Advertisement

Genomics-enabled discovery of phosphonate natural products and their biosynthetic pathways

  • Kou-San Ju
  • James R. Doroghazi
  • William W. Metcalf
Mini-Review

Abstract

Phosphonate natural products have proven to be a rich source of useful pharmaceutical, agricultural, and biotechnology products, whereas study of their biosynthetic pathways has revealed numerous intriguing enzymes that catalyze unprecedented biochemistry. Here we review the history of phosphonate natural product discovery, highlighting technological advances that have played a key role in the recent advances in their discovery. Central to these developments has been the application of genomics, which allowed discovery and development of a global phosphonate metabolic framework to guide research efforts. This framework suggests that the future of phosphonate natural products remains bright, with many new compounds and pathways yet to be discovered.

Keywords

Phosphonate Natural product Antibiotic Genome mining Streptomyces 

Notes

Acknowledgments

This work was supported by the National Institute of General Medical Science of the National Institutes of Health under P01GM077596 awarded to WWM. KSJ was funded by an NIH Ruth L. Kirschstein National Research Service Award (F32GM100658) from NIGMS, and JRD by an Institute for Genomic Biology Postdoctoral Fellowship. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

References

  1. 1.
    Baeyer E, Gugel KH, Haegele K, Hagenmaier H, Jessipow S, Koenig WA, Zaehner J (1972) Stofwechselprodukte von Mikroorganismen 98. Phosphinothricin and phosphinothricyle-alanyl-alanin. Helv Chim Acata 55:224–239CrossRefGoogle Scholar
  2. 2.
    Bérdy J (2012) Thoughts and facts about antibiotics: where we are now and where we are heading. J Antibiot 65(8):385–395PubMedCrossRefGoogle Scholar
  3. 3.
    Block MD, Botterman J, Vandewiele M, Dockx J, Thoen C, Gossele V, Movva NR, Thompson C, Montagu MV, Leemans J (1987) Engineering herbicide resistance in plants by expression of a detoxifying enzyme. EMBO J 6(9):2513–2518PubMedGoogle Scholar
  4. 4.
    Blodgett JA, Zhang JK, Metcalf WW (2005) Molecular cloning, sequence analysis, and heterologous expression of the phosphinothricin tripeptide biosynthetic gene cluster from Streptomyces viridochromogenes DSM 40736. Antimicrob Agents Chemother 49(1):230–240PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Blodgett JAV, Thomas PM, Li G, Velasquez JE, van der Donk WA, Kelleher NL, Metcalf WW (2007) Unusual transformations in the biosynthesis of the antibiotic phosphinothricin tripeptide. Nat Chem Biol 3:480–485 (d8f2bb67-9a19-5a0a-b099-335bae156967)PubMedCrossRefGoogle Scholar
  6. 6.
    Borisova SA, Circello BT, Zhang JK, van der Donk WA, Metcalf WW (2010) Biosynthesis of rhizocticins, antifungal phosphonate oligopeptides produced by Bacillus subtilis ATCC6633. Chem Biol 17(1):28–37PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Bowman E, McQueney M, Barry RJ, Dunaway-Mariano D (1988) Catalysis and thermodynamics of the phosphoenolpyruvate/phosphonopyruvate rearrangement. Entry into the phosphonate class of naturally occurring organophosphorus compounds. J Am Chem Soc 110:5575–5576CrossRefGoogle Scholar
  8. 8.
    Christensen BG, Leanza WJ, Beattie TR, Patchett AA, Arison BH, Ormond RE, Kuehl FA Jr, Albers-Schonberg G, Jardetzky O (1969) Phosphonomycin: structure and synthesis. Science 166(3901):123–125PubMedCrossRefGoogle Scholar
