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'''Yersiniabactin'''(Ybt) is a [[siderophore]] found in the pathogenic [[bacteria]] ''Yersinia pestis'', ''Yersinia pseudotuberculosis'', and ''Yersinia enterocolitica'', as well as several strains of enteropathogenic ''Escherichia coli''. Siderophores, compounds of low molecular mass with high affinities for ferric iron, are important [[virulence factors]] in pathogenic bacteria. Iron, an essential element for life utilized by such cellular processes as [[Cellular respiration|respiration]] and DNA replication, is extensively chelated by host proteins like [[lactoferrin]] and [[ferritin]]; thus, the pathogen produces molecules with an even higher affinity for Fe3+ than these proteins in order to acquire sufficient iron for growth.<ref>Perry, R. D., P. B. Balbo, H. A. Jones, J. D. Fetherston, and E. DeMoll. "Yersiniabactin from Yersinia Pestis: Biochemical Characterization of the Siderophore and Its Role in Iron Transport and Regulation." Microbiology 145.5 (1999): 1181-190. {{doi|10.1099/13500872-145-5-1181}} PMID 10376834</ref> As a part of such an iron-uptake system, yersiniabactin plays an important role in pathogenicity of ''Y. pestis'', ''Y. pseudotuberculosis'', and ''Y. entercolitica''.
'''Yersiniabactin'''(Ybt) is a [[siderophore]] found in the pathogenic [[bacteria]] ''Yersinia pestis'', ''Yersinia pseudotuberculosis'', and ''Yersinia enterocolitica'', as well as several strains of enteropathogenic ''Escherichia coli''. Siderophores, compounds of low molecular mass with high affinities for ferric iron, are important [[virulence factors]] in pathogenic bacteria. Iron, an essential element for life utilized by such cellular processes as [[Cellular respiration|respiration]] and DNA replication, is extensively chelated by host proteins like [[lactoferrin]] and [[ferritin]]; thus, the pathogen produces molecules with an even higher affinity for Fe3+ than these proteins in order to acquire sufficient iron for growth.<ref>{{Cite doi|10.1099/13500872-145-5-1181|noedit}}</ref> As a part of such an iron-uptake system, yersiniabactin plays an important role in pathogenicity of ''Y. pestis'', ''Y. pseudotuberculosis'', and ''Y. entercolitica''.


==Structure and coordination properties==
==Structure and coordination properties==
Yersiniabactin is a four ring structure composed of carbon, hydrogen, nitrogen, oxygen, and sulfur. According to [[X-ray crystallography]], it binds Fe<sup>3+</sup>as a 1:1 complex by three nitrogen electron pairs and three negatively charged oxygen atoms with a distorted octahedral structure.<ref>Miller, M. Clarke, Sean Parkin, Jacqueline Fetherston, Robert D. Perry, and Edward DeMoll. "Crystal Structure of Ferric-yersiniabactin, a Virulence Factor of Yersinia Pestis." Journal of Inorganic Biochemistry 100.9 (2006): 1495-500. {{doi|10.1016/j.jinorgbio.2006.04.007}} PMID 16806483</ref> The Ybt-Fe<sup>3+</sup> complex has a proton-independent formation constant of 4 x 10<sup>36</sup>.<ref>Perry, R. D., P. B. Balbo, H. A. Jones, J. D. Fetherston, and E. DeMoll. "Yersiniabactin from Yersinia Pestis: Biochemical Characterization of the Siderophore and Its Role in Iron Transport and Regulation." Microbiology 145.5 (1999): 1181-190. {{doi| 10.1099/13500872-145-5-1181}} PMID 10376834</ref>
Yersiniabactin is a four ring structure composed of carbon, hydrogen, nitrogen, oxygen, and sulfur. According to [[X-ray crystallography]], it binds Fe<sup>3+</sup>as a 1:1 complex by three nitrogen electron pairs and three negatively charged oxygen atoms with a distorted octahedral structure.<ref>{{Cite doi|10.1016/j.jinorgbio.2006.04.007|noedit}}</ref> The Ybt-Fe<sup>3+</sup> complex has a proton-independent formation constant of 4 x 10<sup>36</sup>.<ref>{{Cite doi| 10.1099/13500872-145-5-1181|noedit}}</ref>


