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Biosynthesis of the Mitomycins

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Biosynthesis

Part of the book series: Antibiotics ((ANTIBIOTICS,volume 4))

Abstract

The mitomycins and porfiromycin (Fig. 1) constitute a complex of anticancer antibiotics which are produced by Streptomyces caespitosus (Hata et al., 1956), Streptomyces ardus sp. n (DeBoer et al., 1960) Streptomyces verticillatus (Lefemine etal., 1962) and Streptomyces michiganensis (Wolf et al., 1975). Their structures have been determined by chemical, physicochemical, and X-ray methods (Webb etal., 1962a, 1962b; Stevens etal., 1965; Tulinsky and Van den Hende, 1967; Yahashi and Matsubara, 1976). Mitomycin A (Ia) (Tulinsky and Van den Hende, 1967) and Mitomycin B (Ib) (Yahashi and Matsubara, 1976) differ stereochemically at C-9. The structure of mitiromycin (II), a biologically inactive close relative, has been reported (Morton et al., 1970). The mitomycins and the Streptomyces metabolite (S)-2,3-dicarboxyaziridine (III) (Naganawa etal., 1975) are unique among naturally occurring metabolites owing to the presence of an aziridine ring. A related ring system, an azirine ring, occurs in the Streptomyces aureus antibiotic azirinomycin (IV)Miller etal., 1971

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References

  • Akhtar MH, Begleiter A, Johnson D, Lown JW, McLaughlin L, Sim S-K (1975) Studies related to antitumor antibiotics. VI. Correlation of covalent cross-linking of DNA by bifunctional aziridinoquinones with their antineoplastic activity. Can J Chem 53:2891–2905

    Article  CAS  Google Scholar 

  • Bezanson GS, Vining LC (1971) Studies on the biosynthesis of mitomycin C by Streptomyces verticillatus. Can J Biochem 49:911–918

    Article  PubMed  CAS  Google Scholar 

  • Brewer SJ, Boyle TT, Turner MK (1977) The carbamoylation of the 3-hydroxymethyl group of 7α-methoxy-7β-(5-D-aminoadipamido)-3-hydroxymethylceph-3-em-4-carboxcylic acid (desacetyl-7α-methoxycephalosporin C) by homogenates of Streptomyces clavuligerus. Biochem Soc Trans 5:1026–1029

    PubMed  CAS  Google Scholar 

  • Crooke ST, Bradner WT (1976) Mitomycin C: a review. Cancer Treat Rev 3:121–139

    Article  PubMed  CAS  Google Scholar 

  • DeBoer C, Dietz A, Lummis NE, Savage GM (1960) Porfiromycin, a new antibiotic. I. Discovery and biological activities. Antimicrob Agents Ann 17–22

    Google Scholar 

  • Fukuyama T, Nakatsubo F, Cocuzza AJ, Kishi Y (1977) Synthetic studies toward mitomycins. III. Total syntheses of mitomycins A and C. Tetrahedron Lett 4295–4298

    Google Scholar 

  • Gabriel O, Lindquist LC (1968) Biological mechanisms involved in the formation of deoxy sugars. IV. Enzymatic conversion of thymidine diphosphoglucose-4T to thymidine diphospho-4-keto-6-deoxyglucose-6T. J Biol Chem 243:1479–1484

    PubMed  CAS  Google Scholar 

  • Ghisalba O, Nuesch J (1978) A genetic approach to the biosynthesis of the rifamycin chromophore in Nocardia mediterranei. I. Isolation and characterization of a pentose-excreting auxotrophic mutant of Norcardia mediterranei with drastically reduced rifamycin production. J Antibiot 31:202–214

    PubMed  CAS  Google Scholar 

  • Haber A, Johnson RD, Rinehart Jr KL (1977) Biosynthetic origin of the C2 units of geldanamycin and distribution of label from D-[6-13C]glucose. J Am Chem Soc 99:3541–3544

    Article  PubMed  CAS  Google Scholar 

  • Hata T, Sano Y, Sugawara R, Matsumae A, Kanamori K, Shima T, Hochi T (1956) Mitomycin, a new antibiotic from Streptomyces. I. J Antibiot 9:141–146

