Elucidating the Sugar Tailoring Steps in the Cytorhodin Biosynthetic Pathway

Gui, Chun; Mo, Xuhua; Gu, Yu‐Cheng; Ju, Jianhua

doi:10.1021/acs.orglett.7b02758

Cited by 12 publications

(18 citation statements)

References 20 publications

(35 reference statements)

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“…Recently, products of the cytorhodin biosynthetic gene cluster were discovered in a similar way in Streptomyces sp. SCSIO 1666 (12). Based on the quantitative analysis of the intracellular concentration of malonyl-CoA and methylmanlonyl-CoA, deletion of the predominant polyketide pathway in these strains could lead to an enhanced supply of biosynthetic precursors and increase the yield of other polyketide natural products.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, translation level strategies, including engineering of the ribosome (10) and posttranslation modifications on acyl/peptidyl carrier proteins (11), have been occasionally developed to activate silent gene clusters. Discovery of new natural products from the metabolic level usually involves medium screening and the addition of various adjuvants, which are simple and useful strategies aimed at enhancing the supply of substrates or cofactors for effective synthesis of secondary metabolites (12). Despite these various strategies and dozens of successful cases, ways to wake the silent gene clusters remain difficult and require the combination of several strategies.…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

mentioning

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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“…The genomic library of Streptomyces sp. SCSIO 1666 using the SuperCos1 vector has been constructed previously 3,25 . Secondary metabolite BGC were detected and analyzed using online antiSMASH software (http://antismash.secondarymetabolites.org/).…”

Section: Methodsmentioning

confidence: 99%

“…A total of 14 anthracycline antibiotics were purified from marine-derived Streptomyces sp. SCSIO 1666 3 . To our surprise, five C-7 deoxyanthracycline antibiotics, cytorhodins X ( 1 ) and Y ( 2 ), cosmomycins A ( 3 ) and B ( 4 ), and iremycin ( 5 ) 3–7 (Fig.…”

Section: Introductionmentioning

confidence: 99%

“…We have characterized the cytorhodin gene cluster ( cyt ) and elucidated three glycosyltransferases (GTs) involved in tailoring steps from Streptomyces sp. SCSIO 1666 3 . As indicated, the cyt cluster shows high similarity on the amino acid sequence level (>80% amino acid identity, Supplementary Table 1) to that of cosmomycin D gene cluster ( cos ).…”

Section: Introductionmentioning

confidence: 99%

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CytA, a reductase in the cytorhodin biosynthesis pathway, inactivates anthracycline drugs in Streptomyces

et al. 2019

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Antibiotic-producing microorganism can develop strategies to deal with self-toxicity. Cytorhodins X and Y, cosmomycins A and B, and iremycin, are produced as final products from a marine-derived Streptomyces sp. SCSIO 1666. These C-7 reduced metabolites show reduced antimicrobial and comparable cytotoxic activities relative to their C-7 glycosylated counterparts. However, the biosynthetic mechanisms and relevant enzymes that drive C-7 reduction in cytorhodin biosynthesis have not yet been characterized. Here we report the discovery and characterization of a reductase, CytA, that mediates C-7 reduction of this anthracycline scaffold; CytA endows the producer Streptomyces sp. SCSIO 1666 with a means of protecting itself from the effects of its anthracycline products. Additionally, we identified cosmomycins C and D as two intermediates involved in cytorhodin biosynthesis and we also broadened the substrate specificity of CytA to clinically used anthracycline drugs.

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Assembly Line and Post-PKS Modifications in the Biosynthesis of Marine Polyketide Natural Products

Zhang

Yang

et al. 2020

Comprehensive Natural Products III

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Elucidating the Sugar Tailoring Steps in the Cytorhodin Biosynthetic Pathway

Cited by 12 publications

References 20 publications

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

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

CytA, a reductase in the cytorhodin biosynthesis pathway, inactivates anthracycline drugs in Streptomyces

Assembly Line and Post-PKS Modifications in the Biosynthesis of Marine Polyketide Natural Products

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