==Biosynthesis==
==Biosynthesis==
Ybt synthesis occurs by a mixed nonribosomal peptide synthetase (NRPS)/[[polyketide synthase]] (PKS) mechanism. Several enzymes, most notably the HMWP2-HMWP1complex,<ref>Bisseret, Philippe, Sabine Thielges, Stephane Bourg, Marcus Miethke, Mohamed A. Marahiel, and Jacques Eustache. "Synthesis of a 2-Indolylphosphonamide Derivative with Inhibitory Activity Against Yersiniabactin Biosynthesis." ChemInform 38.49 (2007). {{doi|10.1016/j.tetlet.2007.06.150}}</ref> assemble salicylate, three cysteines, a malonyl linker group and three methyl groups into a four-ring structure made of salicylate, one thiazolidine, and two thiazoline rings with a malonyl linker between the thiazoline and the thiazolidine. YbtD, a phosphopantetheinyl transferase, adds phosphopantetheine tethers to the cysteine, salicylate and malonyl groups to HMWP1 and HMWP2. YbtS synthesizes salicylate from chorismate, which is then adenylated by YbtE and transferred to the HMWP2–HMWP1 assembly complex. HMWP2, which consists of two multidomain NRPS modules, accepts the activated salicylate unit through a carrier protein, then cyclizes and condenses two cysteines to form two [[thiazoline]] rings. A malonyl linker is added by the PKS portion of HMWP1, and YbtU reduces the second thiazoline ring to [[thiazolidine]] before cyclization and condensation of the final thiazoline ring on HMWP1’s NRPs domain.<ref>Pfeifer, B. A., C. C. Wang, C. T. Walsh, and C. Khosla. "Biosynthesis of Yersiniabactin, a Complex Polyketide-Nonribosomal Peptide, Using ''Escherichia Coli'' as a Heterologous Host." Applied and Environmental Microbiology 69.11 (2003): 6698-702. {{doi| 10.1128/AEM.69.11.6698–6702.2003}}</ref> YbtT thioesterase may serve some editing function to remove abnormal molecules from the enzyme complex, and a thioesterase domain of HMWP1 releases the completed siderophore from the enzyme complex.<ref> Sebane, Florent, Clayton Jarrett, Donald Gardner, Daniel Long, and B. Joseph Hinnebusch. "Role of the Yersinia Pestis Yersiniabactin Iron Acquisition System in the Incidence of Flea-Borne Plague." PLoS One. National Institute of Health, 17 Dec. 2010.<http://www.ncbi.nlm.nih.gov>. {{doi|10.1371/journal.pone.0014379}} {{PMC|3003698}} </ref><ref> Carniel, Elisabeth. "The Yersinia High-pathogenicity Island: an Iron-uptake Island." Microbes and Infection 3.7 (2001): 561-69. {{doi|10.1016/S1286-4579(01)01412-5}} PMID 11418330</ref>
Ybt synthesis occurs by a mixed nonribosomal peptide synthetase (NRPS)/[[polyketide synthase]] (PKS) mechanism. Several enzymes, most notably the HMWP2-HMWP1complex,<ref>{{Cite doi|10.1016/j.tetlet.2007.06.150|noedit}}</ref> assemble salicylate, three cysteines, a malonyl linker group and three methyl groups into a four-ring structure made of salicylate, one thiazolidine, and two thiazoline rings with a malonyl linker between the thiazoline and the thiazolidine. YbtD, a phosphopantetheinyl transferase, adds phosphopantetheine tethers to the cysteine, salicylate and malonyl groups to HMWP1 and HMWP2. YbtS synthesizes salicylate from chorismate, which is then adenylated by YbtE and transferred to the HMWP2–HMWP1 assembly complex. HMWP2, which consists of two multidomain NRPS modules, accepts the activated salicylate unit through a carrier protein, then cyclizes and condenses two cysteines to form two [[thiazoline]] rings. A malonyl linker is added by the PKS portion of HMWP1, and YbtU reduces the second thiazoline ring to [[thiazolidine]] before cyclization and condensation of the final thiazoline ring on HMWP1’s NRPs domain.<ref>{{Cite doi| 10.1128/AEM.69.11.6698-6702.2003|noedit}}</ref> YbtT thioesterase may serve some editing function to remove abnormal molecules from the enzyme complex, and a thioesterase domain of HMWP1 releases the completed siderophore from the enzyme complex.<ref>{{Cite doi|10.1371/journal.pone.0014379|noedit}} </ref><ref>{{Cite doi|10.1016/S1286-4579(01)01412-5|noedit}}</ref>


