Unveiling the Post-PKS Redox Tailoring Steps in Biosynthesis of the Type II Polyketide Antitumor Antibiotic Xantholipin

Zhang, Weike; Wang, Lu; Kong, Lingxin; Wang, Tao; Chu, Yiwen; Deng, Zixin; You, Delin

doi:10.1016/j.chembiol.2012.01.016

Cited by 58 publications

(75 citation statements)

References 42 publications

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“…9 The 52-kb XAN biosynthetic gene cluster has been identified in S. flavogriseus and reveals type II polyketide synthases, regulators and tailoring enzymes responsible for the formation of the unusual functional groups. 18 Type II polyketide synthases form the nascent polyketide intermediate, and the in vivo work confirmed that xanthone scaffold formation is catalyzed by the FAD (flavin adenine dinucleotide)-binding monooxygenase XanO4, with tailoring steps including the formation of the σ-lactam moiety by the asparagine synthetase XanA, the methylene dioxy bridge by the P450 monooxygenase XanO2 and the hydrolysis of the carbon backbone by the FAD-binding monooxygenase XanO5. 18 Here, we report the construction of a stnR replacement mutant (designated WJN-1) of the streptonigrin producer Streptomyces flocculus CGMCC4.1223.…”

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confidence: 63%

“…18 Type II polyketide synthases form the nascent polyketide intermediate, and the in vivo work confirmed that xanthone scaffold formation is catalyzed by the FAD (flavin adenine dinucleotide)-binding monooxygenase XanO4, with tailoring steps including the formation of the σ-lactam moiety by the asparagine synthetase XanA, the methylene dioxy bridge by the P450 monooxygenase XanO2 and the hydrolysis of the carbon backbone by the FAD-binding monooxygenase XanO5. 18 Here, we report the construction of a stnR replacement mutant (designated WJN-1) of the streptonigrin producer Streptomyces flocculus CGMCC4.1223. Comparative metabolite profiling revealed two compounds apparently unrelated to streptonigrin biosynthesis that accumulated in strain WJN-1.…”

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confidence: 63%

“…18 The XAN biosynthetic pathway features a type II polyketide synthase that is responsible for the assembly of the XAN skeleton and several oxidoreductases for catalyzing most of the post-polyketide synthase oxidative tailoring modification steps. 18 Analogous to the biosynthesis of XAN in S. flavogriseus, the same pathway could be proposed for S. flocculus CGMCC 4.1223 that harbors the same XAN gene cluster but which is silent under the culture conditions used for streptonigrin production. Interestingly, this silent gene cluster was activated when the aminotransferase-encoding gene stnR, which is unrelated to XAN biosynthesis, was replaced by the apramycin resistance cassette.…”

Section: Xantholipin B Supports the Proposed Xantholipin Biosyntheticmentioning

confidence: 99%

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Xantholipin B produced by the stnR inactivation mutant Streptomyces flocculus CGMCC 4.1223 WJN-1

Huang

Xie

et al. 2016

J Antibiot

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Xantholipin is a polycyclic xanthone antibiotic that exhibits potent cytotoxic and antibacterial activity. In this study, a new xanthone-type antibiotic, xantholipin B (1), was isolated for the first time along with its known derivative, xantholipin (2), from strain WJN-1, an aminotransferase inactivation mutant of the streptonigrin-producer Streptomyces flocculus CGMCC 4.1223. The structure of 1 was established based on spectroscopic analysis and supports the previously proposed biosynthetic pathway as a key intermediate of 2. Moreover, 1 showed 3- to 10-fold greater cytotoxicity than 2 against a select panel of human cancer cell lines. In addition, 1 demonstrated powerful antimicrobial activity against both Gram-positive bacteria and fungi. Importantly, both 1 and 2 inhibited the methicillin-resistant strain Staphylococcus aureus Mu50, with the MIC value of 0.025 μg ml. The new structural features of 1 enrich the structural diversity of xantholipin family compounds and shed new light on the structure-activity relationship of 1 as a promising antitumor drug candidate.

