Deciphering the biosynthetic codes for the potent anti-SARS-CoV cyclodepsipeptide valinomycin in Streptomyces tsusimaensis ATCC 15141.
Valinomycin was recently reported to be the most potent agent against severe acute respiratory-syndrome coronavirus (SARS-CoV) in infected Vero E6 cells. Aimed at generating analogues by metabolic engineering, the valinomycin biosynthetic gene cluster has been cloned from Streptomyces tsusimaensis ATCC 15141. Targeted disruption of a nonribosomal peptide synthetase (NRPS) gene abolishes valinomycin production, which confirms its predicted nonribosomal-peptide origin. Sequence analysis of the NRPS system reveals four distinctive modules, two of which contain unusual domain organizations that are presumably involved in the generation of biosynthetic precursors D-alpha-hydroxyisovaleric acid and L-lactic acid. The respective adenylation domains in these two modules contain novel substrate-specificity-conferring codes that might specify for a class of hydroxyl acids for the biosynthesis of the depsipeptide natural products.
Cheng
Yi-Qiang
YQ
Department of Biological Sciences, Biotechnology Program, University of Wisconsin-Milwaukee, Milwaukee, WI 53211, USA. ycheng@uwm.edu
D000818:Animals; D000900:Anti-Bacterial Agents / Q000096:biosynthesis*; D000998:Antiviral Agents / Q000378:metabolism* / Q000494:pharmacology; D002522:Chlorocebus aethiops; D005798:Genes, Bacterial; D008969:Molecular Sequence Data; D005810:Multigene Family; D045473:Severe acute respiratory syndrome-related coronavirus / Q000187:drug effects*; D013302:Streptomyces / Q000235:genetics / Q000378:metabolism*; D014634:Valinomycin / Q000096:biosynthesis*; D014709:Vero Cells
D000900:Anti-Bacterial Agents; D000998:Antiviral Agents; D014634:Valinomycin