Biosynthesis of the β-Amino Acid Moiety of the Enediyne Antitumor Antibiotic C-1027 Featuring β-Amino Acyl-S-carrier Protein Intermediates

摘要

C-1027, a chromoprotein natural product produced by Strepto-myces globisporus and composed of an apoprotein and the C-1027 chromophore (1), belongs to the enediyne family of antitumor antibiotics that have been considered as some of the most potent, highly active anticancer agents ever discovered. We have previously cloned and characterized the C-1027 biosynthetic gene cluster from S. globisporus and proposed that the biosynthesis of the (S)-3-chloro-4,5-dihydroxy-β-phenylalanine moiety (2) from L-tyrosine (3) and its incorporation into 1 are catalyzed by six enzymes: SgcC, SgcC1, SgcC2, SgcC3, SgcC4, and SgcC5. We now report the delineation of this pathway by in vivo and in vitro studies of five of the six enzymes. Our findings unveil a novel strategy for β-amino acid modification, featuring β-amino acyl-S-carrier protein intermediates, and shed new light into engineering the C-1027 biosynthetic machinery for the production of novel analogues as exemplified by 20-deschloro-C-1027 (4) and 20-deschloro-22-deshydroxy-C-1027 (5) (Figure 1).