  9. 9.
    Cioni JP, Doroghazi J, Ju K-S, Yu X, Evans BS, Metcalf WW (2013) A cyanohydrin phosphonate natural product from Streptomyces regensis (under review)Google Scholar
  10. 10.
    Circello BT, Miller CG, Lee JH, van der Donk WA, Metcalf WW (2011) The antibiotic dehydrophos is converted to a toxic pyruvate analog by peptide bond cleavage in Salmonella enterica. Antimicrob Agents Chemother 55(7):3357–3362PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    D’Halluin K, De Block M, Denecke J, Janssens J, Leemans J, Reynaerts A, Botterman J (1992) The bar gene as selectable and screenable marker in plant engineering. Methods Enzymol 216:415–426PubMedGoogle Scholar
  12. 12.
    Diddens H, Zahner H, Kraas E, Gohring W, Jung G (1976) On the transport of tripeptide antibiotics in bacteria. Eur J Biochem/FEBS 66(1):11–23CrossRefGoogle Scholar
  13. 13.
    Doroghazi JR, Metcalf WW (2013) Comparative genomics of actinomycetes with a focus on natural product biosynthetic genes. BMC Genomics 14(1):611PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Eliot AC, Griffin BM, Thomas PM, Johannes TW, Kelleher NL, Zhao H, Metcalf WW (2008) Cloning, expression, and biochemical characterization of Streptomyces rubellomurinus genes required for biosynthesis of antimalarial compound FR900098. Chem Biol 15(8):765–770PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Evans BS, Zhao C, Gao J, Evans CM, Ju KS, Doroghazi JR, van der Donk WA, Kelleher NL, Metcalf WW (2013) Discovery of the antibiotic phosacetamycin via a new mass spectrometry-based method for phosphonic acid detection. ACS Chem Biol 8(5):908–913PubMedCrossRefGoogle Scholar
  16. 16.
    Fields SC (1999) Synthesis of natural products containing a C–P bond. Tetrahedron 55:12237–12273CrossRefGoogle Scholar
  17. 17.
    Gao J, Ju K-S, Yu X, Velasquez JE, Mukherjee S, Lee J, Zhao C, Evans BS, Doroghazi J, Metcalf WW, van der Donk WA (2013) Use of a phosphonate methyltransferase in the identification of the fosfazinomycin biosynthetic gene cluster (under review)Google Scholar
  18. 18.
    Gunji S, Arima K, Beppu T (1983) Screening of antifungal antibiotics according to activities inducing morphological abnormalities. Agric Biol Chem 47:2061–2069CrossRefGoogle Scholar
  19. 19.
    Hendlin D, Stapley EO, Jackson M, Wallick H, Miller AK, Wolf FJ, Miller TW, Chaiet L, Kahan FM, Foltz EL, Woodruff HB, Mata JM, Hernandez S, Mochales S (1969) Phosphonomycin, a new antibiotic produced by strains of Streptomyces. Science 166(3901):122–123PubMedCrossRefGoogle Scholar
  20. 20.
    Hidaka T, Mori M, Imai S, Hara O, Nagaoka K, Seto H (1989) Studies on the biosynthesis of bialaphos (SF-1293). 9. Biochemical mechanism of C–P bond formation in bialaphos: discovery of phosphoenolpyruvate phosphomutase which catalyzes the formation of phosphonopyruvate from phosphoenolpyruvate. J Antibiot 42(3):491–494PubMedCrossRefGoogle Scholar
  21. 21.
    Hilderbrand RL (1983) The role of phosphonates in living systems. CRC Press, USAGoogle Scholar
  22. 22.
    Horiguchi M, Kandatsu M (1959) Isolation of 2-aminoethane phosphonic acid from rumen protozoa. Nature 184(Suppl 12):901–902PubMedCrossRefGoogle Scholar
  23. 23.
