<ref name="Walker">{{cite journal | author = E. L. Walker and E. L. Connolly | title = Time to pump iron: iron-deficiency-signaling mechanisms of higher plants | journal = [[Current Opinion in Plant Biology]] | year = 2008 | volume = 11 | pages = 530–535 | doi = 10.1016/j.pbi.2008.06.013 | pmid = 18722804}}</ref> Nicotianamine translocates iron in [[phloem]] to all plant parts.

==Siderophore ecology==
Siderophores become important in the ecological niche defined by low iron availability, iron being one of the critical growth limiting factors for virtually all aerobic microorganisms. There are four major ecological habitats: soil and surface water, marine water, plant tissue (pathogens) and animal tissue (pathogens).

===Soil and surface water===
The soil is a rich source of bacterial and fungal genera. Common Gram-positive species are those belonging to the Actinomycetales and species of the genera ''Bacillus'', ''Arthrobacter'' and ''Nocardia''. Many of these organisms produce and secrete ferrioxamines which lead to growth promotion of not only the producing organisms, but also other microbial populations that are able to utilize exogenous siderophores . Soil fungi include ''Aspergillus'' and ''Penicillium'' which predominately produce ferrichromes. This group of siderophores consist of cyclic hexapeptides and consequently are highly resistant to environmental degradation associated with the wide range of hydrolytic enzymes that are present in humic soil.<ref name="Winkelmann">{{cite journal | author = G. Winkelmann | title = Ecology of siderophores with special reference to the fungi | journal = [[BioMetals (journal)|BioMetals]] | year = 2007 | volume = 20 | pages = 379–392 | pmid = 17235665 | doi=10.1007/s10534-006-9076-1 | issue=3-4}}</ref> Soils containing decaying plant material possess pH values as low as 3–4. Under such conditions organisms that produce hydroxamate siderophores have an advantage due to the extreme acid stability of these molecules. The microbial population of fresh water is similar to that of soil, indeed many bacteria are washed out from the soil. In addition, fresh-water lakes contain large populations of ''Pseudomonas'', ''Azomonas'', ''Aeromonos'' and ''Alcaligenes'' species.<ref name="Winkelmann1">{{cite book | author = G. Winkelmann; Crosa, J. H. Mey, A. R. and Payne, S. M. (editor)| year=2004 |title=Iron transport in Bacteria.| publisher=[[ASM press]] | chapter = 28 | pages = 437–450 | isbn= 1-55581-292-9}}</ref>

===Marine water===
In contrast to most fresh-water sources, iron levels in surface sea-water are extremely low (1 nM to 1 μM in the upper 200 m) and much lower than those of V, Cr, Co, Ni, Cu and Zn. Virtually all this iron is in the iron(III) state and [[Coordination complex|complexed]] to organic ligands.<ref name="Rue">{{cite journal | author = E. L. Rue and K. W. Bruland | title = Complexation of iron(III) by natural organic ligands in the Central North Pacific as determined by a new competitive ligand equilibration/adsorptive cathodic stripping voltammetric method | journal = [[Mar. Chem.]] | year = 1995 | volume = 50 | pages = 117–138 | doi = 10.1016/0304-4203(95)00031-L}}</ref> These low levels of iron limit the primary production of phytoplankton and have led to the [[Iron fertilization|Iron Hypothesis]]<ref name="Martin">{{cite journal | author = J. H. Martin | title = Glacial-interglacial CO<sub>2</sub> change: The Iron Hypothesis |journal = [[Paleoceanography (journal)|Paleoceanography]] | year = 1990 | volume = 5 | pages = 1–13 | doi = 10.1029/PA005i001p00001 | bibcode=1990PalOc...5....1M}}</ref> where it was proposed that an influx of iron would promote phytoplankton growth and thereby reduce atmospheric CO<sub>2</sub>. This hypothesis has been tested on more than 10 different occasions and in all cases, massive blooms resulted. However, the blooms persisted for variable periods of time. An interesting observation made in some of these studies was that the concentration of the organic ligands increased over a short time span in order to match the concentration of added iron, thus implying biological origin and in view of their affinity for iron possibly being of a siderophore or siderophore-like nature.<ref name="A. Butler">{{cite journal | author = A. Butler | title = Marine siderophores and microbial iron mobilization. | journal = [[BioMetals (journal)|BioMetals]] | year = 2005 | volume = 18 | pages = 369–374 | pmid = 16158229 | doi=10.1007/s10534-005-3711-0 | issue=4}}</ref> Significantly, [[heterotroph]]ic bacteria were also found to markedly increase in number in the iron-induced blooms. Thus there is the element of synergism between phytoplankton and heterotrophic bacteria. Phytoplankton require iron (provided by bacterial siderophores), and heterotrophic bacteria require non-CO<sub>2</sub> carbon sources (provided by phytoplankton).