==Regulation of expression==
==Regulation of expression==
The HPI upon which the genes encoding the Ybt biosynthesis proteins are located is controlled by a series of molecular regulators. All four promoter regions of the yersiniabactin region (psn, irp2, ybtA and ybtP) possess a Fur-binding site and are negatively regulated by this repressor in the presence of iron.<ref>Bisseret, Philippe, Sabine Thielges, Stephane Bourg, Marcus Miethke, Mohamed A. Marahiel, and Jacques Eustache. "Synthesis of a 2-Indolylphosphonamide Derivative with Inhibitory Activity Against Yersiniabactin Biosynthesis." ChemInform 38.49 (2007). {{doi|10.1016/j.tetlet.2007.06.150}}</ref> In the presence of Ybt, a member of the AraC family of transcriptional regulators, activates expression from the psn, irp2 and ybtP (transport and biosynthetic genes) promoters but represses expression of its own promoter. There is also evidence that yersiniabactin itself may upregulate its own expression and that of psn/fyuA and ybtPQXS at the transcription level.<ref>Miller, M. Clarke, Jacqueline D. Fetherston, Carol L. Pickett, Alexander G. Bobrov, Robert H. Weaver, Edward DeMoll, and Robert D. Perry. "Reduced Synthesis of the Ybt Siderophore or Production of Aberrant Ybt-like Molecules Activates Transcription of Yersiniabactin Genes in ''Yersinia Pestis''" Microbiology 156 (2010): 2226-238. {{doi| 10.1099/mic.0.037945-0}}</ref>
The HPI upon which the genes encoding the Ybt biosynthesis proteins are located is controlled by a series of molecular regulators. All four promoter regions of the yersiniabactin region (psn, irp2, ybtA and ybtP) possess a Fur-binding site and are negatively regulated by this repressor in the presence of iron.<ref>{{Cite doi|10.1016/j.tetlet.2007.06.150|noedit}}</ref> In the presence of Ybt, a member of the AraC family of transcriptional regulators, activates expression from the psn, irp2 and ybtP (transport and biosynthetic genes) promoters but represses expression of its own promoter. There is also evidence that yersiniabactin itself may upregulate its own expression and that of psn/fyuA and ybtPQXS at the transcription level.<ref>{{Cite doi|10.1099/mic.0.037945-0|noedit}}</ref>


==Role in ''Yersinia'' pathogenicity==
==Role in ''Yersinia'' pathogenicity==
As previously mentioned, siderophores serve the essential function of iron acquisition for pathogens in the low iron conditions of the host. Thus the successful establishment of disease depends on the ability of the invading organism to acquire iron. Because of its high affinity for iron, yersiniabactin can solubilize the metal bound to host binding proteins and transport it back to the bacteria. The complex yersiniabactin-Fe3+ recognizes the specific bacterial outer membrane receptor TonB and is translocated with the help of membrane-embedded proteins into the cytosol where the iron is discharged from yersiniabactin and utilized in various metabolic pathways.<ref>Perry, R. D., J. Shah, S. W. Bearden, J. M. Thompson, and J. D. Fetherston. "Yersinia Pestis TonB: Role in Iron, Heme, and Hemoprotein Utilization." Infection and Immunity 71.7 (2003): 4159-162. {{doi|10.1128/IAI.71.7.4159-4162.2003}} {{PMC|161968}}</ref> In the absence of a high-affinity iron-chelating compound, pathogenic ''Yersinia'', responsible for such lethal disease as the bubonic plague, only causes local symptoms of moderate intensity. The availability of iron, through an intrinsic high-affinity iron-chelating system such as Ybt, provides the bacteria with the ability to multiply in the host and to cause systemic infections.
As previously mentioned, siderophores serve the essential function of iron acquisition for pathogens in the low iron conditions of the host. Thus the successful establishment of disease depends on the ability of the invading organism to acquire iron. Because of its high affinity for iron, yersiniabactin can solubilize the metal bound to host binding proteins and transport it back to the bacteria. The complex yersiniabactin-Fe3+ recognizes the specific bacterial outer membrane receptor TonB and is translocated with the help of membrane-embedded proteins into the cytosol where the iron is discharged from yersiniabactin and utilized in various metabolic pathways.<ref>{{Cite doi|10.1128/IAI.71.7.4159-4162.2003|noedit}}</ref> In the absence of a high-affinity iron-chelating compound, pathogenic ''Yersinia'', responsible for such lethal disease as the bubonic plague, only causes local symptoms of moderate intensity. The availability of iron, through an intrinsic high-affinity iron-chelating system such as Ybt, provides the bacteria with the ability to multiply in the host and to cause systemic infections.


== References ==
== References ==

Revision as of 23:49, 23 May 2012

Yersiniabactin
Identifiers
3D model (JSmol)
ChEMBL
  • CC(C)([C@H](O)[C@@H]1CSC(N1)[C@H]2CSC(=N2)c3ccccc3O)C4=N[C@](C)(CS4)C(=O)O
Properties
C21H27N3O4S3
Molar mass 481.7 g/mol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Yersiniabactin(Ybt) is a siderophore found in the pathogenic bacteria Yersinia pestis, Yersinia pseudotuberculosis, and Yersinia enterocolitica, as well as several strains of enteropathogenic Escherichia coli. Siderophores, compounds of low molecular mass with high affinities for ferric iron, are important virulence factors in pathogenic bacteria. Iron, an essential element for life utilized by such cellular processes as respiration and DNA replication, is extensively chelated by host proteins like lactoferrin and ferritin; thus, the pathogen produces molecules with an even higher affinity for Fe3+ than these proteins in order to acquire sufficient iron for growth.[1] As a part of such an iron-uptake system, yersiniabactin plays an important role in pathogenicity of Y. pestis, Y. pseudotuberculosis, and Y. entercolitica.

