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Puromycins B–E, Naturally Occurring Amino-Nucleosides Produced by the Himalayan Isolate Streptomyces sp. PU-14G

Abbas, Muhammad, Elshahawi, Sherif I., Wang, Xiachang, Ponomareva, Larissa V., Sajid, Imran, Shaaban, Khaled A., Thorson, Jon S.
Journal of natural products 2018 v.81 no.11 pp. 2560-2566
Streptomyces, amino acids, antibacterial properties, bacteria, biocatalysts, biosynthesis, cell lines, ligases, metabolites, neoplasm cells, puromycin, toxicity testing, Pakistan
The isolation and structure elucidation of four new naturally occurring amino-nucleoside [puromycins B–E (1–4)] metabolites from a Himalayan isolate (Streptomyces sp. PU-14-G, isolated from the Bara Gali region of northern Pakistan) is reported. Consistent with prior reports, comparative antimicrobial assays revealed the need for the free 2″-amine for anti-Gram-positive bacteria and antimycobacterial activity. Similarly, comparative cancer cell line cytotoxicity assays highlighted the importance of the puromycin-free 2″-amine and the impact of 3′-nucleoside substitution. These studies extend the repertoire of known naturally occurring puromycins and their corresponding SAR. Notably, 1 represents the first reported naturally occurring bacterial puromycin-related metabolite with a 3′-N-amino acid substitution that differs from the 3′-N-tyrosinyl of classical puromycin-type natural products. This discovery suggests the biosynthesis of 1 in Streptomyces sp. PU-14G may invoke a uniquely permissive amino-nucleoside synthetase and/or multiple synthetases and sets the stage for further studies to elucidate, and potentially exploit, new biocatalysts for puromycin chemoenzymatic diversification.