The dilute nature of the [[Pelagic zone|pelagic]] marine environment promotes large diffusive losses and renders the efficiency of the normal siderophore-based iron uptake strategies problematic. However, many heterotrophic marine bacteria do produce siderophores, albeit with properties different from those produced by terrestrial organisms. Many marine siderophores are surface-active and tend to form molecular aggregates, for example aquachelins. The presence of the fatty acyl chain renders the molecules with a high surface activity and an ability to form [[micelle]]s.<ref name="Xu">{{cite journal | author = G. Xu, J. S. Martinez, J. T. Groves and A. Butler | title = Membrane affinity of the amphiphilic marinobactin siderophores. | journal = [[J. Am. Chem. Soc.]] | year = 2002 | volume = 124 | pages = 13408–13415 | pmid = 12418892 | issue=45 | doi=10.1021/ja026768w}}</ref> Thus, when secreted, these molecules bind to surfaces and to each other, thereby slowing the rate of diffusion away from the secreting organism and maintaining a relatively high local siderophore concentration. Phytoplankton have high iron requirements and yet the majority (and possibly all) do not produce siderophores . Phytoplankton can, however, obtain iron from siderophore complexes by the aid of membrane-bound reductases <ref name="Hopkinson">{{cite journal | author = B. M. Hopkinson and F. M. M. Morel | title = The role of siderophores in iron acquisition by photosynthetic marine microorganisms. | journal = [[BioMetals (journal)|BioMetals]] | year = 2009 | volume = 22 | pages = 659–669 | doi = 10.1007/s10534-009-9235-2 | pmid = 19343508}}</ref> and certainly from iron(II) generated via photochemical decomposition of iron(III) siderophores. Thus a large proportion of iron (possibly all iron) absorbed by phytoplankton is dependent on bacterial siderophore production.

===<ref name="Roth-Walter 17416–17421">{{Cite journal|title = Bet v 1 from birch pollen is a lipocalin-like protein acting as allergen only when devoid of iron by promoting Th2 lymphocytes|url = http://www.ncbi.nlm.nih.gov/pubmed/24798325|journal = The Journal of Biological Chemistry|date = 2014-06-20|issn = 1083-351X|pmc = 4067174|pmid = 24798325|pages = 17416–17421|volume = 289|issue = 25|doi = 10.1074/jbc.M114.567875|first = Franziska|last = Roth-Walter|first2 = Cristina|last2 = Gomez-Casado|first3 = Luis F.|last3 = Pacios|first4 = Nadine|last4 = Mothes-Luksch|first5 = Georg A.|last5 = Roth|first6 = Josef|last6 = Singer|first7 = Araceli|last7 = Diaz-Perales|first8 = Erika|last8 = Jensen-Jarolim}}</ref> Plant pathogens===
[[File:Chrysobactin.png|thumbnail|Chrysobactin]]
[[File:Achromobactin.png|thumbnail|Achromobactin]]

Most [[plant pathogens]] invade the [[apoplast|apoplasm]] by releasing [[pectolytic]] enzymes which facilitate the spread of the invading organism. Bacteria frequently infect plants by gaining entry to the tissue via the [[stomata]]. Having entered the plant they spread and multiply in the intercellular spaces. With bacterial vascular diseases, the infection is spread within the plants through the xylem.

Once within the plant, the bacteria need to be able to scavenge iron from the two main iron-transporting ligands, nicotianamine and citrate.<ref name="von Wiren">{{cite journal | author = N. von Wiren, S. Klair, S. Bansal, J. -F. Briat, H. Khodr, T. Shioiri, R. A. Leigh and R. C. Hider | title = Nicotianamine Chelates Both FeIII and FeII. Implications for Metal Transport in Plants. | journal = [[Plant Physiol.]] | year = 1999 | volume = 119 | pages = 1107–1114 | pmid = 10069850 | issue=3 | doi=10.1104/pp.119.3.1107}}</ref> To do this they produce siderophores, thus the enterobacterial ''[[Erwinia chrysanthemi]]'' produces two siderophores, chrysobactin and achromobactin.<ref name="Expert">{{cite book | author = D. Expert, L. Rauscher and T. Franza; Crosa, J. H. Mey, A. R. and Payne, S. M. (editor)| year=2004 | title= Iron transport in Bacteria. | publisher = [[ASM press]] | chapter = 26 | pages = 402–412 | isbn= 1-55581-292-9}}</ref>