    Huerta-Cepas J, Dopazo J, Gabaldón T (2010) ETE: a python environment for tree exploration. BMC Bioinformatics 11(1):24PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Hunt AH, Elzey TK (1988) Revised structure of A53868A. J Antibiot 41(6):802PubMedCrossRefGoogle Scholar
  25. 25.
    Johnson R, Gordee R, Kastner R, Larsen S, Ose E (1984) Antibiotic A53868 and process for production thereof. UK Patent 2,127,413, 1984; Eli Lilly. In: Chem. Abstr, 1984. p 88837Google Scholar
  26. 26.
    Jomaa H, Wiesner J, Sanderbrand S, Altincicek B, Weidemeyer C, Hintz M, Turbachova I, Eberl M, Zeidler J, Lichtenthaler HK, Soldati D, Beck E (1999) Inhibitors of the nonmevalonate pathway of isoprenoid biosynthesis as antimalarial drugs. Science 285(5433):1573–1576PubMedCrossRefGoogle Scholar
  27. 27.
    Katayama N, Tsubotani S, Nozaki Y, Harada S, Ono H (1990) Fosfadecin and fosfocytocin, new nucleotide antibiotics produced by bacteria. J Antibiot 43(3):238–246PubMedCrossRefGoogle Scholar
  28. 28.
    Kato H, Nagayama K, Abe H, Kobayashi R, Ishihara E (1991) Isolation, structure and biological activity of trialaphos. Agric Biol Chem 55:1133–1134CrossRefGoogle Scholar
  29. 29.
    Kido Y, Hamakado T, Anno M, Miyagawa E, Motoki Y, Wakamiya T, Shiba T (1984) Isolation and characterization of I5B2, a new phosphorus containing inhibitor of angiotensin I converting enzyme produced by Actinomadura sp. J Antibiot 37(9):965–969PubMedCrossRefGoogle Scholar
  30. 30.
    Kim DH, Lees WJ, Kempsell KE, Lane WS, Duncan K, Walsh CT (1996) Characterization of a Cys115 to Asp substitution in the Escherichia coli cell wall biosynthetic enzyme UDP-GlcNAc enolpyruvyl transferase (MurA) that confers resistance to inactivation by the antibiotic fosfomycin. Biochemistry 35(15):4923–4928PubMedCrossRefGoogle Scholar
  31. 31.
    Kim H, Chin J, Choi H, Baek K, Lee TG, Park SE, Wang W, Hahn D, Yang I, Lee J, Mun B, Ekins M, Nam SJ, Kang H (2013) Phosphoiodyns A and B, unique phosphorus-containing iodinated polyacetylenes from a Korean sponge Placospongia sp. Org Lett 15(1):100–103PubMedCrossRefGoogle Scholar
  32. 32.
    Kim SY, Ju KS, Metcalf WW, Evans BS, Kuzuyama T, van der Donk WA (2012) Different biosynthetic pathways to fosfomycin in Pseudomonas syringae and Streptomyces species. Antimicrob Agents Chemother 56(8):4175–4183PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Kimura T, Nakamura K, Takahashi E (1995) Phosphonothrixin, a novel herbicidal antibiotic produced by Saccharothrix sp. ST-888. II. Structure determination. J Antibiot 48(10):1130–1133PubMedCrossRefGoogle Scholar
  34. 34.
    Laber B, Lindell SD, Pohlenz HD (1994) Inactivation of Escherichia coli threonine synthase by DL-Z-2-amino-5-phosphono-3-pentenoic acid. Arch Microbiol 161(5):400–403PubMedGoogle Scholar
  35. 35.
    Lee JH, Bae B, Kuemin M, Circello BT, Metcalf WW, Nair SK, van der Donk WA (2010) Characterization and structure of DhpI, a phosphonate O-methyltransferase involved in dehydrophos biosynthesis. Proc Natl Acad Sci USA 107(41):17557–17562PubMedCrossRefGoogle Scholar
  36. 36.
    Lell B, Ruangweerayut R, Wiesner J, Missinou MA, Schindler A, Baranek T, Hintz M, Hutchinson D, Jomaa H, Kremsner PG (2003) Fosmidomycin, a novel chemotherapeutic agent for malaria. Antimicrob Agents Chemother 47(2):735–738PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Marquardt JL, Brown ED, Lane WS, Haley TM, Ichikawa Y, Wong CH, Walsh CT (1994) Kinetics, stoichiometry, and identification of the reactive thiolate in the inactivation of UDP-GlcNAc enolpyruvoyl transferase by the antibiotic fosfomycin. Biochemistry 33(35):10646–10651PubMedCrossRefGoogle Scholar
