Coordination of Polyketide Release and Multiple Detoxification Pathways for Tolerable Production of Fungal Mycotoxins.

Efficient biosynthesis of microbial bioactive natural products (NPs) is beneficial for the survival of producers, while self-protection is necessary to avoid self-harm resulting from over-accumulation of NPs. The underlying mechanisms for the effective but tolerable production of bioactive NPs are not well understood. Herein, in the biosynthesis of two fungal polyketide mycotoxins aurovertin E (1) and asteltoxin, we show that the cyclases in the gene clusters promote the release of the polyketide backbone, and reveal that a signal peptide is crucial for their subcellular localization and full activity. Meanwhile, the fungus adopts enzymatic acetylation as the major detoxification pathway of 1. If intermediates are over-produced, the non-enzymatic shunt pathways work as salvage pathways to avoid excessive accumulation of the toxic metabolites for self-protection. These findings provided new insight into the interplay of efficient backbone release and multiple detoxification strategies for the production of fungal bioactive NPs.

Complex Interplay and Catalytic Versatility of Tailoring Enzymes for Efficient and Selective Biosynthesis of Fungal Mycotoxins.

Mycotoxins have substantial impacts on agricultural production and food preservation. Some have high similarities in bioactivity but subtle differences on structures from various fungal producers. Understanding of their complex cross-biosynthesis will provide new insights into enzyme functions and food safety. Here, based on structurally related mycotoxins, such as aurovertins, asteltoxin, and citreoviridin, we showed that methyltransferase (MT)-catalyzed methylation is required for efficient oxidation and polyketide stability. MTs have broad interactions with polyketide synthases and flavin-containing monooxygenases (FMOs), while MT AstB is required for FMO AstC functionality in vivo. FMOs have common catalysis on pyrone-polyene intermediates but different catalytic specificity and efficiency on oxidative intermediates for the selective production of more toxic and complex mycotoxins. Thus, the subtle protein interaction and elaborate versatile catalysis of biosynthetic enzymes contribute to the efficient and selective biosynthesis of these structure-related mycotoxins and provide the basis to re-evaluate and control mycotoxins for agricultural and food safety.

A target and efficient synthetic strategy for structural and bioactivity optimization of a fungal natural product.

Drugs have been largely inspired from natural products, while enzymes underlying their biosynthesis have enabled complex structures and diverse bioactivities. Nevertheless, the high enzyme specificity and limited in vivo precursor types have restricted the natural product reservoir, but Nature has imprinted natural products with active sites, which can be readily modified by chemosynthesis with various functional groups for more favorable druggability. Here in the less exploited fungal natural products, we introduced CtvA, a polyketide synthase for a mycotoxin citreoviridin biosynthesis in Aspergillus, into an endophytic fungus Calcarisporium arbuscula to expand tetrahydrofuran (THF) into a dioxabicyclo-octane (DBO) ring moiety based on versatility and promiscuity of the aurovertin biosynthetic enzyme. Alternative acylations on the hydroxyl groups essential for cell toxicity by chemosynthesis produced compounds with improved anti-tumor activities and pharmacokinetics. Thus, we showed an effective strategic way to optimize the fungal natural product efficiently for more promising drug development.

[Relationship between occupational noise exposure and hypertension in male steel workers].

OBJECTIVE: To analyze the effect of occupational noise exposure on hypertension in male steel workers. METHODS: The general information, noise exposure and blood pressure were collected through questionnaires and physical examinations. Chi-square test was used to investigate the prevalence of hypertension under different cumulative noise exposure, and the effect of noise exposure and other factors on hypertension was analyzed by the restrictive cubic spline(RCS) combined with multivariatenon-condition Logistic regression model. RESULTS: The prevalence of hypertension in noise exposure group was higher than that in noise non-exposure group(P<0. 001). After adjusting for multiple factors, the restricted cubic spline model showed a dose-response relationship between cumulative noise exposure(CNE) and hypertension(overall correlation χ~2=75. 76, P<0. 001, and nonlinear χ~2=24. 17, P<0. 001). Compared with the steel workers exposure to lowest dose, the risk of hypertension of steel workers exposure to 82-94 and 95-107 dB(A) in group was 1. 81(95%CI 1. 31-2. 52) times and 2. 60(95%CI 1. 84-3. 68) times. CONCLUSION: There is a non-linear dose-response relationship between cumulative noise exposure and hypertension.

Screening and identification of Aspergillus activity against Xanthomonas oryzae pv. oryzae and analysis of antimicrobial components.

To screen for Aspergillus activity against Xanthomonas oryzae pv. oryzae and analyse the antimicrobial components involved, 60 Aspergillus spp. were isolated and purified from fruits, soil and other habitats. As-75, an Aspergillus strain that can antagonize Xanthomonas oryzae pv. oryzae, was identified based on the zone of inhibition formed during co-culture. According to morphological, ITS rDNA gene sequencing and phylogenetic tree results, the strain showed close homology to Aspergillus sclerotiorum. The biochemical characterization tests showed that the fermentation broth of strain As-75 exhibited a high capacity for environmental adaptation. The results of the antimicrobial spectrum experiments demonstrated that As-75 exhibited fairly strong antagonistic activity against five plant pathogenic fungi and six plant pathogenic bacteria in vitro. The fermentation broth of strain As-75 displayed maximum stability under fluorescent illumination at temperatures below 60°C at pH 6.5. A substance with antagonistic activity was obtained from strain As-75 via fractional extraction, silica gel column chromatography and thin-layer chromatography. Through mass spectrometry, nuclear magnetic resonance and electrospray ionization mass spectrometry (ESI-MS) analyses, the target compound was identified as (2Z)-2-butenedioic acid-2-(1-methylethenyl)-4-methyl ester; its molecular weight of 170.06 daltons and formula of C8H10O4 identify it as a novel compound. Trials of the preventative and curative effects demonstrated that compound S1 exhibited a better control efficiency than the control against rice bacterial blight. Additionally, the M1 processing method was better, and the efficiency of compound S1 in preventing rice bacterial blight in six rice varieties, TN1, IR24, ZF802, Zhonghua 11, Wuyunjing 21, and Nipponbare, was 78.3%, 77.5%, 74.2%, 75.3%, 70.9%, and 72.1%, respectively.