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Targeting Penicillium expansum GMC Oxidoreductase with High Affinity Small Molecules for Reducing Patulin Production.

ABSTRACT: Flavine adenine dinucleotide (FAD) dependent glucose methanol choline oxidoreductase (GMC oxidoreductase) is the terminal key enzyme of the patulin biosynthetic pathway. GMC oxidoreductase catalyzes the oxidative ring closure of (E)-ascladiol to patulin. Currently, no protein involved in the patulin biosynthesis in Penicillium expansum has been experimentally characterized or solved by X-ray diffraction. Consequently, nothing is known about P. expansum GMC oxidoreductase substrate-binding site and mode of action. In the present investigation, a 3D comparative model for P. expansum GMC oxidoreductase has been described. Furthermore, a multistep computational approach was used to identify P. expansum GMC oxidoreductase residues involved in the FAD binding and in substrate recognition. Notably, the obtained 3D comparative model of P. expansum GMC oxidoreductase was used for performing a virtual screening of a chemical/drug library, which allowed to predict new GMC oxidoreductase high affinity ligands to be tested in in vitro/in vivo assays. In vitro assays performed in presence of 6-hydroxycoumarin and meticrane, among the highly affinity predicted binders, confirmed a dose-dependent inhibition (17-81%) of patulin production by 6-hydroxycoumarin (10 µM-1 mM concentration range), whereas the approved drug meticrane inhibited patulin production by 43% already at 10 µM. Furthermore, 6-hydroxycoumarin and meticrane caused a 60 and 41% reduction of patulin production, respectively, in vivo on apples at 100 µg/wound.

SUBMITTER: Tragni V

PROVIDER: S-EPMC7824139 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Targeting Penicillium expansum GMC Oxidoreductase with High Affinity Small Molecules for Reducing Patulin Production.

Tragni Vincenzo V Cotugno Pietro P De Grassi Anna A Cavalluzzi Maria Maddalena MM Mincuzzi Annamaria A Lentini Giovanni G Sanzani Simona Marianna SM Ippolito Antonio A Pierri Ciro Leonardo CL

Biology 20201231 1

Flavine adenine dinucleotide (FAD) dependent glucose methanol choline oxidoreductase (GMC oxidoreductase) is the terminal key enzyme of the patulin biosynthetic pathway. GMC oxidoreductase catalyzes the oxidative ring closure of (E)-ascladiol to patulin. Currently, no protein involved in the patulin biosynthesis in Penicillium expansum has been experimentally characterized or solved by X-ray diffraction. Consequently, nothing is known about P. expansum GMC oxidoreductase sub ...[more]

PMID: 33396459

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Project description:Fruit blue mold disease and patulin contamination caused by Penicillium expansum lead to huge economic losses and food safety concerns worldwide. Many genes have been proven to be involved in the regulation of pathogenic and toxigenic processes of P. expansum. Histone H3 lysine 4 (H3K4) methylation is well recognized for its association with chromatin regulation and gene transcription. However, it is not clear whether H3K4 methylation is related to infection and patulin biosynthesis in Penicillium. Here, we characterized PeSet1, which is responsible for H3K4me1/me2/me3 in P. expansum. The deletion of PeSet1 caused severe defects in hyphal growth, conidiation, colonization, patulin biosynthesis, and stress responses. Moreover, we demonstrated that PeSet1 is involved in the regulation of patulin biosynthesis by mediating the expression of patulin cluster genes and crucial global regulatory factors. Likewise, PeSet1 positively regulated key genes in β-1,3-glucan biosynthesis and the reactive oxygen species scavenging process to modulate cell wall integrity and oxidative stress responses, respectively. Collectively, we have proven for the first time the function of Set1 in patulin biosynthesis and the crucial role of Set1 in colonization and stress responses in P. expansum. IMPORTANCE Penicillium expansum is one of the most important plant fungal pathogens, which not only causes blue mold rot in various fruits, leading to huge decay losses, but also produces mycotoxin patulin, posing a threat to human health. Both pathogenesis and patulin biosynthesis in P. expansum are regulated by complex and sophisticated networks. We focused on the epigenetic modification and identified a conserved histone H3K4 methyltransferase PeSet1 in P. expansum. Our work revealed the important role of PeSet1 in growth, development, colonization, patulin production, and stress responses of P. expansum. In particular, we originally described the regulation of Set1 on patulin biosynthetic pathway. These findings will provide new targets for the prevention and control of blue mold disease and patulin contamination.

Dataset Information

Targeting Penicillium expansum GMC Oxidoreductase with High Affinity Small Molecules for Reducing Patulin Production.

Publications

Targeting <i>Penicillium expansum</i> GMC Oxidoreductase with High Affinity Small Molecules for Reducing Patulin Production.

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