Precursor-directed biosynthesis of 6-deoxyerythronolide B analogues is improved by removal of the initial catalytic sites of the polyketide synthase.

WARD SL, DESAI RP, HU Z, GRAMAJO H, KATZ L

JOURNAL OF INDUSTRIAL MICROBIOLOGY & BIOTECHNOLOGY

SPRINGER HEIDELBERG

Lugar: HEIDELBERG; Año: 2007 vol. 34 p. 9 - 15

1367-5435

Abstract Precursor-directed biosynthesis has been shown to be a powerful tool for the production of polyketide analogues that would be diYcult or cost prohibitive to produce from medicinal chemistry eVorts alone. It has been most extensively demonstrated using a KS1 null mutation (KS1 0 ) to block the Wrst round of condensation in the biosynthesis of the erythromycin polyketide synthase (DEBS) for the production of analogues of its aglycone, 6-deoxyerythronolide B (6-dEB). Here we show that removing the DEBS loading domain and Wrst module (mod1 ), rather than using the KS1 0 system, can lead to an increase in the utilization of some chemical precursors and production of 6-dEB analogues (R-6dEB) in both Streptomyces coelicolor and Saccharopolyspora erythraea. While the diVerence in utilization of the precursor was diketide speciWc, in strains fed (2R*, 3S*)-5-Xuoro- 3-hydroxy-2-methylpentanoate N-propionylcysteamine thioester, twofold increases in both utilization of the diketide and 15-Xuoro-6dEB (15F-6dEB) production were observed in S. coelicolor, and S. erythraea exhibited a tenfold increase in production of 15-Xuoro-erythromycin when utilizing the mod1 rather than the KS1 0 system.