Similar like in humans also plants possess siderophore binding proteins involve in host defense like the major birch pollen allergen, Bet v 1, which are usually secreted and possess a lipocalin-like structure.<ref name="Roth-Walter 17416–17421"/>

===Animal pathogens===
Pathogenic bacteria and fungi have developed the means of survival in animal tissue. They may invade the gastro-intestinal tract (''Escherichia'', ''Shigella'' and ''Salmonella''), the lung (''Pseudomonas'', ''Bordatella'', ''Streptococcus'' and ''Corynebacterium''), skin (''Staphylococcus'') or the urinary tract (''Escherichia'' and ''Pseudomonas''). Such bacteria may colonise wounds (''Vibrio'' and ''Staphylococcus'') and be responsible for septicaemia (''Yersinia'' and ''Bacillus''). Some bacteria survive for long periods of time in intracellular organelles, for instance ''Mycobacterium''. (see table). Because of this continual risk of bacterial and fungal invasion, animals have developed a number of lines of defence based on immunological strategies, the complement system, the production of iron–siderophore binding proteins and the general “withdrawal”of iron.<ref name="Weinberg">{{cite journal | author = E. D. Weinberg | title = Iron availability and infection. | journal = [[Biochim. Biophys. Acta]] | year = 2009 | volume = 1790 | pages = 600–605 | doi = 10.1016/j.bbagen.2008.07.002 | pmid = 18675317}}</ref>

{| class="wikitable"
|-
! '''Infection type''' !! '''Organism''' !! '''Siderophore'''
|-
| Dysentery || ''Shigella'' sp. || Aerobactin
|-
| Intestinal infections || ''Escherichia coli'' || Enterobactin
|-
| Typhoid || ''Salmonella'' sp. || Salmochelin
|-
| Plague || ''Yersinia'' sp. || Yersiniabactin
|-
| Cholera || ''Vibrio'' sp. || Vibriobactin
|-
| Pulmonary infections || ''Pseudomonas'' sp. || Pyoverdins
|-
| Whooping cough || ''Bordetella'' sp. || Alcaligin
|-
| Tuberculosis || ''Mycobacterium tuberculosis'' || Mycobactins
|-
| Skin and mucous membrane infections || ''Staphylococcus'' sp. || Staphyloferrin A
|-
| Anthrax || ''Bacillus anthracis'' || Petrobactin
|}

There are two major types of iron-binding proteins present in most animals that provide protection against microbial invasion – extracellular protection is achieved by the transferrin family of proteins and intracellular protection is achieved by ferritin. Transferrin is present in the serum at approximately 30 μM, and contains two iron-binding sites, each with an extremely high affinity for iron. Under normal conditions it is about 25–40% saturated, which means that any freely available iron in the serum will be immediately scavenged – thus preventing microbial growth . Most siderophores are unable to remove iron from transferrin. Mammals also produce lactoferrin, which is similar to serum transferrin but possesses an even higher affinity for iron.<ref name="Crichton">{{cite book | author = R. Crichton; Crichton, R. (editor) | year = 2001 | title = Inorganic Biochemistry of Iron Metabolism | publisher=[[John Wiley & Sons|Wiley]] | isbn= 0-471-49223-X}}</ref> Lactoferrin is present in secretory fluids, such as sweat, tears and milk, thereby minimising bacterial infection.

Ferritin is present in the cytoplasm of cells and limits the intracellular iron level to approximately 1 μM. Ferritin is a much larger protein than transferrin and is capable of binding several thousand iron atoms in a nontoxic form. Siderophores are unable to directly mobilise iron from ferritin.

