The primary focus in the continuation of our studies on the biosynthesis of antibiotics and other microbial metabolites will be on three Actinomycete antibiotics which contain mC7N units of different biosynthetic origin. These are rifamycin, an antitubercular drug whose semisynthetic derivatives, like rifampicin, are widely used clinically, asukamycin, a member of a family of compounds which have shown, inter alia, inhibition of protein prenylation and of interleukin-1beta converting enzyme, and validamycin, a commercial agent against phytopathogenic fungi but also the precursor for the synthesis of the clinical antidiabetic drug, voglibose. In all three cases the object is to define the biosynthetic pathway and its genetic control, and to unravel key biochemical reaction mechanisms involved in these biosyntheses by a combination of molecular biological and biochemical approaches, and to lay the foundation for the generation of modified bioactive structures through genetic engineering. A secondary focus is on the elucidation, at the genetic, enzymatic and mechanistic level, of the mode of formation of the 2,6-dideoxyhexose moieties of the unusual macrolide antibiotic, chlorothricin, and of the formation and mode of attachment of the 2,6-dideoxy- and 2,3,6- trideoxyhexose moieties of the benzoisochromane quinone antibiotic, granaticin. These studies will help provide the knowledge base and the tools to modify the structures of various bioactive natural products by the attachment of different sugar moieties. Thirdly we will complete ongoing studies on the biosynthesis of phenazine antibiotics, the saphenamycins and esmeraldins, with the aim of identifying unequivocally the structure of the monomeric shikimate pathway derivative which undergoes dimerization to the general precursor, phenazine-1,6-dicarboxylic acid, and on the thiopeptide antibiotics, nosiheptide and thiostrepton, aimed at cloning the correct peptide synthases encoding their formation.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Bio-Organic and Natural Products Chemistry Study Section (BNP)
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University of Washington
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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
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; 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
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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