Biosynthesis pp 313-324 | Cite as

Nitrogen-Nitrogen Bond Containing Antibiotics: Biosynthesis of Streptozocin

  • Ulfert Hornemann
Part of the Antibiotics book series (ANTIBIOTICS, volume 4)


The structures and properties of approximately 20 antibiotics from Streptomycetes as well as other microorganisms and of another 20 metabolites from bacteria, mushrooms, and plants which contain a nitrogen-nitrogen bond were recently reviewed by LaRue (1977). The physiological activities of these compounds comprise antitumor, cytotoxic, carcinogenic, and diabetogenic activities, but, despite the pharmacologic interest in these compounds, only scanty information is available on their biosynthesis and none on the enzymology and genetics of the formation of their nitrogen-nitrogen bonds. Our interest in the biosynthetic capabilities of Streptomycetes in general and a particular interest in the unexplored area of biological nitrogen-nitrogen bond formation prompted us to undertake biosynthetic studies on the antibiotic streptozocin and to initiate such studies with the antibiotic N-acetyl-6-diazo-5-oxo-L-norleucine (N-acetyl DON).


Heterotrophic Nitrification Free Nitrous Acid Nitrite Anion Organic Pathway Diazo Ketone 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Anderson LE, Ehrlich J, Sun SH, Burkholder PR (1956) Strains of Streptomyces, the sources of azaserine, elaiomycin, griseoviridin and viridogrisein. Antibiot Chemother 6:100–115Google Scholar
  2. Anzai K, Suzuki S (1960) A new antibiotic bovinocidin, identified as β-nitropropionic acid. J Antibiot 13:133–136PubMedGoogle Scholar
  3. Anzai K, Nagatsu J, Suzuki S (1961) Pathocidin, a new antifungal antibiotic. I. Isolation, physical and chemical properties, and biological activities. J Antibiot Ser A 14:340–342Google Scholar
  4. Arroyo V, Hall MJ, Hassall CH, Yamasaki Y (1976) Incorporation of amino acids into the cyclohexadepsipeptide, monamycin. Chem Commun 845–846Google Scholar
  5. Ayanaba A, Alexander M (1973) Microbial formation of nitrosamines in vitro. Appl Microbiol 25:862–868PubMedGoogle Scholar
  6. Backus EJ, Tresner HD, Campbell TH (1957) The nucleocidin and alazopeptin producing organisms: Two new species of Streptomyces. Antibiot Chemother 7:532–541Google Scholar
  7. Beylot J, Veyret V, Vallat I, Longy M, Moretti S (1976) Streptozotocine et insulinomes malins. A propos d’un cas. Revue de la literature. Sem Hôp 52:489–496Google Scholar
  8. Bhuyan BK, Fraser TJ, Buskirk HH, Neil GL (1972) Antileukemic activity of streptozotocin (NSC-85998) and its analogs. Cancer Chemother Rep Part 1 56:709–720Google Scholar
  9. Callaham D, Del Tredici P, Torrey JG (1978) Isolation and cultivation in vitro of the actinomycete causing root nodulation in Camptonia. Science 199:899–902PubMedCrossRefGoogle Scholar
  10. Cardillo R, Fuganti C, Ghiringhelli D, Giangrasso D, Graselli P, Santopietro-Amisano A (1974) The biosynthesis of aureothin. Tetrahedron 30:459–461CrossRefGoogle Scholar
  11. Collins-Thompson DL, Sen NP, Aris B, Schwinghamer L (1972) Non-enzymic in vitro formation of nitrosamines by bacteria isolated from meat products. Can J Microbiol 18:1968–1971PubMedCrossRefGoogle Scholar
  12. Corbett MD, Chipko, BR, Baden DG (1978) Chloroperoxidase-catalyzed oxidation of 4-chloroaniline to 4-chloronitrosobenzene. Biochem J 175:353–360PubMedGoogle Scholar
  13. Coronelli C, Pasqualucci CR, Tamoni G, Gallo GG (1966) Isolation and structure of alanosine, a new antibiotic. Farmaco Ed Sci 21:269–277Google Scholar
  14. Dalton H (1974) Fixation of dinitrogen by free-living microorganisms. CRC Crit Rev Microbiol 3:183–220CrossRefGoogle Scholar
  15. Daves GD, Robins RK, Cheng CC (1962) Antibiotics. I. Synthesis of 1,6-dimethyl-5,7-dioxo-1,5,6,7-tetrahydro pyrimido[5,4-e]as-triazine (toxoflavin) and related compounds. J Am Chem Soc 84:1724–1729CrossRefGoogle Scholar
