Abstract
We previously identified the aur1 biosynthetic gene cluster (BGC) in Streptomyces lavendulae subsp. lavendulae CCM 3239 (formerly Streptomyces aureofaciens CCM 3239), which is responsible for the production of the unusual angucycline-like antibiotic auricin. Auricin is produced in a narrow interval of the growth phase after entering the stationary phase, after which it is degraded due to its instability at the high pH values reached after the production phase. The complex regulation of auricin BGC is responsible for this specific production by several regulators, including the key activator Aur1P, which belongs to the family of atypical response regulators. The aur1P gene forms an operon with the downstream aur1O gene, which encodes an unknown protein without any conserved domain. Homologous aur1O genes have been found in several BGCs, which are mainly responsible for the production of angucycline antibiotics. Deletion of the aur1O gene led to a dramatic reduction in auricin production. Transcription from the previously characterized Aur1P-dependent biosynthetic aur1Ap promoter was similarly reduced in the S. lavendulae aur1O mutant strain. The aur1O-specific coactivation of the aur1Ap promoter was demonstrated in a heterologous system using a luciferase reporter gene. In addition, the interaction between Aur1O and Aur1P has been demonstrated by a bacterial two-hybrid system. These results suggest that Aur1O is a specific coactivator of this key auricin-specific positive regulator Aur1P. Bioinformatics analysis of Aur1O and its homologues in other BGCs revealed that they represent a new family of transcriptional coactivators involved in the regulation of secondary metabolite biosynthesis. However, they are divided into two distinct sequence-specific subclasses, each of which is likely to interact with a different family of positive regulators.
Highlights
Gram-positive soil bacteria of the genus Streptomyces are characterized by their ability to produce a wide range of bioactive secondary metabolites, including many known antibiotics
They undergo an exceptional process of morphological differentiation, initiated by germination of spores to form a network of branched multinucleoid hyphae
The genes responsible for the biosynthesis of antibiotics and other secondary metabolites are typically grouped into so-called biosynthetic gene clusters (BGCs) together with genes encoding pathway-specific or cluster-situated regulatory proteins
Summary
Gram-positive soil bacteria of the genus Streptomyces (class Actinobacteria, order Actinomycetales, family Streptomycetaceae) are characterized by their ability to produce a wide range of bioactive secondary metabolites, including many known antibiotics They undergo an exceptional process of morphological differentiation, initiated by germination of spores to form a network of branched multinucleoid hyphae (a so-called substrate mycelium). The genes responsible for the biosynthesis of antibiotics and other secondary metabolites are typically grouped into so-called biosynthetic gene clusters (BGCs) together with genes encoding pathway-specific or cluster-situated regulatory proteins These regulatory genes located in BGCs are controlled by global regulators that integrate physiological and environmental signals to control the production of multiple secondary metabolites and have pleiotropic roles in stress response and morphological differentiation. A number of global regulators have been characterized in Streptomyces (e.g., AbsA2, AdpA, AfsQ1, AtrA, DasR, GlnR, PhoP/PhoR, WblA) [3,4,5,6]
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