    PubMed  CAS  Google Scholar 

  • Hornemann U, Aikman MJ (1973) Mitomycin biosynthesis by Streptomyces verticillatus. Incorporation of the amino group of D-[15N]glucosamine into the aziridine ring of mitomycin B. Chem Commun 88–89

    Google Scholar 

  • Hornemann U, Cloyd JC (1971) Studies on the biosynthesis of the mitomycin antibiotics by Streptomyces verticillatus. Chem Commun 301–302

    Google Scholar 

  • Hornemann U, Kehrer JP, Nunez CS, Ranieri RL (1974a) D-Glucosamine and L-citrulline, precursors in mitomycin biosynthesis by Streptomyces verticillatus. J Am Chem Soc 96:320–322

    Article  PubMed  CAS  Google Scholar 

  • Hornemann U, Kehrer JP, Nunez CS, Ranieri RL, Ho YK (1974b) Precursors in mitomycin biosynthesis by Streptomyces verticillatus. Dev Ind Microbiol 15:82–92

    CAS  Google Scholar 

  • Hornemann U, Kehrer JP, Eggert JH (1974c) Pyruvic acid and D-glucose as precursors in mitomycin biosynthesis by Streptomyces verticillatus. Chem Commun 1045–1046

    Google Scholar 

  • Hornemann U, Eggert JH (1975) Utilization of the intact carbamoyl group of L-(NH4CO-13C, 15N]citrulline in mitomycin biosynthesis by Streptomyces verticillatus. J Antibiot 28:841–843

    PubMed  CAS  Google Scholar 

  • Hornemann U, Ho YK, Mackey Jr JK, Srivastava SC (1976) Studies on the mode of action of the mitomycin antibiotics. Reversible conversion of mitomycin C into sodium-7-aminomitosane-9a-sulfonate. J Am Chem Soc 98:7069–

    Article  PubMed  CAS  Google Scholar 

  • Kersten H (1975) Mechanism of action of mitomycins. In: Handb Exp Pharmacol 38:47–64

    CAS  Google Scholar 

  • Kinoshita S, Uzu K, Nakano K, Shimizu M, Takahashi T (1971) Mitomycin derivatives. I. Preparation of mitosane and mitosene compounds and their biological activities. J Med Chem 14:103–109

    Article  PubMed  CAS  Google Scholar 

  • Kirsch EJ (1967) Mitomycins. In: Gottlieb D, Shaw PD (ed) Antibiotics, Biosynthesis, vol II, pp 66–76. Springer, Berlin Heidelberg New

    Google Scholar 

  • Kirsch EJ, Korshalla JD (1964) Influence of biological methylation on the biosynthesis of mitomycin A. J Bacteriol 87:247–255

    PubMed  CAS  Google Scholar 

  • Lefemine DV, Dann M, Barbatschi F, Hausmann WK, Zbinovsky V, Monnikendam P, Adam J, Bohonos N (1962) Isolation and characterization of mitiromycin and of other antibiotics produced by Streptomyces verticillatus. J Am Chem Soc 84:3184–3185

    Article  CAS  Google Scholar 

  • Lin AJ, Shansky CW, Sartorelli AC (1974) Potential bioreductive alkylating agents. 3. Synthesis and antineoplastic activity of acetoxymethyl and corresponding ethyl carbamate derivatives of benzoquinones. J Med Chem 17:558–561

    Article  PubMed  CAS  Google Scholar 

  • Lipsett MN, Weissbach A (1965) The site of alkylation of nucleic acids by mitomycin. Biochemistry 4:206–211

    Article  CAS  Google Scholar 

  • Lown JW, Weir G (1978) Studies related to antitumor antibiotics. XIV. Reactions of mitomycin B with DNA. Can J Biochem 56:296–304

    Article  CAS  Google Scholar 

  • Maitra US, Sprinson DB (1978) 5-Dehydro-3-deoxy-D-arabino-heptulosonic acid-7-phosphate. J Biol Chem 253:5426–5430

