Macrolide biosynthesis. 7. Incorporation of polyketide chain elongation intermediates into methymycin

Abstract

Administration of [1-[sup 13]C]propionate to cultures of Streptomyces venezuelae SC 2366 gave methymycin (1), which was shown by [sup 13]C NMR analysis to be labeled at the predicted sites, C-1, C-3, C-5, C-9, and C-11. Similarly, incorporation of [1,2-[sup 13]C]acetate gave methymycin labeled at C-7 and C-8. A series of presumptive intermediates of polyketide chain elongation was also successfully incorporated. Thus, feeding of (2S,3R)-[2,3-[sup 13]C[sub 2]]-2-methyl-3-hydroxypentanoyl N-acetylcysteamine (NAC) thioester 7a gave both methymycin (1) and neomethymycin (2) labeled as expected at C-10 and C-11. In a complementary experiment, (2S,3R)-[3-[sup 2]H,3-[sup 13]C]-2-methyl-3-hydroxypentanoyl NAC thioester 7b was incorporated into 1 and 2 without loss of deuterium. Finally, incorporation of (4R,5R)-[2,3-[sup 13]C[sub 2]]-4-methyl-5-hydroxy-2-heptenoyl NAC thioester 10a gave 1 and 2 labeled at C-8 and C-9. These results support a processive model of polyketide chain assembly in which the functionality and oxidation level are adjusted subsequent to each condensation step. 18 refs., 1 tab.