  16. DeVoe SE, Rigler NE, Shay AJ, Martin JH, Boyd TC, Backus EJ, Mowat JH, Bohonos N (1957) Alazopeptin: production, isolation, and chemical characteristics. Antibiot Ann 1956–1957:730–735Google Scholar
  17. Dhawale MR, Hornemann U (1979) nitroalkane oxidation by Streptomycetes. J Bacteriol 137:916–924PubMedGoogle Scholar
  18. Dion HW, Fusari SA, Jakubowski ZL, Zora JG, Bartz QR (1956) 6-Diazo-5-oxo-L-norleucine, a new tumor-inhibitory substance. II, Isolation and characterization. J Am Chem Soc 78:3075–3076CrossRefGoogle Scholar
  19. Fusari GA, Haskell TH, Frohardt RP, Bartz QR (1954) Azaserine, a new tumor-inhibitory substance. Structural studies. J Am Chem Soc 76:2881–2883CrossRefGoogle Scholar
  20. Gottlieb OR, Magalhaes MT (1959) Occurrence of 1-nitro-2-phenylethane in Ocotea pretiosa and Ariba canelilla. J Org Chem 24:2070–2071CrossRefGoogle Scholar
  21. Gruner BJ, DeAngelo AB, Shaw PD (1972) The isolation and some properties of an enzyme system which catalyzes the degradation of β-nitropropionic acid. Arch Biochem Biophys 148:107–114PubMedCrossRefGoogle Scholar
  22. Hassall CH, Morton RB, Ogihara Y, Phillips DAS (1971) Amino-acids and peptides. Part XII. The molecular structures of the monamycins, cyclodepsipeptide antibiotics. J Chem Soc (C): 526–532Google Scholar
  23. Hata T, Umezawa I, Iwai Y, Katagiri M, Awaya J, Komiyama K, Oiwa R, Atsumi K (1973) Studies on the antitumor activity of an alazopeptin isolated from a new strain of Streptomyces. J Antibiot 26:181–183PubMedGoogle Scholar
  24. Herr RR, Jahnke HK, Argoudelis AD (1967) The structure of streptozotocin. J Am Chem Soc 89:4808–4809PubMedCrossRefGoogle Scholar
  25. Herrmann H (1961) Identifizierung eines Stoffwechselproduktes von Clitocybe suaveolens als 4-Methylnitrosaminobenzaldehyd. Hoppe-Seylers Z Physiol Chem 326:13–16PubMedCrossRefGoogle Scholar
  26. Hessler EJ, Jahnke HK (1970) Improved synthesis of streptozotocin, J Org Chem 35:245–246PubMedCrossRefGoogle Scholar
  27. Hirasawa K, Isono K (1978) Formation of 8-azaguanine from guanine by Streptomyces albus. J Antibiot 31:628–629PubMedGoogle Scholar
  28. Hornemann U, Eggert JH (1975) Utilization of the intact carbamoyl group of L-[NH2C0-13C,15N]citrulline in mitomycin biosynthesis by Streptomyces verticillatus. J Antibiot 28:841–843PubMedGoogle Scholar
  29. Inuma H, Takeuchi T, Kondo S, Matsuzaki M, Umezawa H (1972) Dopastin, an inhibitor of dopamine β-hydroxylase. J Antibiot 25:497–500Google Scholar
  30. Kawai S, Kobayashi K, Oshima T, Egami F (1965) Studies on the oxidation of p-aminobenzoate to p-nitrobenzoate by Streptomyces thioluteus. Arch Biochem Biophys 112:537–543PubMedCrossRefGoogle Scholar
  31. Kazumi T, Yoshino G, Fujii S, Baba S (1978) Tumorigenic action of streptozotocin on the pancreas and kidney in male wistar rats. Cancer Res 38:2144–2147PubMedGoogle Scholar
  32. Kido T, Yamamoto T, Soda K (1975) Microbial assimilation of alkyl nitro compounds and formation of nitrite. Arch Mikrobiol 106:165–169Google Scholar
  33. Kido T, Yamamoto T, Soda K (1976) Purification and properties of nitroalkane oxidizing enzyme from Hansenula mrakii. J Bacteriol 126:1261–1265PubMedGoogle Scholar
  34. Koyama G, Maeda K, Umezawa H, Iitaka Y (1966) The structural studies of formycin and formycin B. Tetrahedron Lett 597–602Google Scholar
  35. LaRue TA (1977) Naturally occurring compounds containing a nitrogen-nitrogen bond. Lloydia 40:307–321PubMedGoogle Scholar
  36. LePage GA, Loo TL (1973) Purine antagonists. In: Holland JF, Frei E III (ed) Cancer medicine, p 754. Lea and Febiger, PhiladelphiaGoogle Scholar
  37. Levenberg B (1964) Isolation and structure of agaritine, a γ-glutamyl-substituted arylhydrazine derivative from Agaricaceae. J Biol Chem 239:2267–2273PubMedGoogle Scholar
