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Deciphering a Cyclodipeptide Synthase Pathway Encoding Prenylated Indole Alkaloids in Streptomyces leeuwenhoekii .
Applied and Environmental Microbiology 2021 March 20
Cyclodipeptide synthases (CDPSs) catalyse the formation of cyclodipeptides using aminoacylated-tRNAs as substrates and have great potentials in the production of diverse 2,5-diketopiperazines (2,5-DKPs). Genome mining of Streptomyces leeuwenhoekii NRRL B-24963 revealed a two-gene locus saz encoding a CDPS SazA and a unique fused enzyme SazB harboring two domains: phytoene-synthase-like prenyltransferase (PT) and methyltransferase (MT). Heterologous expression of the saz gene(s) in Streptomyces albus J1074 led to the production of four prenylated indole alkaloids, among which streptoazines A-C (3-5) are new compounds. Expression of different gene combinations showed that the SazA catalyzes the formation of cyclo (L-Trp-L-Trp) (cWW, 1 ), followed by consecutive prenylation and methylation by SazB. Biochemical assays demonstrated that SazB is a bifunctional enzyme, catalyzing sequential C3 / C3' -prenylation(s) by SazB-PT and N1 / N1' -methylation(s) by SazB-MT. Of note substrate selectivity of SazB-PT and SazB-MT was probed, revealing the stringent specificity of SazB-PT but relative flexibility of SazB-MT. IMPORTANCE Natural products with 2,5-DKP skeleton have long sparked the interest in drug discovery and development. Recent advances in microbial genome sequencing have revealed that the potentials of CDPS-dependent pathways encoding new 2,5-DKPs are underexplored. In this study, we report the genome mining of a new CDPS-containing two-gene operon and activation of this cryptic gene cluster through heterologous expression, leading to the discovery of four indole 2,5-DKP alkaloids. The cWW-synthesizing CDPS SazA and the unusual PT-MT fused enzyme SazB were characterized. Our results expand the repertoire of CDPSs and associated tailoring enzymes, setting the stage for accessing diverse prenylated alkaloids using synthetic biology strategies.
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