, Volume 28, Issue 3, pp 445–459 | Cite as

Acyl peptidic siderophores: structures, biosyntheses and post-assembly modifications



Acyl peptidic siderophores are produced by a variety of bacteria and possess unique amphiphilic properties. Amphiphilic siderophores are generally produced in a suite where the iron(III)-binding headgroup remains constant while the fatty acid appendage varies by length and functionality. Acyl peptidic siderophores are commonly synthesized by non-ribosomal peptide synthetases; however, the method of peptide acylation during biosynthesis can vary between siderophores. Following biosynthesis, acyl siderophores can be further modified enzymatically to produce a more hydrophilic compound, which retains its ferric chelating abilities as demonstrated by pyoverdine from Pseudomonas aeruginosa and the marinobactins from certain Marinobacter species. Siderophore hydrophobicity can also be altered through photolysis of the ferric complex of certain β-hydroxyaspartic acid-containing acyl peptidic siderophores.


Amphiphilic siderophore Biosynthesis Acyl peptide Post-assembly modification 



Funding from National Science Foundation Grant CHE-1411941 (A.B.) is gratefully acknowledged.


  1. Barbeau K, Rue E, Bruland K, Butler A (2001) Photochemical cycling of iron in the surface ocean mediated by microbial iron(III)-binding ligands. Nature 413(6854):409–413. doi: 10.1038/35096545 CrossRefPubMedGoogle Scholar
  2. Barbeau K, Rue E, Trick C, Bruland K, Butler A (2003) Photochemical reactivity of siderophores produced by marine heterotrophic bacteria and cyanobacteria based on characteristic Fe(III) binding groups. Limnol Oceanogr 48(3):1069–1078CrossRefGoogle Scholar
  3. Bokhove M, Jimenez P, Quax W, Dijkstra B (2010) The quorum-quenching N-acyl homoserine lactone acylase PvdQ is an Ntn-hydrolase with an unusual substrate-binding pocket. Proc Natl Acad Sci USA 107(2):686–691. doi: 10.1073/pnas.0911839107 CrossRefPubMedCentralPubMedGoogle Scholar
  4. Butler A, Theisen R (2010) Iron(III)-siderophore coordination chemistry: reactivity of marine siderophores. Coord Chem Rev 254(3–4):288–296. doi: 10.1016/j.ccr.2009.09.010 CrossRefPubMedCentralPubMedGoogle Scholar
  5. Challis G, Ravel J, Townsend C (2000) Predictive, structure-based model of amino acid recognition by nonribosomal peptide synthetase adenylation domains. Chem Biol 7(3):211–224. doi: 10.1016/S1074-5521(00)00091-0 CrossRefPubMedGoogle Scholar
  6. Cisar J, Tan D (2008) Small molecule inhibition of microbial natural product biosynthesis—an emerging antibiotic strategy. Chem Soc Rev 37(7):1320–1329CrossRefPubMedCentralPubMedGoogle Scholar
  7. Clevenger K, Wu R, Er J, Liu D, Fast W (2013) Rational design of a transition state analogue with picomolar affinity for Pseudomonas aeruginosa PvdQ, a siderophore biosynthetic enzyme. ACS Chem Biol 8(10):2192–2200. doi: 10.1021/cb400345h CrossRefPubMedGoogle Scholar
  8. Crosa J, Walsh C (2002) Genetics and assembly line enzymology of siderophore biosynthesis in bacteria. Microbiol Mol Biol Rev 66(2):223–249. doi: 10.1128/MMBR.66.2.223-249.2002
  9. Drake E, Gulick A (2011) Structural characterization and high-throughput screening of inhibitors of PvdQ, an NTN hydrolase involved in pyoverdine synthesis. ACS Chem Biol 6(11):1277–1286. doi: 10.1021/cb2002973 CrossRefPubMedCentralPubMedGoogle Scholar
