Abstract

The research outlined in this proposal is aimed at elucidating the mode of biosynthesis of a number of antibiotics. Compounds to be studied are pyrrolnitrin and the pyrrolomycins, the hydroaromatic antibiotics ketomycin, dihydrophenylalanine and anticapsin, some benzoisochromane quinone antibiotics, the macrocyclic antibiotics aplasmomycin, naphthomycin and ansatrienine, several compounds containing biosynthetically unusual structural units like asukamycin, manumycin, reductiomycin and acarbose, and the modified peptide antibiotics nosiheptide and thiostreptone. Biological structure modification based on biosynthetic information is also envisioned with some of these compounds. The methods to be used include (a) feeding experiments with precursors labeled with radioactive isotopes, but also to a large extent the use of 13C, 15N, 18O and deuterium labeled compounds in conjunction with Fourier Transform NMR Spectroscopy, (b) isolation of pathway intermediates from blocked mutants, (c) isolation of enzymes carrying out some of these transformations and (d) synthesis and use of stereospecifically labeled substrates to probe the stereochemistry and mechanism of some of the biosynthetic reactions.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI020264-05
Application #
3129828
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Project Start
1982-12-01
Project End
1988-11-30
Budget Start
1986-12-01
Budget End
1987-11-30
Support Year
5
Fiscal Year
1987
Total Cost
Indirect Cost

  Institution

Name
Ohio State University
Department
Type
Schools of Arts and Sciences
DUNS #
098987217
City
Columbus
State
OH
Country
United States
Zip Code
43210

  Publications

Floss, Heinz G (2006) Combinatorial biosynthesis--potential and problems. J Biotechnol 124:242-57
Yu, Yi; Bai, Linquan; Minagawa, Kazuyuki et al. (2005) Gene cluster responsible for validamycin biosynthesis in Streptomyces hygroscopicus subsp. jinggangensis 5008. Appl Environ Microbiol 71:5066-76
Floss, Heinz G; Yu, Tin-Wein (2005) Rifamycin-mode of action, resistance, and biosynthesis. Chem Rev 105:621-32
Xu, Jun; Wan, Eva; Kim, Chang-Joon et al. (2005) Identification of tailoring genes involved in the modification of the polyketide backbone of rifamycin B by Amycolatopsis mediterranei S699. Microbiology 151:2515-28
Arakawa, Kenji; Bowers, Simeon G; Michels, Benjamin et al. (2003) Biosynthetic studies on the alpha-glucosidase inhibitor acarbose: the chemical synthesis of isotopically labeled 2-epi-5-epi-valiolone analogs. Carbohydr Res 338:2075-82
Xu, Jun; Mahmud, Taifo; Floss, Heinz G (2003) Isolation and characterization of 27-O-demethylrifamycin SV methyltransferase provides new insights into the post-PKS modification steps during the biosynthesis of the antitubercular drug rifamycin B by Amycolatopsis mediterranei S699. Arch Biochem Biophys 411:277-88
Arakawa, Kenji; Muller, Rolf; Mahmud, Taifo et al. (2002) Characterization of the early stage aminoshikimate pathway in the formation of 3-amino-5-hydroxybenzoic acid: the RifN protein specifically converts kanosamine into kanosamine 6-phosphate. J Am Chem Soc 124:10644-5
Mahmud, T; Lee, S; Floss, H G (2001) The biosynthesis of acarbose and validamycin. Chem Rec 1:300-10
Floss, H G (2001) Antibiotic biosynthesis: from natural to unnatural compounds. J Ind Microbiol Biotechnol 27:183-94
Yu, T W; Muller, R; Muller, M et al. (2001) Mutational analysis and reconstituted expression of the biosynthetic genes involved in the formation of 3-amino-5-hydroxybenzoic acid, the starter unit of rifamycin biosynthesis in amycolatopsis Mediterranei S699. J Biol Chem 276:12546-55

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