Structure and coordination properties

Yersiniabactin is a four ring structure composed of carbon, hydrogen, nitrogen, oxygen, and sulfur. According to X-ray crystallography, it binds Fe3+as a 1:1 complex by three nitrogen electron pairs and three negatively charged oxygen atoms with a distorted octahedral structure.[2] The Ybt-Fe3+ complex has a proton-independent formation constant of 4 x 1036.[3]

Biosynthesis

Ybt synthesis occurs by a mixed nonribosomal peptide synthetase (NRPS)/polyketide synthase (PKS) mechanism. Several enzymes, most notably the HMWP2-HMWP1complex,[4] assemble salicylate, three cysteines, a malonyl linker group and three methyl groups into a four-ring structure made of salicylate, one thiazolidine, and two thiazoline rings with a malonyl linker between the thiazoline and the thiazolidine. YbtD, a phosphopantetheinyl transferase, adds phosphopantetheine tethers to the cysteine, salicylate and malonyl groups to HMWP1 and HMWP2. YbtS synthesizes salicylate from chorismate, which is then adenylated by YbtE and transferred to the HMWP2–HMWP1 assembly complex. HMWP2, which consists of two multidomain NRPS modules, accepts the activated salicylate unit through a carrier protein, then cyclizes and condenses two cysteines to form two thiazoline rings. A malonyl linker is added by the PKS portion of HMWP1, and YbtU reduces the second thiazoline ring to thiazolidine before cyclization and condensation of the final thiazoline ring on HMWP1’s NRPs domain.[5] YbtT thioesterase may serve some editing function to remove abnormal molecules from the enzyme complex, and a thioesterase domain of HMWP1 releases the completed siderophore from the enzyme complex.[6][7]

Regulation of expression

The HPI upon which the genes encoding the Ybt biosynthesis proteins are located is controlled by a series of molecular regulators. All four promoter regions of the yersiniabactin region (psn, irp2, ybtA and ybtP) possess a Fur-binding site and are negatively regulated by this repressor in the presence of iron.[8] In the presence of Ybt, a member of the AraC family of transcriptional regulators, activates expression from the psn, irp2 and ybtP (transport and biosynthetic genes) promoters but represses expression of its own promoter. There is also evidence that yersiniabactin itself may upregulate its own expression and that of psn/fyuA and ybtPQXS at the transcription level.[9]

Role in Yersinia pathogenicity

As previously mentioned, siderophores serve the essential function of iron acquisition for pathogens in the low iron conditions of the host. Thus the successful establishment of disease depends on the ability of the invading organism to acquire iron. Because of its high affinity for iron, yersiniabactin can solubilize the metal bound to host binding proteins and transport it back to the bacteria. The complex yersiniabactin-Fe3+ recognizes the specific bacterial outer membrane receptor TonB and is translocated with the help of membrane-embedded proteins into the cytosol where the iron is discharged from yersiniabactin and utilized in various metabolic pathways.[10] In the absence of a high-affinity iron-chelating compound, pathogenic Yersinia, responsible for such lethal disease as the bubonic plague, only causes local symptoms of moderate intensity. The availability of iron, through an intrinsic high-affinity iron-chelating system such as Ybt, provides the bacteria with the ability to multiply in the host and to cause systemic infections.

References

  1. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1099/13500872-145-5-1181, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1099/13500872-145-5-1181 instead.
  2. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1016/j.jinorgbio.2006.04.007, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1016/j.jinorgbio.2006.04.007 instead.
  3. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi: 10.1099/13500872-145-5-1181, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi= 10.1099/13500872-145-5-1181 instead.
  4. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1016/j.tetlet.2007.06.150, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1016/j.tetlet.2007.06.150 instead.
  5. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi: 10.1128/AEM.69.11.6698-6702.2003, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi= 10.1128/AEM.69.11.6698-6702.2003 instead.
  6. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1371/journal.pone.0014379, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1371/journal.pone.0014379 instead.
  7. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1016/S1286-4579(01)01412-5, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1016/S1286-4579(01)01412-5 instead.
  8. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1016/j.tetlet.2007.06.150, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1016/j.tetlet.2007.06.150 instead.
  9. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1099/mic.0.037945-0, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1099/mic.0.037945-0 instead.
  10. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1128/IAI.71.7.4159-4162.2003, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1128/IAI.71.7.4159-4162.2003 instead.
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