Late-Stage Terpene Cyclization by an Integral Membrane Cyclase in the Biosynthesis of Isoprenoid Epoxycyclohexenone Natural Products

Tang, Man-Cheng; Cui, Xiaoqing; He, Xin; Ding, Zhuang; Zhu, Tianjiao; Tang, Yi; Li, Dehai

doi:10.1021/acs.orglett.7b02653

Cited by 56 publications

(51 citation statements)

References 39 publications

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“…anditomin) 39 cyclisation, or acid-catalysed cyclisation (e.g. the macrophorins) 40 . During xenovulene biosynthesis, however, the terpene is cyclised before attachment to the polyketide.…”

Section: Discussionmentioning

confidence: 99%

Three previously unrecognised classes of biosynthetic enzymes revealed during the production of xenovulene A

et al. 2018

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Xenovulene A is a complex fungal meroterpenoid, produced by the organism hitherto known as Acremonium strictum IMI 501407, for which limited biosynthetic evidence exists. Here, we generate a draft genome and show that the producing organism is previously unknown and should be renamed as Sarocladium schorii. A biosynthetic gene cluster is discovered which bears resemblance to those involved in the biosynthesis of fungal tropolones, with additional genes of unknown function. Heterologous reconstruction of the entire pathway in Aspergillus oryzae allows the chemical steps of biosynthesis to be dissected. The pathway shows very limited similarity to the biosynthesis of other fungal meroterpenoids. The pathway features: the initial formation of tropolone intermediates; the likely involvement of a hetero Diels–Alder enzyme; a terpene cyclase with no significant sequence homology to any known terpene cyclase and two enzymes catalysing oxidative-ring contractions.

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“…anditomin) 39 cyclisation, or acid-catalysed cyclisation (e.g. the macrophorins) 40 . During xenovulene biosynthesis, however, the terpene is cyclised before attachment to the polyketide.…”

Section: Discussionmentioning

confidence: 99%

Three previously unrecognised classes of biosynthetic enzymes revealed during the production of xenovulene A

et al. 2018

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“…58 ). Very recently, a similar fungal membrane TC MacJ, involved in macrophorins biosynthesis, was identified from Penicillium terrestris , which also bears an additional acidic residue Asp96 related to catalysis 35 . The residue Y33 was also found to be conserved among all the membrane TCs and might contribute to increase the nucleophilicity of the acidic residues.…”

Section: Discussionmentioning

confidence: 99%

Genome mining of cyclodipeptide synthases unravels unusual tRNA-dependent diketopiperazine-terpene biosynthetic machinery

Yao

Liu

et al. 2018

Nat Commun

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Cyclodipeptide synthases (CDPSs) can catalyze the formation of two successive peptide bonds by hijacking aminoacyl-tRNAs from the ribosomal machinery resulting in diketopiperazines (DKPs). Here, three CDPS-containing loci (dmt1–3) are discovered by genome mining and comparative genome analysis of Streptomyces strains. Among them, CDPS DmtB1, encoded by the gene of dmt1 locus, can synthesize cyclo(L-Trp-L-Xaa) (with Xaa being Val, Pro, Leu, Ile, or Ala). Systematic mutagenesis experiments demonstrate the importance of the residues constituting substrate-binding pocket P1 for the incorporation of the second aa-tRNA in DmtB1. Characterization of dmt1–3 unravels that CDPS-dependent machinery is involved in CDPS-synthesized DKP formation followed by tailoring steps of prenylation and cyclization to afford terpenylated DKP compounds drimentines. A phytoene-synthase-like family prenyltransferase (DmtC1) and a membrane terpene cyclase (DmtA1) are required for drimentines biosynthesis. These results set the foundation for further increasing the natural diversity of complex DKP derivatives.

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“…Importantly, tumor-animals groups treated with the extract showed 100% survival rate in all doses, being significantly different when compared to controls (Figure 5b). Tang et al [32], Fang et al [29]. and He et al [33].…”

Section: P Purpurogenum Extract Showed Activity Against Ehrlich's Somentioning

confidence: 99%

Penicillium purpurogenumexerts antitumor effects and ameliorates inflammations in Erlich mice model

Teles

Pontes

Guimarães

et al. 2020

Preprint

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ABSTRACTBackgroundThe bioactive metabolites production contributes to the resistance of fungi towards adverse environmental conditions. Some metabolites often have interesting health-promoting activities. This study addressed the anti-tumoural properties of Penicillium purpurogenum isolated from a polluted lagoon in Northeastern Brazil.MethodsThe extract obtained from the polished environment strain P. purpurogenum was fermented, filtered, concentrated and lyophilized, giving rise to the Ethyl Acetate Extracellular Extract (EAE). The metabolites of the extracellular extract of P. purpurogenum were studied using direct infusion mass spectrometry. The solid Ehrlic tumor model was used to evaluate the extract antitumor activity. Female Swiss mice were divided in groups (n=10/group) as follow: Negative control (CTL-) treated with phosphate buffered solution; Positive Control (CTL+) treated with cyclophosphamide (25mg/mL); Extracts treatment at doses 4, 20 and 100mg/Kg; Animals without tumor or treatment (Sham); and animals without tumor treated with intermediate dose (EAE20). All treatments were performed intraperitoneally, daily during 15 days. After, the animals were eutanized and the tumor, lymphoid organs and serum were used for immunological, histological and biochemical parameters evaluation.ResultsThe extract was rich in meroterpenoids. All doses of the extract significantly reduced tumor size compared to CLT- and were associated with 100% survival. Histologically, the 20 and 100mg/kg doses reduced tumour-associated inflammation and tumour necrosis. The extract also reduced cellular infiltration of lymphoid organs and circulating TNF-α levels when compared with CLT-. The extract did not induce weight loss and renal or hepatic toxic changes.ConclusionsThese results indicate that P. purpurogenum from a polluted marine environment produce hybrid natural products of the terpenoid pathway that exhibits immunomodulatory and antitumor properties in vivo. Thus, fungal fermentation is a biotechnological approach for the production of antitumour agents.

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Late-Stage Terpene Cyclization by an Integral Membrane Cyclase in the Biosynthesis of Isoprenoid Epoxycyclohexenone Natural Products

Cited by 56 publications

References 39 publications

Three previously unrecognised classes of biosynthetic enzymes revealed during the production of xenovulene A

Three previously unrecognised classes of biosynthetic enzymes revealed during the production of xenovulene A

Genome mining of cyclodipeptide synthases unravels unusual tRNA-dependent diketopiperazine-terpene biosynthetic machinery

Penicillium purpurogenumexerts antitumor effects and ameliorates inflammations in Erlich mice model

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