Isolation and Biosynthesis of Phenazine–Polyketide Hybrids from Streptomyces sp. KIB-H483

Abstract

A phenazine−polyketide hybrid compound, nexphenazine A (1), was isolated from Streptomyces sp. KIB-H483. The bioinformatic analysis of the draft genome of the producing strain and gene inactivation experiments revealed that the biosynthesis of 1 involves a phenazine−polyketide hybrid gene cluster. The abolished production of 1 as well as the accumulation of shunt metabolites 4−7 in mutant strain ΔnpzI revealed the key role of the npzI gene, which encodes an NAD(P)H-dependent ketoreductase, in nexphenazine biosynthesis. The structures and absolute configurations of the isolated intermediates were established on the basis of spectroscopic data analysis, singlecrystal X-ray diffraction, chiral chromatography, and chemical conversion experiments. NpzI exhibited stereochemical selectivity in reducing the carbonyl group of 4. Nexphenazine biosynthesis is proposed to involve a condensation of the carboxyl group of phenazine with one molecule of methylmalonyl-CoA by a type I PKS, followed by a ketone reduction by NpzI and an unknown methylation reaction.

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“…The red compounds 2 and 3 represent new glucosylated phenazine derivatives different to known glycosylated phenazines [47,56,[61][62][63][79][80][81][82][83]. So far, no N-glycosylated phenazines have been reported.…”

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