Activation of cryptic metabolite production through gene disruption: Dimethyl furan-2,4-dicarboxylate produced by <i>Streptomyces sahachiroi</i>

Simkhada, Dinesh; Zhang, Huitu; Mori, Shogo; Williams, Howard J.; Watanabe, Coran M. H.

doi:10.3762/bjoc.9.205

Cited by 3 publications

(4 citation statements)

References 20 publications

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“…All three compounds are likely derived from isoleucine via the coenzyme A thioester 2-methylbutyryl-SCoA. Cyclopentanone (46) was widespread, while its alkylated and unsaturated derivatives were only found in a few strains and its higher homolog cyclohexanone (49) was only detected in Streptomyces sclerotialus NRRL ISP-5269. Hexan-2,4-dione (45) was the only dione and was emitted by Amycolatopsis alba DSM 44262.…”

Section: Scheme 2 Hydrocarbonsmentioning

confidence: 99%

“…Hexan-2,4-dione (45) was the only dione and was emitted by Amycolatopsis alba DSM 44262. Cyclopentanone (46) was widespread, while its alkylated and unsaturated derivatives were only found in a few strains and its higher homolog cyclohexanone (49) was only detected in Streptomyces sclerotialus NRRL ISP-5269. Cyclohept-4-enone (53) that corresponds to the alcohol 34 was present in many strains.…”

Section: Alcoholsmentioning

confidence: 99%

“…20,45 The representatives 2-furanmethanol (116), 2-(methoxymethyl)furan (117), (5-methylfuran-2-yl)methanol (118), methyl furan-2-carboxylate (119) and 2-acetylfuran (122) were widespread, while methyl 5-methylfuran-2-carboxylate (120) and 2-acetyl-5-methylfuran (123) occurred less often, and dimethyl furan-2,4-dicarboxylate (121) only in S. californicus. It was recently reported that disruption of a gene coding for a non-ribosomal peptide synthetase (NRPS) involved in azinomycin biosynthesis resulted in the enhanced formation of 121 in Streptomyces sahachiroi, 46 but information about genes or enzymes for the biosynthesis of any of the volatile furans is lacking.…”

Section: Furansmentioning

confidence: 99%

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Volatiles from nineteen recently genome sequenced actinomycetes

et al. 2015

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The volatiles released by agar plate cultures of nineteen actinomycetes whose genomes were recently sequenced were collected by use of a closed-loop stripping apparatus (CLSA) and analysed by GC/MS. In total, 178 compounds from various classes were identified. The most interesting findings were the detection of the insect pheromone frontalin in Streptomyces varsoviensis, and the emission of the unusual plant metabolite 1-nitro-2-phenylethane. Its biosynthesis from phenylalanine was investigated in isotopic labelling experiments. Furthermore, the identified terpenes were correlated to the information about terpene cyclase homologs encoded in the investigated strains. The analytical data were in line with functionally characterised bacterial terpene cyclases and particularly corroborated the recently suggested function of a terpene cyclase from Streptomyces violaceusniger by the identification of a functional homolog in Streptomyces rapamycinicus.

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Section: Scheme 2 Hydrocarbonsmentioning

confidence: 99%

Section: Alcoholsmentioning

confidence: 99%

Section: Furansmentioning

confidence: 99%

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Volatiles from nineteen recently genome sequenced actinomycetes

et al. 2015

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“…Some cryptic secondary metabolites were also gained by deleting PKS or nonribosomal peptide synthetase (NRPS) genes. Knockout of an NRPS gene, aziA2, in the biosynthetic pathway of azinomycins resulted in the production of dimethyl furan-2,4-dicarboxylate in Streptomyces sahachiroi (39). Disruption of the repressor gene (srrB) and the PKS genes lkcF-KR1 and lkmE in Streptomyces rochei, creating a triple mutant, led to the loss of production of polyketides lankacidin and lankamycin but produced an azoxyalkene, KA57-A (40).…”

Section: Discussionmentioning

confidence: 99%

Discovery of 16-Demethylrifamycins by Removing the Predominant Polyketide Biosynthesis Pathway in Micromonospora sp. Strain TP-A0468

Zhou

Luo

Zhang

et al. 2019

Appl Environ Microbiol

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A number of strategies have been developed to mine novel natural products based on biosynthetic gene clusters and there have been dozens of successful cases facilitated by the development of genomic sequencing. During our study on biosynthesis of the antitumor polyketide kosinostatin (KST), we found that the genome of Micromonospora sp. strain TP-A0468, the producer of KST, contains other potential polyketide gene clusters, with no encoded products detected. Deletion of kst cluster led to abolishment of KST and the enrichment of several new compounds, which were isolated and characterized as 16-demethylrifamycins (referred to here as compounds 3 to 6). Transcriptional analysis demonstrated that the expression of the essential genes related to the biosynthesis of compounds 3 to 6 was comparable to the level in the wild-type and in the kst cluster deletion strain. This indicates that the accumulation of these compounds was due to the redirection of metabolic flux rather than transcriptional activation. Genetic disruption, chemical complementation, and bioinformatic analysis revealed that the production of compounds 3 to 6 was accomplished by cross talk between the two distantly placed polyketide gene clusters pks3 and M-rif. This finding not only enriches the analogue pool and the biosynthetic diversity of rifamycins but also provides an auxiliary strategy for natural product discovery through genome mining in polyketide-producing microorganisms. IMPORTANCE Natural products are essential in the development of novel clinically used drugs. Discovering new natural products and modifying known compounds are still the two main ways to generate new candidates. Here, we have discovered several rifamycins with varied skeleton structures by redirecting the metabolic flux from the predominant polyketide biosynthetic pathway to the rifamycin pathway in the marine actinomycetes species Micromonospora sp. strain TP-A0468. Rifamycins are indispensable chemotherapeutics in the treatment of various diseases such as tuberculosis, leprosy, and AIDS-related mycobacterial infections. This study exemplifies a useful method for the discovery of cryptic natural products in genome-sequenced microbes. Moreover, the 16-demethylrifamycins and their genetically manipulable producer provide a new opportunity in the construction of novel rifamycin derivates to aid in the defense against the ever-growing drug resistance of Mycobacterium tuberculosis.

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