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Bacterial aromatic polyketides are compounds with multiple aromatic rings synthesized by bacterial type II polyketide synthases (PKSs), some of which have been developed into clinical drugs. Compounds containing aromatic polyketides synthesized by hybrid type I and type II PKSs are extremely rare. Here, we report the discovery of a gene cluster encoding both modular type I and type II PKSs as well as KAS III through extensive bioinformatics analysis, leading to the characterization of the hybrid polyketide, spirocycline A. The structure of spirocycline A is rare among all aromatic polyketides, featuring a unique starter unit and four spirocycles and forming a dimer. Biosynthetic studies indicate that the starter unit of this molecule is synthesized by type I PKS in collaboration with two trans -acting ketoreductase (KR) and enoylreductase (ER). It is then transferred by KAS III to the type II PKS system, which synthesizes the tricyclic aromatic polyketide backbone. The subsequent formation of the spirocycle and dimerization are carried out by four redox enzymes encoded in the gene cluster. Overall, the discovery of spirocycline A provides a new approach for identifying novel aromatic polyketides and offers potential enzymatic tools for the bioengineering of these hybrid polyketides.

Flavoprotein monooxygenases (FPMOs) play important roles in generating structural complexity and diversity in natural products biosynthesized by type II polyketide synthases (PKSs). In this study, we used genome mining to discover novel mutaxanthene analogues and investigated the biosynthesis of these aromatic polyketides and their unusual xanthene framework. We determined the complete biosynthetic pathway of mutaxathene through in vivo gene deletion and in vitro biochemical experiments. We show that a multifunctional FPMO, MtxO4, catalyzes ring rearrangement and generates the required xanthene ring through a multistep transformation. In addition, we successfully obtained all necessary enzymes for in vitro reconstitution and completed the total biosynthesis of mutaxanthene in a stepwise manner. Our results revealed the formation of a rare xanthene ring in type II polyketide biosynthesis, and demonstrate the potential of using total biosynthesis for the discovery of natural products synthesized by type II PKSs., (© 2023 Wiley-VCH GmbH.)

Lorneic acid and related natural products are characterized by a trialkyl-substituted benzene ring. The formation of the aromatic core in the middle of the polyketide chain is unusual. We characterized a cytochrome P450 enzyme that can catalyze the hallmark benzene ring formation from an acyclic polyene substrate through genetic and biochemical analysis. Using this P450 as a beacon for genome mining, we obtained 12 homologous type I polyketide synthase (PKS) gene clusters, among which two gene clusters are activated and able to produce trialkyl-substituted aromatic polyketides. Quantum chemical calculations were performed to elucidate the plausible mechanism for P450-catalyzed benzene ring formation. Our work expands our knowledge of the catalytic diversity of cytochrome P450., (© 2022 Wiley-VCH GmbH.)

Spirocitromycetin, an antiosteoporotic polyketide bearing a unique spirocycle, was characterized from a human mucus sputum-derived Penicillium velutinum . Its structure and absolute configuration were elucidated spectrally, with its biosynthetic pathway likely mediated via polivione, a reported heptaketide. Spirocitromycetin was shown to be antiosteoporotic at 0.1 μM in the prednisolone-induced osteoporotic zebrafish model. A combination of spirocitromycetin variant synthesis and bioassay has identified 5'-methyl-3' H -spiro[chromane-3,2'-furan]-3',4-dione as an unreported antiosteroporotic pharmacophore. Collectively, this work offers new starting (sub)structures that may be of significance for antiosteoporotic drug discovery.

On our ongoing searching for bioactive natural products derived from entophytes, two polyketides possessing novel skeletons, alternatones A-B ( 1 - 2 ), were identified from the culture of Alternaria alternate L-10. Their structures were established by a combination of spectroscopic and single-crystal X-ray diffraction with Cu K a radiation. Alternatone A ( 1 ) exhibited cytotoxic activity against human hepatoma carcinoma HepG-2 cell line. The putative biosynthetic pathways for compounds 1 - 2 were also proposed.

Six novel aromatic polyketide dimers, bialternacins A-F (1-6), were isolated from a plant endophytic Alternaria sp. The structures of compounds 1-6 were elucidated on the basis of extensive spectroscopic analysis, single-crystal X-ray diffraction, and electronic circular dichroism analysis. Compounds 1, 2, 5, and 6 were characterized as four pairs of racemic mixtures. Compound (+)-5 was demonstrated to show acetylcholinesterase inhibitory activity with an IC 50 value of 15.5 μM. A putative biosynthetic pathway for these compounds was proposed.

Mayamycin B, a new antibacterial type II polyketide, together with its known congener mayamycin A, were isolated from Streptomyces sp. 120454. The structure of new compound was elucidated by extensive spectroscopic analysis and comparison with literature data. Sequencing and bioinformatics analysis revealed the biosynthetic gene cluster for mayamycins A and B.