In addition to these two classes of iron-binding proteins, a hormone, hepcidin, is involved in controlling the release of iron from absorptive enterocytes, iron-storing hepatocytes and macrophages.<ref name="Rivera">{{cite journal | author = S. Rivera, L. Liu, E. Nemeth, V. Gabayan, O. E. Sorensen and T. Ganz | title = Hepcidin excess induces the sequestration of iron and exacerbates tumor-associated anemia. |journal = [[Blood (journal)|Blood]] | year = 2005 | volume = 105 | pages = 1797–1802 | doi = 10.1182/blood-2004-08-3375 | pmid = 15479721}}</ref> Infection leads to inflammation and the release of interleukin-6 (IL-6 ) which stimulates hepcidin expression. In humans, IL-6 production results in low serum iron, making it difficult for invading pathogens to infect. Such iron depletion has been demonstrated to limit bacterial growth in both extracellular and intracellular locations.<ref name="Weinberg" />

In addition to “iron withdrawal” tactics, mammals produce an iron –siderophore binding protein, siderochelin. Siderochelin is a member of the lipocalin family of proteins, which while diverse in sequence, displays a highly conserved structural fold, an 8-stranded antiparallel β-barrel that forms a binding site with several adjacent β-strands. Siderocalin (lipocalin 2) has 3 positively charged residues also located in the hydrophobic pocket, and these create a high affinity binding site for iron(III)–enterobactin.<ref name="Raymond1">{{cite journal | author = K. N. Raymond, E. A. Dertz and S. S. Kim | title = Enterobactin: an archetype for microbial iron transport. | journal = [[Proc. Natl. Acad. Sci. U.S.A.]] | year = 2003 | volume = 100 | pages = 3584–3588 | doi = 10.1073/pnas.0630018100 | pmid = 12655062 | pmc=152965}}</ref> Siderocalin is a potent bacteriostatic agent against ''E. coli''. As a result of infection it is secreted by both macrophages and hepatocytes, enterobactin being scavenged from the extracellular space.

==Medical applications==
Siderophores have applications in medicine for iron and aluminum overload therapy and antibiotics for improved targeting.<ref name="R. C. Hider"/> Understanding the mechanistic pathways of siderophores has led to opportunities for designing small-molecule inhibitors that block siderophore biosynthesis and therefore bacterial growth and virulence in iron-limiting environments.<ref name="Julian">{{cite journal | author = Julian A Ferreras, Jae-Sang Ryu, Federico Di Lello, Derek S Tanand Luis E N Quadri | title = Small-molecule inhibition of siderophore biosynthesis in Mycobacterium tuberculosis and Yersinia pestis | journal = [[Nature Chemical Biology]] | year = 2005 | volume = 1 | pages = 29–32 | doi = 10.1038/nchembio706 | pmid = 16407990 | issue = 1}}</ref>

Siderophores are useful as drugs in facilitating iron mobilization in humans, especially in the treatment of iron diseases, due to their high affinity for iron. One potentially powerful application is to use the iron transport abilities of siderophores to carry drugs into cells by preparation of conjugates between siderophores and antimicrobial agents. Because microbes recognize and utilize only certain siderophores, such conjugates are anticipated to have selective antimicrobial activity.<ref name="Miller"/><ref name="John M. Roosenberg"/>

Microbial iron transport (siderophore)-mediated drug delivery makes use of the recognition of siderophores as iron delivery agents in order to have the microbe assimilate siderophore conjugates with attached drugs. These drugs are lethal to the microbe and cause the microbe to [[apoptosis]]e when it assimilates the siderophore conjugate.<ref name="Miller"/> Through the addition of the iron-binding functional groups of siderophores into antibiotics, their potency has been greatly increased. This is due to the siderophore-mediated iron uptake system of the bacteria.

==Agricultural applications==
[[Poaceae]] (grasses) including agriculturally important species such as [[barley]] and [[wheat]] are able to efficiently sequester iron by releasing [[phytosiderophores]] via their [[root]] into the surrounding [[soil]] [[rhizosphere]].<ref name="Crowley"/> Chemical compounds produced by microorganisms in the rhizosphere can also increase the availability and uptake of iron. Plants such as oats are able to assimilate iron via these microbial siderophores. It has been demonstrated that plants are able to use the hydroxamate-type siderophores ferrichrome, rodotorulic acid and ferrioxamine B; the catechol-type siderophores, agrobactin; and the mixed ligand catechol-hydroxamate-hydroxy acid siderophores biosynthesized by saprophytic root-colonizing bacteria. All of these compounds are produced by rhizospheric bacterial strains, which have simple nutritional requirements, and are found in nature in soils, foliage, fresh water, sediments, and seawater.<ref name="G. Carrillo">{{cite journal | author = G. Carrillo-Castañeda, J. Juárez Muños, J. R. Peralta-Videa, E. Gomez, K. J. Tiemannb, M. Duarte-Gardea and J. L. Gardea-Torresdey | title = Alfalfa growth promotion by bacteria grown under iron limiting conditions | journal = [[Advances in Environmental Research]] | year = 2002 | volume = 6| pages = 391–399 | doi = 10.1016/S1093-0191(02)00054-0 | issue = 3}}</ref>