    PubMed  CAS  Google Scholar 

  • Miller TW, Tristram EW, Wolf FJ (1971) Azirinomycin. II. Isolation and chemical characterization as 3-methyl-2(2H)-azirine carboxylic acid. J Antibiot 24:48–50

    PubMed  CAS  Google Scholar 

  • Morton GO, Van Lear GE, Fulmor W (1970) The structure of mitiromycin. J Am Chem Soc 92:2588–2590

    Article  PubMed  CAS  Google Scholar 

  • Naganawa H, Usui N, Takita T, Hamada M, Umezawa H (1975) S-2,3-dicarboxy-aziridine, a new metabolite from a streptomyces. J Antibiot 28:828–829

    PubMed  CAS  Google Scholar 

  • Nakatsubo F, Fukuyama T, Cocuzza AJ, Kishi Y (1977) Synthetic studies toward mitomycins. 2. Total synthesis of dl-porfiromycin. J Am Chem Soc 99:8115–8116

    Article  CAS  Google Scholar 

  • Nelsestuen GL, Kirkwood S (1971) The mechanism of action of the enzyme uridine diphosphoglucose 4-epimerase. Proof of an oxidation-reduction mechanism with direct transfer of hydrogen between substrate and the β-position of the enzyme-bound pyridine nucleotide. J Biol Chem 246:7533–7543

    CAS  Google Scholar 

  • Nishikohori K, Fukui S (1975) Biosynthesis of mitomcyin in Streptomyces caespitosus. Relation of intracellular vitamin B12 level to mitomycin synthesis and enzymatic methylation of a demethylated derivative of mitomycin. Eur J Appl Microbiol 1:129–145

    Article  Google Scholar 

  • Otsuji N, Murayama I (1972) Deoxyribonucleic acid damage by monofunctional mitomycins and its repair in Escherichia coli. J Bacteriol 109:475–483

    PubMed  CAS  Google Scholar 

  • Patrick JB, Williams RP, Meyer WE, Fulmor W, Cosulich DB, Broschard RW, Webb JS (1964) Aziridinomitosenes: a new class of antibiotics related to the mitomycins. J Am Chem Soc 86:1889–1890

    Article  CAS  Google Scholar 

  • Redman KL, Hornemann U (1978) Interaction of pyruvate, phosphate dikinase, pyruvate kinase, alanine dehydrogenase and phosphoenolpyruvate carboxylase from Streptomyces verticillatus with Cibaron Blue 3G-A-Sepharose. Abstr Joint Central-Great Lakes Reg Meet Am Chem Soc, Indianapolis, Indiana, BIOL-16

    Google Scholar 

  • Snipes CE, Chang CJ, Floss HG (1979) Biosynthesis of the antibiotic granaticin. J Am Chem Soc 101:701–706

    Article  CAS  Google Scholar 

  • Srinivasan PR, Shigeura HT, Sprecher M, Sprinson DB, Davis BD (1956) The biosynthesis of shikimic acid from D-glucose. J Biol Chem 220:477–497

    Google Scholar 

  • Stevens CL, Taylor KG, Munk ME, Marshall WS, Noll K, Shah GD, Shah LG, Uzu K (1965) Chemistry and structure of mitomycin C. J Med Chem 8:1–10

    Article  PubMed  CAS  Google Scholar 

  • Szybalski W, Iyer VN (1964) Crosslinking of DNA by enzymatically or chemically activated mitomycins and porfiromycins, bifunctionally “alkylating” antibiotics. Fed Proc 23:946–957

    PubMed  CAS  Google Scholar 

  • Szybalski W, Iyer VN (1967) The mitomycins and porfiromycin. In: Gottlieb D, Shaw PD (ed) Antibiotics. Mechanism of Action, Vol I, pp 211–245. Springer, Berlin Heidelberg New York

    Google Scholar 

  • Taylor WG, Leadbetter G, Fost DL, Remers WA (1977) Mitomycin antibiotics. Synthesis and activity of 1,2-disubstituted mitosenes. J Med Chem 20:138–141

