Aromatic Polyketide GTRI‐02 is a Previously Unidentified Product of the act Gene Cluster in Streptomyces coelicolor A3(2)

Abstract

The biosynthesis of aromatic polyketides derived from type II polyketide synthases (PKSs) is complex, and it is not uncommon that highly similar gene clusters give rise to diverse structural architectures. The act biosynthetic gene cluster (BGC) of the model actinomycete Streptomyces coelicolor A3(2) is an archetypal type II PKS. Here we show that the act BGC also specifies the aromatic polyketide GTRI-02 (1) and propose a mechanism for the biogenesis of its 3,4-dihydronaphthalen-1(2H)-one backbone. Polyketide 1 was also produced by Streptomyces sp. MBT76 after activation of the act-like qin gene cluster by overexpression of the pathway-specific activator. Mining of this strain also identified dehydroxy-GTRI-02 (2), which most likely originated from dehydration of 1 during the isolation process. This work shows that even extensively studied model gene clusters such as act of S. coelicolor can still produce new chemistry, offering new perspectives for drug discovery.

Insights into the Role of Ketoreductases in the Biosynthesis of Partially Reduced Bacterial Aromatic Polyketides*

“…GTRI‐02 is also produced by Streptomyces sp. strains GW4184, ANK313, and Gö C4/4, and recently was identified in Streptomyces violaceoruber and Streptomyces coelicolor A3(2) . According to a bio‐retrosynthetic analysis (using fungal biogenesis), 2 is synthesized chemoenzymatically by use of a fungal enzyme.…”

“…One might assume that the biosynthesis of 2 in bacteria also involves the reduction of aromatic substrate 1 , a strategy we have successfully applied in its total synthesis . However, more recently, 2 has been identified as an additional product of the act gene cluster in S. coelicolor A3(2) …”

“…The corresponding ketoreductase is ActIII KR, which is supposed to reduce linear octaketide 3 prior to cyclization and aromatization (Scheme , path B) . Herein, we resolve the issue pertaining to the substrate of bacterial KRs during the biosynthesis of GTRI‐02 by testing three bacterial KRs with mono‐, bi‐, and tricyclic aromatic substrates.…”

Immunosuppressants produced by Streptomyces: evolution, hygiene hypothesis, tumour rapalog resistance and probiotics

“…In animal models, rapamycin also moderately changed gut metagenomes, and some metagenomic effects were associated with immune outcomes (Hurez et al ., ). Anti‐inflammatory compounds produced by Streptomyces violaceoruber and Streptomyces coelicolor might also reduce chronic inflammation (Ma et al ., ; Wu et al ., ). Based on these facts, the Streptomycetes might reduce inflammatory disorders at mucosal surfaces by the suppression of (i) an excessive proliferation of some microorganisms, and (ii) the local immune response.…”

“…In addition to the therapeutically relevant products (rapamycin, tacrolimus and FK520) (Tamaki et al ., ), Streptomycetes produce some other immunosuppressants whose clinical applications are needed to be determined. For example, Streptomyces violaceoruber and Streptomyces coelicolor have strong anti‐inflammatory secondary metabolites, such as GTRI‐02, which inhibit nitric oxide production from macrophages, a critical pathway in chronic inflammation (Ma et al ., ; Wu et al ., ).…”