Fluorescent pseudomonads have been recognized as biocontrol agents against certain soil-borne plant pathogens. They produce yellow-green pigments (pyoverdines) which fluoresce under UV light and function as siderophores. They deprive pathogens of the iron required for their growth and pathogenesis.<ref name="K. S. Jagadeesh">{{cite journal | author = K. S. Jagadeesh, J. H. Kulkarni and P. U. Krishnaraj | title = Evaluation of the role of fluorescent siderophore in the biological control of bacterial wilt in tomato using Tn5 mutants of fluorescent Pseudomonas sp | journal = [[Current Science]] | year = 2001 | volume = 81 | pages = 882}}</ref>

==Other metals chelated==
Siderophores can chelate metals other than iron. Examples include [[aluminium]],<ref name="J. B. Neilands"/><ref name="A. del Olmo"/><ref name="G. Carrillo"/><ref name="Hider">{{cite journal | author = R. C. Hider and A. D. Hall | title = Clinically useful chelators of tripositive elements. | journal = [[Prog. Med. Chem.]] | year = 1991| volume = 28 | pages = 41–137 | pmid = 1843549 | doi=10.1016/s0079-6468(08)70363-1}}</ref> [[gallium]],<ref name="J. B. Neilands"/><ref name="A. del Olmo"/><ref name="G. Carrillo"/><ref name="Hider"/> [[chromium]],<ref name="A. del Olmo"/><ref name="G. Carrillo"/> [[copper]],<ref name="A. del Olmo"/><ref name="G. Carrillo"/><ref name="Hider"/> [[zinc]],<ref name="A. del Olmo"/><ref name="Hider"/> [[lead]],<ref name="A. del Olmo"/> [[manganese]],<ref name="A. del Olmo"/> [[cadmium]],<ref name="A. del Olmo"/> [[vanadium]],<ref name="A. del Olmo"/> [[indium]],<ref name="A. del Olmo"/><ref name="Hider"/> [[plutonium]],<ref name="John, Seth G.">{{cite journal | author = John, Seth G., Ruggiero, Christy E., Hersman, Larry E., Tung, Chang-Shung., and Neu, Mary P. | title = Siderophore Mediated Plutonium Accumulation by Microbacterium flavescens (JG-9) | journal = [[Environ. Sci. Technol.]] | year = 2001 | volume = 35 | pages = 2942–2948 | doi = 10.1021/es010590g | pmid=11478246 | issue = 14}}</ref> and [[uranium]].<ref name="John, Seth G."/>

==Related processes==
Alternative means of assimilating iron are surface reduction, lowering of pH, utilization of heme, or extraction of protein-complexed metal.<ref name="J. B. Neilands"/>-->

==Note==
<references/>


== Voci correlate ==
== Voci correlate ==
* [[Enterobactina]]
* [[Enterobactina]]
* [[Ferricromo]]
* [[Ferricromo]]*

* [[ionoforo]]


[[Categoria:Agenti chelanti]]
[[Categoria:Agenti chelanti]]

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Con il nome di sideroforo si indica una piccola molecola con elevata affinità per il ferro e in grado di chelarlo efficacemente, prodotta generalmente da microrganismi, funghi e graminacee.[1][2][3][4][5][6] I siderofori sono tra i più forti agenti chelanti del Fe3+ conosciuti.

La scarsità di ferro solubile

Il ferro è essenziale per quasi tutta la vita per processi come la respirazione cellulare e la sintesi del DNA. Nonostante sia uno degli elementi più abbondanti nella crosta terrestre, la biodisponibilità di ferro in molti ambienti, come il suolo o il mare è limitato dalla bassissima solubilità del ferro. Questo è lo stato predominante del ferro in ambienti acquosi, non acidi e ossigenati. Si accumula in fasi minerali comuni come gli ossidi e idrossidi di ferro (i minerali che sono responsabili per il colore rosso e giallo del suolo), quindi, non può essere facilmente utilizzato dagli organismi.[7] I microbi rilasciano i siderofori utilizzando il ferro da questi minerali formando complessi Fe3+ che possono essere accettati dai meccanismi di trasporto attivo. Molti siderofori sono peptidi non ribosomiali,[3][8] anche se molti sono biosintetizzati indipendentemente.[9]