    Article  PubMed  CAS  Google Scholar 

  • Thoai NV, Thome-Bean F, Olomucki A (1966) Induction et spécificité des enzymes de la nouvelle voie catabolique de l’arginine. Biochim Biophys Acta 115:73–80

    Article  Google Scholar 

  • Tomasz M, Mercado CM, Olson J, Chatterjie N (1974) The mode of interaction of mitomycin C with deoxyribonucleic acid and other polynucleotides in vitro. Biochemistry 13:4878–4887

    Article  PubMed  CAS  Google Scholar 

  • Tulinski A, Van den Hende JH (1967) The crystal and molecular structure of N-brosylmitomycin A. J Am Chem Soc 89:2905–2911

    Article  Google Scholar 

  • Van Lear GE (1970) Mass spectrometric studies of antibiotics. I. Mass spectra of mitomycin antibiotics. Tetrahedron 26:2587–2597

    Article  PubMed  Google Scholar 

  • Webb JS, Cosulich DB, Mowat JH, Patrick JB, Broschard RW, Meyer WE, Williams RP, Wolf CF, Fulmor W, Pidacks C, Lancaster JE (1962a) The structures of mitomycins A, B and C and porfiromycin. Part I. J Am Chem Soc 84:3185–3186

    Article  CAS  Google Scholar 

  • Webb JS, Cosulich DB, Mowat JH, Patrick JB, Broschard RW, Meyer WE, Williams RP, Wolf CF, Fulmor W, Pidacks C, Lancaster JE (1962b) The structures of mitomycins A, B and C and poriformycin. Part II. J Am Chem Soc 84:3186–3188

    Google Scholar 

  • Weller DD, Rinehart Jr KL (1978) Biosynthesis of the antitumor antibiotic pactamycin. A methionine-derived ethyl group and a C7N unit. J Am Chem Soc 100:6757–6760

    Article  CAS  Google Scholar 

  • White RJ, Martinelli E (1974) Ansamycin biogenesis: Incorporation of [1-13C]glucose and [1-13C]glycerate into the chromophore of rifamycin S. FEBS Lett 49:233–236

    Article  PubMed  CAS  Google Scholar 

  • Wiley PF, Elrod DW, Marshall VP (1978) Biosynthesis of the anthracycline antibiotics nogalamycin and steffimycin B. J Org Chem 43:3457–3461

    Article  CAS  Google Scholar 

  • Wolf G, Wörth J, Achenbach H (1975) Mitomycin und ein neues Phenoxazon-Pigment aus Streptomyces michiganensis. Stoffwechselprodukte von Mikroorganismen. Arch Mikrobiol 106:245–259

    CAS  Google Scholar 

  • Wood HG, O’Brien WE, Michaels G (1977) Properties of carboxytransphosphorylase; pyruvate, phosphate dikinase; pyrophosphate phosphofructokinase and pyrophosphate-acetate kinase and their roles in the metabolism of inorganic pyrophosphate. In: Meister A (ed) Advances in enzymology, pp 85–155. Wiley and Sons, New York

    Google Scholar 

  • Yahashi R, Matsubara I (1976) The molecular structure of 7-demethoxy-7-p-bromoanilino mitomycin B. J Antibiot 29:104–106 and correction notice published in J Antibiot 31: issue of June 1978 last page

    PubMed  CAS  Google Scholar 

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Authors
  1. Ulfert Hornemann
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Editors and Affiliations

  1. Department of Biochemistry The Medical and Dental Schools, Northwestern University, Chicago, IL, 60611, USA

    John W. Corcoran Ph.D.

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© 1981 Springer-Verlag Berlin · Heidelberg

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Hornemann, U. (1981). Biosynthesis of the Mitomycins. In: Corcoran, J.W. (eds) Biosynthesis. Antibiotics, vol 4. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-67724-3_13

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  • DOI: https://doi.org/10.1007/978-3-642-67724-3_13

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-67726-7

  • Online ISBN: 978-3-642-67724-3

  • eBook Packages: Springer Book Archive

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