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Section: Xantholipin B Supports the Proposed Xantholipin Biosyntheticmentioning

confidence: 99%

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Xantholipin B produced by the stnR inactivation mutant Streptomyces flocculus CGMCC 4.1223 WJN-1

Huang

Xie

et al. 2016

J Antibiot

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“…Several cryptic reactions in other natural product biosynthetic pathways have been reported recently. Cryptic methyl esterification (22), chlorination (23), acylation (24), and demethoxylation (25,26) have been shown to be indispensable in the biosynthesis of streptonigrin, coronatine, saframycin, and xantholipin, respectively. However, to the best of our knowledge, glucose, which is the main carbon source, is used to mediate the biosynthesis of natural products, has not been previously reported in microbial natural product pathways.…”

Section: Discussionmentioning

confidence: 99%

Biosynthesis of the pyrrolidine protein synthesis inhibitor anisomycin involves novel gene ensemble and cryptic biosynthetic steps

Zheng

Cheng

Yao

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The protein synthesis inhibitor anisomycin features a unique benzylpyrrolidine system and exhibits diverse biological and pharmacologic activities. Its biosynthetic origin has remained obscure for more than 60 y, however. Here we report the identification of the biosynthetic gene cluster (BGC) of anisomycin in Streptomyces hygrospinosus var. beijingensis by a bioactivity-guided high-throughput screening method. Using a combination of bioinformatic analysis, reverse genetics, chemical analysis, and in vitro biochemical assays, we have identified a core four-gene ensemble responsible for the synthesis of the pyrrolidine system in anisomycin: aniQ, encoding a aminotransferase that catalyzes an initial deamination and a later reamination steps; aniP, encoding a transketolase implicated to bring together an glycolysis intermediate with 4-hydroxyphenylpyruvic acid to form the anisomycin molecular backbone; aniO, encoding a glycosyltransferase that catalyzes a cryptic glycosylation crucial for downstream enzyme processing; and aniN, encoding a bifunctional dehydrogenase that mediates multistep pyrrolidine formation. The results reveal a BGC for pyrrolidine alkaloid biosynthesis that is distinct from known bacterial alkaloid pathways, and provide the signature sequences that will facilitate the discovery of BGCs encoding novel pyrrolidine alkaloids in bacterial genomes. The biosynthetic insights from this study further set the foundation for biosynthetic engineering of pyrrolidine antibiotics.

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“…A close inspection of pentangular polyphenol KS β gene phylogeny indicates that its divergence correlates strongly with the detailed differences in the functional output of their respective gene clusters (Figure 1). 11–18 In other words, this single gene can predict not only the general class of a type II PKS gene cluster (e.g., anthracycline, tetracycline, angucycline, pentangular polyphenol etc.) but also many of the tailoring details encoded within a type II PKS gene cluster.…”

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Arixanthomycins A–C: Phylogeny-Guided Discovery of Biologically Active eDNA-Derived Pentangular Polyphenols

Kang

Brady

2014

ACS Chem. Biol.

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Soil microbiomes are a rich source of uncharacterized natural product biosynthetic gene clusters. Here we use short conserved biosynthetic gene sequences (natural product sequence tags) amplified from soil microbiomes as phylogenetic markers to correlate genotype to chemotype and target the discovery of novel bioactive pentangular polyphenols from the environment. The heterologous expression of an environmental DNA-derived gene cluster (the ARX cluster), whose ketosynthase beta (KSβ) sequence tag was phylogenetically distinct from any known KSβ sequence, led to the discovery of the arixanthomycins. Arixanthomycin A (1) exhibits potent antiproliferative activity against human cancer cell lines.

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Unveiling the Post-PKS Redox Tailoring Steps in Biosynthesis of the Type II Polyketide Antitumor Antibiotic Xantholipin

Cited by 58 publications

References 42 publications

Xantholipin B produced by the stnR inactivation mutant Streptomyces flocculus CGMCC 4.1223 WJN-1

Xantholipin B produced by the stnR inactivation mutant Streptomyces flocculus CGMCC 4.1223 WJN-1

Biosynthesis of the pyrrolidine protein synthesis inhibitor anisomycin involves novel gene ensemble and cryptic biosynthetic steps

Arixanthomycins A–C: Phylogeny-Guided Discovery of Biologically Active eDNA-Derived Pentangular Polyphenols

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