  10. Engelhart C, Aldrich C (2013) Synthesis of chromone, quinolone, and benzoxazinone sulfonamide nucleosides as conformationally constrained inhibitors of adenylating enzymes required for siderophore biosynthesis. J Org Chem 78(15):7470–7481CrossRefPubMedCentralPubMedGoogle Scholar
  11. Ferreras J, Ryu J-S, Di Lello F, Tan D, Quadri L (2005) Small-molecule inhibition of siderophore biosynthesis in Mycobacterium tuberculosis and Yersinia pestis. Nat Chem Biol 1(1):29–32. doi: 10.1038/nchembio706 CrossRefPubMedGoogle Scholar
  12. Gauglitz J, Butler A (2013) Amino acid variability in the peptide composition of a suite of amphiphilic peptide siderophores from an open ocean Vibrio species. J Biol Inorg Chem 18(5):489–497. doi: 10.1007/s00775-013-0995-3 CrossRefPubMedCentralPubMedGoogle Scholar
  13. Gauglitz J, Inishi A, Ito Y, Butler A (2014) Microbial tailoring of acyl peptidic siderophores. Biochemistry 53(16):2624–2631. doi: 10.1021/bi500266x CrossRefPubMedCentralPubMedGoogle Scholar
  14. Gehring A, Mori I, Walsh C (1998) Reconstitution and characterization of the Escherichia coli enterobactin synthetase from EntB, EntE, and EntF. Biochemistry 37(8):2648–2659. doi: 10.1021/bi9726584 CrossRefPubMedGoogle Scholar
  15. Gobin J, Horwitz M (1996) Exochelins of Mycobacterium tuberculosis remove iron from human iron-binding proteins and donate iron to mycobactins in the M. tuberculosis cell wall. J Exp Med 183(4):1527–1532. doi: 10.1084/jem.183.4.1527 CrossRefPubMedGoogle Scholar
  16. Gobin J, Moore C, Reeve J, Wong D, Gibson B, Horwitz M (1995) Iron acquisition by Mycobacterium tuberculosis: isolation and characterization of a family of iron-binding exochelins. Proc Natl Acad Sci USA 92(11):5189–5193. doi: 10.1073/pnas.92.11.5189 CrossRefPubMedCentralPubMedGoogle Scholar
  17. Grunewald J, Marahiel M (2006) Chemoenzymatic and template-directed synthesis of bioactive macrocyclic peptides. Microbiol Mol Biol Rev 70(1):121–146. doi: 10.1128/MMBR.70.1.121-146.2006
  18. Guillon L, El Mecherki M, Altenburger S, Graumann P, Schalk I (2012) High cellular organization of pyoverdine biosynthesis in Pseudomonas aeruginosa: clustering of PvdA at the old cell pole. Environ Microbiol 14(8):1982–1994. doi: 10.1111/j.1462-2920.2012.02741.x CrossRefPubMedGoogle Scholar
  19. Hannauer M, Schafer M, Hoegy F, Gizzi P, Wehrung P, Mislin G, Budzikiewicz H, Schalk I (2012) Biosynthesis of the pyoverdine siderophore of Pseudomonas aeruginosa involves precursors with a myristic or a myristoleic acid chain. FEBS Lett 586(1):96–101. doi: 10.1016/j.febslet.2011.12.004 CrossRefPubMedGoogle Scholar
  20. Homann V, Sandy M, Tincu J, Templeton A, Tebo B, Butler A (2009) Loihichelins A–F, a suite of amphiphilic siderophores produced by the marine bacterium Halomonas LOB-5. J Nat Prod 72(5):884–888. doi: 10.1021/np800640h CrossRefPubMedCentralPubMedGoogle Scholar
  21. Huang J, Han J, Zhang L, Leadbetter J (2003) Utilization of acyl-homoserine lactone quorum signals for growth by a soil pseudomonad and Pseudomonas aeruginosa PAO1. Appl Environ Microbiol 69(10):5941–5949. doi: 10.1128/AEM.69.10.5941-5949.2003 CrossRefPubMedCentralPubMedGoogle Scholar
  22. Ito Y, Butler A (2005) Structure of synechobactins, new siderophores of the marine cyanobacterium Synechococcus sp. PCC 7002. Limnol Oceanogr 50(6):1918–1923CrossRefGoogle Scholar
