BIOSYNTHESIS OF STREPTAZOLIN

The biosynthetic origin of streptazolin (1) was studied by feedings of sodium [C-13]acetates, sodium [C-13]formate, [C-13]urea, L-[methyl-C-13]methionine, [N-15(2)]ammonium sulfate, and L-[N-15]glutamic acid to the producing microorganism Streptomyces sp. (strain FH-S 2184). NMR spectra analysis of the produced streptazolin (1) provided information about the biogenetic construction of its carbon skeleton. The unique tricyclic streptazolin (1) is assembled by a mixed biosynthesis via the polyketide pathway, the one-carbon and nitrogen pool, as well as oxygen from air. Acetyl-CoA seems to act as the pentaketide starter (C-12/C-13), which is subsequently elongated by four malonate units and the linkage of a building block deriving from the one-carbon pool. Urea, carbamoyl phosphate, or even carbon dioxide are discussed as ultimative precursors of the C1-pool moiety in 1. A fermentation in an [O-18(2)]-enriched atmosphere established the origin of the oxygen atom at 5-OH from molecular oxygen. The origin of the nitrogen atom was investigated by feedings of [N-15]ammonium sulfate and L-[N-15]glutamic acid indicating its introduction into 1 from the common nitrogen pool via a C1-pool metabolite (C1N-unit). A biosynthetic scheme for 1 including mechanistic aspects of the ring cyclization reactions leading to 1 is discussed.