  38. Levenberg B, Linton SN (1966) On the biosynthesis of toxoflavin, an azapteridine antibiotic produced by Pseudomonas cocovenenans. J Biol Chem 241:846–852PubMedGoogle Scholar
  39. Like AA, Rossini AA (1976) Streptozotocin-induced pancreatic insulinitis: New model of diabetes mellitus. Science 193:415–417PubMedCrossRefGoogle Scholar
  40. Mills AL, Alexander M (1976) N-Nitrosamine formation by cultures of several microorganisms. Appl Environ Microbiol 31:892–895PubMedGoogle Scholar
  41. Moruzzi A, Montero JL, Oiry J, Imbach JL (1978) Sur de nouveaux analogues de la streptozotocine. Eur J Med Chem 13:421–424Google Scholar
  42. Murayama A, Tamura S (1970) Über Fragin, ein neues biologisches Stoffwechselproduct von Pseudomonas fragi. II. Mitt. Zur Struktur und Chemie des Fragins. Agric Biol Chem 34:122–129CrossRefGoogle Scholar
  43. Ochi K, Kikuchi S, Yashima S, Eguchi Y (1976) Biosynthesis of formycin. Incorporation and distribution of labeled compounds into formycin. J Antibiot 29:638–645PubMedGoogle Scholar
  44. O’Donovan DG, Forde TJ (1970) Biosynthesis of withasomnine, a unique pyrazole alkaloid. Tetrahedron Lett 3637–3638Google Scholar
  45. Okogun JI, Ekong DEU (1969) The fragrant principle of the fruits of Dennettia tripetala S. Baker: a new naturally occurring nitrocompound. Chem Ind 1272Google Scholar
  46. Onaka T (1968) Biogenetic-type three-step synthesis of withasomnine. Tetrahedron Lett 5711–5714Google Scholar
  47. Raistrick H, Stössl A (1958) Studies in the biochemistry of microorganisms. 104. Metabolites of Penicillium atrovenetum G. Smith: β-nitropropionic acid, a major metabolite. Biochem J 68:647–653PubMedGoogle Scholar
  48. Rao KV (1961) Chemistry of the duazomycins. I. Duazomycin A. Antimicrob Agents Chemother 178–183Google Scholar
  49. Rao KV (1962) Chemistry of the duazomycins. II. Duazomycin B. Antimicrob Agents Chemother 179–187Google Scholar
  50. Rao KV, Brooks Jr SC, Kugelman M, Romano AA (1960) Diazomycin A, B and C, three antitumor substances. I. Isolation and characterization. Antibiot Ann 1959-1960:943–949Google Scholar
  51. Sander J (1968) Nitrosaminsynthase durch Bacterien. Hoppe-Seylers Z Physiol Chem 349:429–432PubMedCrossRefGoogle Scholar
  52. Schütte HR, Liebisch HW, Miersch O, Senf L (1972) Untersuchungen zur Biosynthese des Agaritins in Agaricus bisporus. Anal Quim 68:899–903Google Scholar
  53. Shaw PD, DeAngelo AB (1969) Role of ammonium ion in the biosynthesis of β-nitropropionic acid. J Bacteriol 99:463–468PubMedGoogle Scholar
  54. Singaram S, Lawrence RS, Hornemann U (1979) Studies on the biosynthesis of the antibiotic streptozotocin by Streptomyces achromogenes var streptozoticus. Feeding experiments with carbon-14 and tritium labeled precursors. J Antibiot 32:501–507Google Scholar
  55. Tannenbaum SR, Fett D, Young VR, Land PD, Bruce WR (1978) Nitrite and nitrate are formed by endogenous synthesis in the human intestine. Science 200:1487–1489PubMedCrossRefGoogle Scholar
  56. Vavra JJ, DeBoer C, Dietz A, Hanka LJ, Sokolski WT (1960) Streptozotocin a new antibacterial antibiotic. Antibiot Ann 1959-1960:230–235Google Scholar
  57. Verstraete W, Alexander M (1972a) Heterotrophic nitrification by Arthrobacter sp. J Bacteriol 110:955–961PubMedGoogle Scholar
  58. Verstraete W, Alexander M (1972b) Mechanism of nitrification by Arthrobacter sp. J Bacteriol 110:962–967PubMedGoogle Scholar
  59. Wiley PF, Herr RR, Jahnke HK, Chidester CG, Mizsak SA, Spaulding LB, Argoudelis AD (1979) Streptozocin: Structure and Chemistry. J Org Chem 44:9–16CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin · Heidelberg 1981

Authors and Affiliations

  • Ulfert Hornemann

There are no affiliations available

Personalised recommendations