  23. Jimenez P, Koch G, Papaioannou E, Wahjudi M, Krzeslak J, Coenye T, Cool R, Quax W (2010) Role of PvdQ in Pseudomonas aeruginosa virulence under iron-limiting conditions. Microbiol SGM 156:49–59. doi: 10.1099/mic.0.030973-0 CrossRefGoogle Scholar
  24. Kem M, Zane H, Springer S, Gauglitz J, Butler A (2014) Amphiphilic siderophore production by oil-associating microbes. Metallomics 6(6):1150–1155. doi: 10.1039/c4mt00047a CrossRefPubMedGoogle Scholar
  25. Kem M, Naka H, Iinishi A, Haygood M, Butler A (2015) Fatty acid hydrolysis of acyl marinobactin siderophores by Marinobacter acylases. ACS Biochem. doi: 10.1021/bi5013673 Google Scholar
  26. Koch G, Jimenez P, Muntendam R, Chen Y, Papaioannou E, Heeb S, Camara M, Williams P, Cool R, Quax W (2010) The acylase PvdQ has a conserved function among fluorescent Pseudomonas spp. Environ Microbiol Rep 2(3):433–439. doi: 10.1111/j.1758-2229.2010.00157.x CrossRefPubMedGoogle Scholar
  27. Koch G, Nadal-Jimenez P, Reis C, Muntendam R, Bokhove M, Melillo E, Dijkstra B, Cool R, Quax W (2014) Reducing virulence of the human pathogen Burkholderia by altering the substrate specificity of the quorum-quenching acylase PvdQ. Proc Natl Acad Sci USA 111(4):1568–1573. doi: 10.1073/pnas.1311263111 CrossRefPubMedCentralPubMedGoogle Scholar
  28. Kraas F, Helmetag V, Wittmann M, Strieker M, Marahiel M (2010) Functional dissection of surfactin synthetase initiation module reveals insights into the mechanism of lipoinitiation. Chem Biol 17(8):872–880. doi: 10.1016/j.chembiol.2010.06.015 CrossRefPubMedGoogle Scholar
  29. Kreutzer M, Nett M (2012) Genomics-driven discovery of taiwachelin, a lipopeptide siderophore from Cupriavidus taiwanensis. Org Biomol Chem 10(47):9338–9343. doi: 10.1039/c2ob26296g CrossRefPubMedGoogle Scholar
  30. Kreutzer M, Kage H, Nett M (2012) Structure and biosynthetic assembly of cupriachelin, a photoreactive siderophore from the bioplastic producer Cupriavidus necator H16. J Am Chem Soc 134(11):5415–5422. doi: 10.1021/ja300520z CrossRefPubMedGoogle Scholar
  31. Krithika R, Marathe U, Saxena P, Ansari M, Mohanty D, Gokhale R (2006) A genetic locus required for iron acquisition in Mycobacterium tuberculosis. Proc Natl Acad Sci USA 103(7):2069–2074. doi: 10.1073/pnas.0507924103 CrossRefPubMedCentralPubMedGoogle Scholar
  32. Kupper F, Carrano C, Kuhn J, Butler A (2006) Photoreactivity of iron(III)–Aerobactin: photoproduct structure and iron(III) coordination. Inorg Chem 45(15):6028–6033. doi: 10.1021/ic0604967 CrossRefPubMedGoogle Scholar
  33. Lane S, Marshall P, Upton R, Ratledge C, Ewing M (1995) Novel extracellular mycobactins, the carboxymycobactins from Mycobacterium avium. Tetrahedron Lett 36(23):4129–4132. doi: 10.1016/0040-4039(95)00676-4 CrossRefGoogle Scholar
  34. Lin Y, Xu J, Hu J, Wang L, Ong S, Leadbetter J, Zhang L (2003) Acyl-homoserine lactone acylase from Ralstonia strain XJ12B represents a novel and potent class of quorum-quenching enzymes. Mol Microbiol 47(3):849–860. doi: 10.1046/j.1365-2958.2003.03351.x CrossRefPubMedGoogle Scholar
  35. Luo M, Lin H, Fischbach M, Liu D, Walsh C, Groves J (2006) Enzymatic tailoring of enterobactin alters membrane partitioning and iron acquisition. ACS Chem Biol 1(1):29–32. doi: 10.1021/cb0500034 CrossRefPubMedGoogle Scholar
  36. Madigan C, Cheng T, Layre E, Young D, McConnell M, Debono C, Murry J, Wei J, Barry C, Rodriguez G, Matsunaga I, Rubin E, Moody D (2012) Lipidomic discovery of deoxysiderophores reveals a revised mycobactin biosynthesis pathway in Mycobacterium tuberculosis. Proc Natl Acad Sci USA 109(4):1257–1262. doi: 10.1073/pnas.1109958109 CrossRefPubMedCentralPubMedGoogle Scholar
