Activating a Cryptic Ansamycin Biosynthetic Gene Cluster To Produce Three New Naphthalenic Octaketide Ansamycins with n-Pentyl and n-Butyl Side Chains

Abstract

Genome mining is a rational approach to discovering new natural products. The genome sequence analysis of Streptomyces sp. LZ35 revealed the presence of a putative ansamycin gene cluster (nam). Constitutive overexpression of the pathway-specific transcriptional regulatory gene nam1 successfully activated the nam gene cluster, and three novel naphthalenic octaketide ansamycins were discovered with unprecedented n-pentylmalonyl-CoA or n-butylmalonyl-CoA extender units. This study represents the first example of discovering novel ansamycin scaffolds via activation of a cryptic gene cluster.

Neoansamycins from Streptomyces sp. LZ35

“…S13 †). Interpretation of the NMR data (Tables 1 and 2) revealed that 1 had similar structure as that of neoansamycin B, 15 except for the substitute of a hexyl at C-20 instead of an amyl side chain, and which was further conrmed by the 1 H-1 H COSY and HMBC correlations (ESI Table S1 and Fig. S1 †).…”

“…13,14 Recently, Streptomyces sp. LZ35 was activated to produce novel naphthalenic ansamycins (neoansamycins A-C) by constitutive overexpression of a LuxR family transcriptional regulatory gene, 15 and further ten new benzenic ansamycins (5,10-seco-neoansamycins A-J) were obtained by disrupting the nam7 gene in the SR201nam1OE strain. 16 The intriguing structure diversity of the neoansamycins A-C and 5,10-seco-neoansamycins A-J encouraged us to search for more new congeners of neoansamycins.…”

The Combinatorial Biosynthesis of “Unnatural” Products with Polyketides

“…(3) Silence genes activation. Li et al [21] activated a putative ansamycin gene cluster (nam) of Streptomyces sp. LZ35, and three new naphthalenic octaketide ansamycins (3-5 Fig.…”

Breaking the silence: new strategies for discovering novel natural products

“…XZQH13 were discovered when the large ATP-binding regulators of the LuxR family (LAL) transcriptional activator genes, vemR and astG1 were constitutively expressed, respectively [12,13]. Moreover, two novel chattamycins were discovered when overexpressing an atypical response regulator (ARR) family regulator gene, chaI [14]; and overexpression of a LuxR family activator gene nam1 led to production of three new naphthalenic octaketide ansamycins [15]. For the jadomycin and gaudimycin biosynthetic pathways, however, no significant effects were observed when ARR family activator genes were overexpressed [16 • ].…”