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Special Issue "Molecular Biology and Chemistry of Mycotoxins and Phytotoxins"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Toxicology".

Deadline for manuscript submissions: closed (31 January 2021).

Special Issue Editors

Dr. Makoto Kimura
E-Mail Website1 Website2
Guest Editor
Department of Biological Mechanisms and Function, Graduate School of Bioagricultural Sciences, Nagoya University, Furo‐cho, Chikusa‐ku, Nagoya, Aichi 464‐8601, Japan
Interests: fungal molecular biology; mycotoxin biosynthesis and regulation; secondary metabolism; plant-pathogen interaction; gene expression
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Motoichiro Kodama
E-Mail Website
Guest Editor
Faculty of Agriculture, Tottori University, 4-101 Koyama-Minami, Tottori 680-8553, Japan
Dr. Florence Richard-Forget
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Guest Editor
Dr. Donald Gardiner
E-Mail Website
Guest Editor
Commonwealth Scientific and Industrial Research Organisation, Agriculture and Food, 306 Carmody Road, St Lucia, Brisbane, QLD, Australia
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Yin-Won Lee
E-Mail
Guest Editor
Department of Agricultural Biotechnology and Research Institute of Agriculture and Life Sciences, Seoul National University, Seoul 08826, Korea

Special Issue Information

Dear Colleagues, 

Many filamentous fungi can grow on pre- or post-harvest crops under favorable growth conditions, either parasitically or saprophytically. In this process, they often produce secondary metabolites with ecological significance. Such small molecules were traditionally termed as mycotoxins (fungal toxins active toward animals) and phytotoxins (fungal toxins active toward plants); however, it is now evident that this categorization does not appropriately represent the nature of the toxic chemicals. For example, fumonisins and AAL-toxins (host-specific toxins) are mycotoxins and phytotoxins, respectively, and yet they share the same polyketide backbone and biological activity. Trichothecene mycotoxins contribute to plant disease development and play minor roles as phytotoxins. Biosynthesis genes of toxins involved in biological interactions tend to evolve extensively and generate structural diversity of the toxin side-chains.

This Special Issue, “Molecular Biology and Chemistry of Mycotoxins and Phytotoxins,” deals with the various aspects of fungal toxins potentially involved in the survival of the producers in their ecological niche. The scope of this Issue includes but is not limited to:  

  • Biosynthesis of fungal secondary metabolites with ecological significance
  • Structural diversity of fungal toxins, such as trichothecenes and fumonisins
  • Regulation of fungal toxin gene expression
  • Plant, microbial, and animal responses to toxigenic fungi and toxins

We wholeheartedly welcome both original research articles and reviews on fungal toxins.

Dr. Makoto Kimura
Prof. Dr. Motoichiro Kodama
Dr. Florence Richard-Forget
Dr. Donald Gardiner
Prof. Dr. Lee Yin-Won
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • aflatoxins
  • trichothecenes
  • fumonisins
  • ochratoxins
  • host-specific toxins
  • Alternaria toxins
  • emerging mycotoxins
  • biosynthesis
  • gene cluster
  • transcriptional regulation
  • toxicity
  • modification
  • ecological role

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Published Papers (11 papers)