  37. Marahiel M, Stachelhaus T, Mootz H (1997) Modular peptide synthetases involved in nonribosomal peptide synthesis. Chem Rev 97(7):2651–2673. doi: 10.1021/cr960029e CrossRefPubMedGoogle Scholar
  38. Martin J, Ito Y, Homann V, Haygood M, Butler A (2006) Structure and membrane affinity of new amphiphilic siderophores produced by Ochrobactrum sp. SP18. J Biol Inorg Chem 11(5):633–641. doi: 10.1007/s00775-006-0112-y CrossRefPubMedGoogle Scholar
  39. Martinez J, Butler A (2007) Marine amphiphilic siderophores: marinobactin structure, uptake, and microbial partitioning. J Inorg Biochem 101(11–12):1692–1698. doi: 10.1016/j.jinorgbio.2007.07.007 CrossRefPubMedCentralPubMedGoogle Scholar
  40. Martinez J, Zhang G, Holt P, Jung H, Carrano C, Haygood M, Butler A (2000) Self-assembling amphiphilic siderophores from marine bacteria. Science 287(5456):1245–1247. doi: 10.1126/science.287.5456.1245 CrossRefPubMedGoogle Scholar
  41. McMahon M, Rush J, Thomas M (2012) Analyses of MbtB, MbtE, and MbtF suggest revisions to the mycobactin biosynthesis pathway in Mycobacterium tuberculosis. J Bacteriol 194(11):2809–2818. doi: 10.1128/JB.00088-12 CrossRefPubMedCentralPubMedGoogle Scholar
  42. Neres J, Wilson D, Celia L, Beck B, Aldrich C (2008) Aryl acid adenylating enzymes involved in siderophore biosynthesis: fluorescence polarization assay, ligand specificity, and discovery of non-nucleoside inhibitors via high-throughput screening. Biochemistry 47(45):11735–11749CrossRefPubMedCentralPubMedGoogle Scholar
  43. Quadri L, Sello J, Keating T, Weinreb P, Walsh C (1998) Identification of a Mycobacterium tuberculosis gene cluster encoding the biosynthetic enzymes for assembly of the virulence-conferring siderophore mycobactin. Chem Biol 5(11):631–645. doi: 10.1016/S1074-5521(98)90291-5 CrossRefPubMedGoogle Scholar
  44. Ratledge C (2004) Iron, mycobacteria and tuberculosis. Tuberculosis 84(1–2):110–130. doi: 10.1016/ CrossRefPubMedGoogle Scholar
  45. Rosconi F, Davyt D, Martinez V, Martinez M, Abin-Carriquiry J, Zane H, Butler A, de Souza E, Fabiano E (2013) Identification and structural characterization of serobactins, a suite of lipopeptide siderophores produced by the grass endophyte Herbaspirillum seropedicae. Environ Microbiol 15(3):916–927. doi: 10.1111/1462-2920.12075 CrossRefPubMedGoogle Scholar
  46. Sandy M, Butler A (2009) Microbial iron acquisition: marine and terrestrial siderophores. Chem Rev 109(10):4580–4595. doi: 10.1021/cr9002787 CrossRefPubMedCentralPubMedGoogle Scholar
  47. Schalk I, Guillon L (2013) Pyoverdine biosynthesis and secretion in Pseudomonas aeruginosa: implications for metal homeostasis. Environ Microbiol 15(6):1661–1673. doi: 10.1111/1462-2920.12013 CrossRefPubMedGoogle Scholar
  48. Shen B (2003) Polyketide biosynthesis beyond the type I, II and III polyketide synthase paradigms. Curr Opin Chem Biol 7(2):285–295. doi: 10.1016/S1367-5931(03)00020-6 CrossRefPubMedGoogle Scholar
  49. Sio C, Otten L, Cool R, Diggle S, Braun P, Bos R, Daykin M, Camara M, Williams P, Quax W (2006) Quorum quenching by an N-acyl-homoserine lactone acylase from Pseudomonas aeruginosa PAO1. Infect Immun 74(3):1673–1682. doi: 10.1128/IAI.74.3.1673-1682.2006 CrossRefPubMedCentralPubMedGoogle Scholar