  38. 38.
    Metcalf WW, Griffin BM, Cicchillo RM, Gao J, Janga SC, Cooke HA, Circello BT, Evans BS, Martens-Habbena W, Stahl DA, van der Donk WA (2012) Synthesis of methylphosphonic acid by marine microbes: a source for methane in the aerobic ocean. Science 337(6098):1104–1107PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Metcalf WW, van der Donk WA (2009) Biosynthesis of phosphonic and phosphinic acid natural products. Annu Rev Biochem 78:65–94PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Moschidis MC (1985) Phosphonolipids. Prog Lipid Res 23:223–246CrossRefGoogle Scholar
  41. 41.
    Ogawa H, Tsuruoka T, Inouye S, Niida T (1973) Studies on a new antibiotic SF-1293. Sci Rep Meiji Seika Kaisha 13:42–48Google Scholar
  42. 42.
    Ogita T, Gunji S, Fukawa Y, Terahara A, Kinoshita T, Nagaki H (1983) The structures of fosfazinomycins A and B. Tetrahedron Lett 24:2283–2286CrossRefGoogle Scholar
  43. 43.
    Okuhara M, Kuroda Y, Goto T, Okamoto M, Terano H, Kohsaka M, Aoki H, Imanaka H (1980) Studies on new phosphonic acid antibiotics. I. FR-900098, isolation and characterization. J Antibiot 33(1):13–17PubMedCrossRefGoogle Scholar
  44. 44.
    Okuhara M, Kuroda Y, Goto T, Okamoto M, Terano H, Kohsaka M, Aoki H, Imanaka H (1980) Studies on new phosphonic acid antibiotics. III. Isolation and characterization of FR-31564, FR-32863 and FR-33289. J Antibiot 33(1):24–28PubMedCrossRefGoogle Scholar
  45. 45.
    Omura S, Hinotozawa K, Imamura N, Murata M (1984) The structure of phosalacine, a new herbicidal antibiotic containing phosphinothricin. J Antibiot 37(8):939–940PubMedCrossRefGoogle Scholar
  46. 46.
    Omura S, Murata M, Hanaki H, Hinotozawa K, Oiwa R, Tanaka H (1984) Phosalacine, a new herbicidal antibiotic containing phosphinothricin. Fermentation, isolation, biological activity and mechanism of action. J Antibiot 37(8):829–835PubMedCrossRefGoogle Scholar
  47. 47.
    Park BK, Hirota A, Sakai H (1976) 2-Amino-5-phosphono-3-pentenoic acid, a new amino acid from N-1409 substance, an antagonist of threonine. Agric Biol Chem 40:1905–1906CrossRefGoogle Scholar
  48. 48.
    Park BK, Hirota A, Sakai H (1977) Structure of plumbemycin A and B, antagonists of l-threonine from Streptomyces plumbeus. Agric Biol Chem 41:573–579CrossRefGoogle Scholar
  49. 49.
    Park BK, Hirota A, Sakai H (1977) Studies on new antimetabolite N-1409. Agric Biol Chem 41:161–167CrossRefGoogle Scholar
  50. 50.
    Price MN, Dehal PS, Arkin AP (2010) FastTree 2–approximately maximum-likelihood trees for large alignments. PLoS One 5(3):e9490PubMedCentralPubMedCrossRefGoogle Scholar
  51. 51.
    Rapp C, Jung G, Kugler M, Loeffler W (1988) Rhizocticins—new phosphono-oligopeptides with antifungal activity. Liebigs Annalen der Chemie 7:655–661Google Scholar
  52. 52.
    Sarker SD, Latif Z, Gray AI (2005) Natural products isolation, vol 20. Springer, New YorkCrossRefGoogle Scholar
  53. 53.
    Seidel HM, Freeman S, Seto H, Knowles JR (1988) Phosphonate biosynthesis: isolation of the enzyme responsible for the formation of a carbon–phosphorus bond. Nature 335(6189):457–458PubMedCrossRefGoogle Scholar