I siderofori sono anche importanti per alcuni batteri patogeni per la loro acquisizione di ferro.[3][4][6] Nei mammiferi, il ferro è strettamente legato alle proteine come emoglobina, transferrina, lattoferrina e ferritina. La rigida omeostasi del ferro porta ad una concentrazione libera di circa 10−24 mol L−1,[10] quindi non ci sono grandi pressioni evolutive su batteri patogeni per ottenere questo metallo. Ad esempio, l’agente patogeno antrace Bacillus anthracis rilascia due siderofori, bacillibactina e petrobactina, per rimuovere il ferro ferrico dalle proteine. Mentre bacillibactina ha dimostrato di legarsi alla proteina del sistema immunitario siderocalina,[11] petrobactina si presume che eluda il sistema immunitario e ha dimostrato di essere importante per la virulenza nei topi.[12]

I siderofori sono tra i più forti leganti di Fe3+ conosciuti, e l'enterobactina uno di essi.[10] A causa di questa proprietà, hanno attirato l'interesse della scienza medica nella terapia chelante metallica con il sideroforo deferoxamina B, guadagnando ampio utilizzo nei trattamenti per l'avvelenamento da ferro e per la talassemia.[13]

Struttura

Varietà

Note

  1. ^ J. B. Neilands, A Crystalline Organo-iron Pigment from a Rust Fungus (Ustilago sphaerogena), in J. Am. Chem. Soc, vol. 74, n. 19, 1952, pp. 4846–4847, DOI:10.1021/ja01139a033.
  2. ^ J. B. Neilands, Siderophores: Structure and Function of Microbial Iron Transport Compounds, in J. Biol. Chem., vol. 270, n. 45, 1995, pp. 26723–26726, DOI:10.1074/jbc.270.45.26723.
  3. ^ a b c R. C. Hider and X. Kong, Chemistry and biology of siderophores, in Nat. Prod. Rep., vol. 27, 2010, pp. 637–657, DOI:10.1039/b906679a.
  4. ^ a b J. H. Crosa, A. R. Mey, S. M. Payne (editor), Iron Transport in Bacteria, ASM Press, 2004, ISBN 1-55581-292-9.
  5. ^ Cornelis, P; Andrews, SC (editor), Iron Uptake and Homeostasis in Microorganisms, Caister Academic Press, 2010, ISBN 978-1-904455-65-3.
  6. ^ a b Miller, Marvin J. Siderophores (microbial iron chelators) and siderophore-drug conjugates (new methods for microbially selective drug delivery). University of Notre Dame, 4/21/2008 http://www.nd.edu/~mmiller1/page2.html
  7. ^ Kraemer, Stephan M., Iron oxide dissolution and solubility in the presence of siderophores, in Aquatic Sciences, vol. 66, 2005, pp. 3–18, DOI:10.1007/s00027-003-0690-5.
  8. ^ Miethke, M.; Marahiel, M., Siderophore-Based Iron Acquisition and Pathogen Control, in Microbiology and Molecular Biology Reviews, vol. 71, n. 3, 2007, pp. 413–451, DOI:10.1128/MMBR.00012-07.
  9. ^ Challis, G. L., A widely distributed bacterial pathway for siderophore biosynthesis independent of nonribosomal peptide synthetases, in ChemBioChem, vol. 6, n. 4, 2005, pp. 601–611, DOI:10.1002/cbic.200400283.
  10. ^ a b Raymond, K. N.; Dertz, E. A.; Kim, S. S., Enterobactin: An archetype for microbial iron transport, in PNAS, vol. 100, n. 7, 2003, pp. 3584–3588, DOI:10.1073/pnas.0630018100.
  11. ^ Rebecca J. Abergel, Melissa K. Wilson, Jean E. L. Arceneaux, Trisha M. Hoette, Roland K. Strong, B. Rowe Byers, and Kenneth N. Raymond, Anthrax pathogen evades the mammalian immune system through stealth siderophore production, in PNAS, vol. 103, n. 49, 2006, pp. 18499–18503, DOI:10.1073/pnas.0607055103.
  12. ^ Cendrowski, S., W. MacArthur, and P. Hanna., Bacillus anthracis requires siderophore biosynthesis for growth in macrophages and mouse virulence, in Molecular Microbiology, vol. 51, n. 2, 2004, pp. 407–417, DOI:10.1046/j.1365-2958.2003.03861.x.
  13. ^ T. Zhou, Y. Ma, X. Kong and R. C. Hider, Design of iron chelators with therapeutic application., in Dalton. Trans., vol. 41, n. 21, 2012, pp. 6371–6389, DOI:10.1039/c2dt12159j.

Voci correlate

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