  50. Snow G (1965) Isolation and structure of mycobactin T, a growth factor from Mycobacterium tuberculosis. Biochem J 97(1):166–175PubMedCentralPubMedGoogle Scholar
  51. Somu R, Boshoff H, Qiao C, Bennett E, Barry C III, Aldrich C (2006) Rationally designed nucleoside antibiotics that inhibit siderophore biosynthesis of Mycobacterium tuberculosis. J Med Chem 49(1):31–34CrossRefPubMedGoogle Scholar
  52. Stachelhaus T, Mootz H, Marahiel M (1999) The specificity-conferring code of adenylation domains in nonribosomal peptide synthetases. Chem Biol 6(8):493–505. doi: 10.1016/S1074-5521(99)80082-9 CrossRefPubMedGoogle Scholar
  53. Staunton J, Weissman K (2001) Polyketide biosynthesis: a millennium review. Nat Prod Rep 18(4):380–416. doi: 10.1039/a909079g CrossRefPubMedGoogle Scholar
  54. Vergnolle O, Xu H, Blanchard J (2013) Mechanism and regulation of mycobactin fatty acyl-AMP ligase FadD33. J Biol Chem 288(39):28116–28125. doi: 10.1074/jbc.M113.495549 CrossRefPubMedCentralPubMedGoogle Scholar
  55. Visca P, Imperi F, Lamont I (2007) Pyoverdine siderophores: from biogenesis to biosignificance. Trends Microbiol 15(1):22–30. doi: 10.1016/j.tim.2006.11.004 CrossRefPubMedGoogle Scholar
  56. Vraspir J, Holt P, Butler A (2011) Identification of new members within suites of amphiphilic marine siderophores. Biometals 24(1):85–92. doi: 10.1007/s10534-010-9378-1 CrossRefPubMedCentralPubMedGoogle Scholar
  57. Wahjudi M, Papaioannou E, Hendrawati O, van Assen A, van Merkerk R, Cool R, Poelarends G, Ouax W (2011) PA0305 of Pseudomonas aeruginosa is a quorum quenching acylhomoserine lactone acylase belonging to the Ntn hydrolase superfamily. Microbiol SGM 157:2042–2055. doi: 10.1099/mic.0.043935-0 CrossRefGoogle Scholar
  58. Walsh C, Chen H, Keating T, Hubbard B, Losey H, Luo L, Marshall C, Miller D, Patel H (2001) Tailoring enzymes that modify nonribosomal peptides during and after chain elongation on NRPS assembly lines. Curr Opin Chem Biol 5(5):525–534. doi: 10.1016/S1367-5931(00)00235-0 CrossRefPubMedGoogle Scholar
  59. Wurst J, Drake E, Theriault J, Jewett I, VerPlank L, Perez J, Dandapani S, Palmer M, Moskowitz S, Schreiber S, Munoz B, Gulick A (2014) Identification of inhibitors of PvdQ, an enzyme involved in the synthesis of the siderophore pyoverdine. ACS Chem Biol 9(7):1536–1544. doi: 10.1021/cb5001586 CrossRefPubMedGoogle Scholar
  60. Xu G, Martinez J, Groves J, Butler A (2002) Membrane affinity of the amphiphilic marinobactin siderophores. J Am Chem Soc 124(45):13408–13415. doi: 10.1021/ja026768w CrossRefPubMedGoogle Scholar
  61. Yeterian E, Martin L, Guillon L, Journet L, Lamont I, Schalk I (2010) Synthesis of the siderophore pyoverdine in Pseudomonas aeruginosa involves a periplasmic maturation. Aminoacids 38(5):1447–1459. doi: 10.1007/s00726-009-0358-0 Google Scholar
  62. Zane H, Naka H, Rosconi F, Sandy M, Haygood M, Butler A (2014) Biosynthesis of amphi-enterobactin siderophores by Vibrio harveyi BAA-1116: identification of a bifunctional nonribosomal peptide synthetase condensation domain. J Am Chem Soc 136(15):5615–5618. doi: 10.1021/ja5019942 CrossRefPubMedGoogle Scholar

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© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Department of Chemistry and BiochemistryUniversity of CaliforniaSanta BarbaraUSA

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