  54. 54.
    Shigi Y (1989) Inhibition of bacterial isoprenoid synthesis by fosmidomycin, a phosphonic-acid antibiotic. J Antimicrob Chemother 24:131–145PubMedCrossRefGoogle Scholar
  55. 55.
    Shoji J, Kato T, Hinoo H, Hattori T, Hirooka K, Matsumoto K, Tanimoto T, Kondo E (1986) Production of fosfomycin (phosphonomycin) by Pseudomonas syringae. J Antibiot 39(7):1011–1012PubMedCrossRefGoogle Scholar
  56. 56.
    Strauch E, Wohlleben W, Puhler A (1988) Cloning of a phosphinothricin N-acetyltransferase gene from Streptomyces viridochromogenes Tu494 and its expression in Streptomyces lividans and Escherichia coli. Gene 63(1):65–74PubMedCrossRefGoogle Scholar
  57. 57.
    Takahashi E, Kimura T, Nakamura K, Arahira M, Iida M (1995) Phosphonothrixin, a novel herbicidal antibiotic produced by Saccharothrix sp. ST-888. I. Taxonomy, fermentation, isolation and biological properties. J Antibiot 48(10):1124–1129PubMedCrossRefGoogle Scholar
  58. 58.
    Takeuchi M, Nakajima M, Ogita T, Inukai M, Kodama K, Furuya K, Nagaki H, Haneishi T (1989) Fosfonochlorin, a new antibiotic with spheroplast forming activity. J Antibiot 42(2):198–205PubMedCrossRefGoogle Scholar
  59. 59.
    Thompson CJ, Movva NR, Tizard R, Crameri R, Davies JE, Lauwereys M, Botterman J (1987) Characterization of the herbicide-resistance gene bar from Streptomyces hygroscopicus. EMBO J 6(9):2519–2523PubMedGoogle Scholar
  60. 60.
    Watanabe H, Yoshida J, Tanaka E, Ito M, Miyadoh S, Shomura T (1986) Studies on a new phosphonic acid antibiotic, SF-2312. Sci Rep Meiji Seika Kaisha 25:12–17Google Scholar
  61. 61.
    Widler L, Jahnke W, Green JR (2012) The chemistry of bisphosphonates: from antiscaling agents to clinical therapeutics. Anticancer Agents Med Chem 12(2):95–101PubMedCrossRefGoogle Scholar
  62. 62.
    Wiesner J, Borrmann S, Jomaa H (2003) Fosmidomycin for the treatment of malaria. Parasitol Res 90(Suppl 2):S71–S76PubMedCrossRefGoogle Scholar
  63. 63.
    Wohlleben W, Arnold W, Broer I, Hillemann D, Strauch E, Puhler A (1988) Nucleotide sequence of the phosphinothricin N-acetyltransferase gene from Streptomyces viridochromogenes Tu494 and its expression in Nicotiana tabacum. Gene 70(1):25–37PubMedCrossRefGoogle Scholar
  64. 64.
    Woodyer RD, Shao Z, Thomas PM, Kelleher NL, Blodgett JA, Metcalf WW, van der Donk WA, Zhao H (2006) Heterologous production of fosfomycin and identification of the minimal biosynthetic gene cluster. Chem Biol 13(11):1171–1182PubMedCrossRefGoogle Scholar
  65. 65.
    Yamato M, Koguchi T, Okachi R, Yamada K, Nakayama K, Kase H, Karasawa A, Shuto K (1986) K-26, a novel inhibitor of angiotensin I converting enzyme produced by an actinomycete K-26. J Antibiot 39(1):44–52PubMedCrossRefGoogle Scholar
  66. 66.
    Yu X, Doroghazi JR, Janga SC, Zhang JK, Circello BT, Griffin BM, Metcalf WW (2013) Diversity and abundance of phosphonate biosynthetic genes in nature. Proc Natl Acad Sci USA (in press)Google Scholar

Copyright information

© Society for Industrial Microbiology and Biotechnology 2013

Authors and Affiliations

  • Kou-San Ju
    • 1
  • James R. Doroghazi
    • 1
  • William W. Metcalf
    • 1
    • 2
  1. 1.Institute for Genomic BiologyUniversity of IllinoisUrbana-ChampaignUSA
  2. 2.Department of MicrobiologyUniversity of IllinoisUrbana-ChampaignUSA

Personalised recommendations