Three new polyketides, named daldinone F (1), nodulisporin G (2), and dalmanol C (3), together with five known compounds, 4-8, were isolated from cultures of Daldinia eschscholzii. The structures of the new compounds were elucidated by extensive NMR and MS analyses. Compound 1 showed moderate cytotoxic activity against SW480 cancer cells with an IC50 value of 9.59 μM, and its absolute configuration was determined by single crystal X-ray diffraction., (Copyright © 2015 Verlag Helvetica Chimica Acta AG, Zürich.)

Chemical study of the ethyl acetate extract of the plant endophytic fungus Cladosporium sp. (strain no. IFB3lp-2) yielded three new polyketides (1-3), together with nine known compounds. All of the structures were elucidated on the basis of spectroscopic methods. The isolated compounds were screened for their cytotoxic, antiviral, and acetyl cholinesterase inhibitory activities. Regretfully, no compounds showed any significant activity in these assays.

Lorneic acid and related natural products are characterized by a trialkyl‐substituted benzene ring. The formation of the aromatic core in the middle of the polyketide chain is unusual. We characterized a cytochrome P450 enzyme that can catalyze the hallmark benzene ring formation from an acyclic polyene substrate through genetic and biochemical analysis. Using this P450 as a beacon for genome mining, we obtained 12 homologous type I polyketide synthase (PKS) gene clusters, among which two gene clusters are activated and able to produce trialkyl‐substituted aromatic polyketides. Quantum chemical calculations were performed to elucidate the plausible mechanism for P450‐catalyzed benzene ring formation. Our work expands our knowledge of the catalytic diversity of cytochrome P450. [ABSTRACT FROM AUTHOR]

Redox tailoring enzymes play key roles in generating structural complexity and diversity in type II polyketides. In chartreusin biosynthesis, the early 13C‐labeling experiments and bioinformatic analysis suggest the unusual aglycone is originated from a tetracyclic anthracyclic polyketide. Here, we demonstrated that the carbon skeleton rearrangement from a linear anthracyclic polyketide to an angular pentacyclic biosynthetic intermediate requires two redox enzymes. The flavin‐dependent monooxygenase ChaZ catalyses a Baeyer–Villiger oxidation on resomycin C to form a seven‐membered lactone. Subsequently, a ketoreductase ChaE rearranges the carbon skeleton and affords the α‐pyrone containing pentacyclic intermediate in an NADPH‐dependent manner via tandem reactions including the reduction of the lactone carbonyl group, Aldol‐type reaction, followed by a spontaneous γ‐lactone ring formation, oxidation and aromatization. Our work reveals an unprecedented function of a ketoreductase that contributes to generate structural complexity of aromatic polyketide. [ABSTRACT FROM AUTHOR]

Dalesconols (dalesconols A and B) are novel polyketides with strong immunosuppressive activity produced by Daldinia eschscholzii . In this work, the effects of different media (M1, M2, and M3) on fungus growth and dalesconols biosynthesis were firstly tested and compared. Intermediates and enzyme analysis indicated that laccase had the major contribution to dalesconols biosynthesis. The key role of laccase on dalesconols biosynthesis was further experimentally confirmed, which suggested that the modified M2 was more favored for laccase and dalesconols production. Thereafter, the medium composition was optimized by RSM with a fermentation titer of 36.66 mg/L obtained. Furthermore, Ca 2+ induction was employed to up-regulate of laccase activity and further enhanced dalesconols production (76.90 mg/L), which was 308% higher than that in M2. In addition, dalesconols production reached 63.42 mg/L in scale-up experiments. This work indicated great potential of laccase as a key enzyme on regulation of dalesconols production. [ABSTRACT FROM AUTHOR]

• Murayaquinones B-E (1 – 4) were isolated from an insect derived actinobacterium. • Structures of new compounds were elucidated by analysis their spectroscopic data. • Murayaquinone D exhibited cytotoxic activities against six cancer cell lines. Chemical study of the insect-derived bacterium, Streptomyces sp. NA4286, led to the discovery of four new polyketides, murayaquinones B-E (1 – 4), together with a known compound, murayaquinone (5). The structures of new compounds (1 – 4) were determined by extensive analysis of their NMR and HRESIMS data. The absolute configuration of (+)- 1 and (−)- 1 was assigned through comparison of experimental and calculated ECD spectra. Murayaquinone D (3) exhibited potent cytotoxic activities against six human cancer cell lines with IC 50 values ranging from 1.03 to 9.99 μM. [ABSTRACT FROM AUTHOR]

Five new aromatic polyketides, alternaphenols A–E ( 1 – 5 ), and two known compounds ( 6 – 7 ) were isolated from a liquid culture of Alternaria sp. (strain no. NF2198), a caterpillar associated fungus. Their structures were determined by extensive spectroscopic analysis and single crystal X-ray crystallography. Compounds 1 – 7 were evaluated for their cytotoxic activities against a human skin melanoma A-375 cell line. Only compounds 4 and 5 showed weak cytotoxic activities. [ABSTRACT FROM AUTHOR]

The article presents chemical equations related to the article "Polyketides from Mantis-Associated Fungus Daldinia eschscholzii IFB-TL01" by G. Wang and others, published in the "Chemistry & Biodiversity" in 2015.