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Research

Jump to: Review

Article
Active Transport of Hepatotoxic Pyrrolizidine Alkaloids in HepaRG Cells
Int. J. Mol. Sci. 2021, 22(8), 3821; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22083821 - 07 Apr 2021
Cited by 2 | Viewed by 609
Abstract
1,2-unsaturated pyrrolizidine alkaloids (PAs) are secondary plant metabolites occurring as food contaminants that can cause severe liver damage upon metabolic activation in hepatocytes. However, it is yet unknown how these contaminants enter the cells. The role of hepatic transporters is only at the [...] Read more.
1,2-unsaturated pyrrolizidine alkaloids (PAs) are secondary plant metabolites occurring as food contaminants that can cause severe liver damage upon metabolic activation in hepatocytes. However, it is yet unknown how these contaminants enter the cells. The role of hepatic transporters is only at the beginning of being recognized as a key determinant of PA toxicity. Therefore, this study concentrated on assessing the general mode of action of PA transport in the human hepatoma cell line HepaRG using seven structurally different PAs. Furthermore, several hepatic uptake and efflux transporters were targeted with pharmacological inhibitors to identify their role in the uptake of the PAs retrorsine and senecionine and in the disposition of their N-oxides (PANO). For this purpose, PA and PANO content was measured in the supernatant using LC-MS/MS. Also, PA-mediated cytotoxicity was analyzed after transport inhibition. It was found that PAs are taken up into HepaRG cells in a predominantly active and structure-dependent manner. This pattern correlates with other experimental endpoints such as cytotoxicity. Pharmacological inhibition of the influx transporters Na+/taurocholate co-transporting polypeptide (SLC10A1) and organic cation transporter 1 (SLC22A1) led to a reduced uptake of retrorsine and senecionine into HepaRG cells, emphasizing the relevance of these transporters for PA toxicokinetics. Full article
(This article belongs to the Special Issue Molecular Biology and Chemistry of Mycotoxins and Phytotoxins)
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Article
Nicotinamide Effectively Suppresses Fusarium Head Blight in Wheat Plants
Int. J. Mol. Sci. 2021, 22(6), 2968; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22062968 - 15 Mar 2021
Viewed by 1265
Abstract
Pyridine nucleotides such as a nicotinamide adenine dinucleotide (NAD) are known as plant defense activators. We previously reported that nicotinamide mononucleotide (NMN) enhanced disease resistance against fungal pathogen Fusarium graminearum in barley and Arabidopsis. In this study, we reveal that the pretreatment of [...] Read more.
Pyridine nucleotides such as a nicotinamide adenine dinucleotide (NAD) are known as plant defense activators. We previously reported that nicotinamide mononucleotide (NMN) enhanced disease resistance against fungal pathogen Fusarium graminearum in barley and Arabidopsis. In this study, we reveal that the pretreatment of nicotinamide (NIM), which does not contain nucleotides, effectively suppresses disease development of Fusarium Head Blight (FHB) in wheat plants. Correspondingly, deoxynivalenol (DON) mycotoxin accumulation was also significantly decreased by NIM pretreatment. A metabolome analysis showed that several antioxidant and antifungal compounds such as trigonelline were significantly accumulated in the NIM-pretreated spikes after inoculation of F. graminearum. In addition, some metabolites involved in the DNA hypomethylation were accumulated in the NIM-pretreated spikes. On the other hand, fungal metabolites DON and ergosterol peroxide were significantly reduced by the NIM pretreatment. Since NIM is relative stable and inexpensive compared with NMN and NAD, it may be more useful for the control of symptoms of FHB and DON accumulation in wheat and other crops. Full article
(This article belongs to the Special Issue Molecular Biology and Chemistry of Mycotoxins and Phytotoxins)
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Article
Nicotinamide Mononucleotide Potentiates Resistance to Biotrophic Invasion of Fungal Pathogens in Barley
Int. J. Mol. Sci. 2021, 22(5), 2696; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052696 - 07 Mar 2021
Viewed by 959
Abstract
Nicotinamide mononucleotide (NMN), a precursor of nicotinamide adenine dinucleotide (NAD), induces disease resistance to the Fusarium head blight fungus Fusarium graminearum in Arabidopsis and barley, but it is unknown at which stage of the infection it acts. Since the rate of haustorial formation [...] Read more.
Nicotinamide mononucleotide (NMN), a precursor of nicotinamide adenine dinucleotide (NAD), induces disease resistance to the Fusarium head blight fungus Fusarium graminearum in Arabidopsis and barley, but it is unknown at which stage of the infection it acts. Since the rate of haustorial formation of an obligate biotrophic barley powdery mildew fungus Blumeria graminis f. sp. hordei (Bgh) was significantly reduced in NMN-treated coleoptile epidermal cells, the possibility that NMN induces resistance to the biotrophic stage of F. graminearum was investigated. The results show that NMN treatment caused the wandering of hyphal growth and suppressed the formation of appressoria-like structures. Furthermore, we developed an experimental system to monitor the early stage of infection in real-time and analyzed the infection behavior. We observed that the hyphae elongated windingly by NMN treatment. These results suggest that NMN potentiates resistance to the biotrophic invasion of F. graminearum as well as Bgh. Full article
(This article belongs to the Special Issue Molecular Biology and Chemistry of Mycotoxins and Phytotoxins)
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Article
Efficiency of Hydroxycinnamic Phenolic Acids to Inhibit the Production of Ochratoxin A by Aspergillus westerdijkiae and Penicillium verrucosum
Int. J. Mol. Sci. 2020, 21(22), 8548; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228548 - 13 Nov 2020
Cited by 1 | Viewed by 824
Abstract
Ochratoxin A (OTA) is one of the worldwide most important mycotoxins in terms of health and agroeconomic consequences. With the aim to promote the use of phytochemicals as alternatives to synthetic fungicides, the effect of hydroxycinnamic acids on the fungal growth and OTA [...] Read more.
Ochratoxin A (OTA) is one of the worldwide most important mycotoxins in terms of health and agroeconomic consequences. With the aim to promote the use of phytochemicals as alternatives to synthetic fungicides, the effect of hydroxycinnamic acids on the fungal growth and OTA yield by two major OTA-producing species was investigated. After a first step dedicated to the definition of most suitable culture conditions, the impact of 0.5 mM ferulic (FER), p-coumaric (COUM), caffeic and chlorogenic acids was evaluated on Aspergillus westerdijkiae and Penicillium verrucosum. Whereas no fungal growth reduction was observed regardless of the phenolic acid and fungal isolate, our results demonstrated the capacity of FER and COUM to inhibit OTA production. The most efficient compound was FER that led to a 70% reduction of OTA yielded by P. verrucosum and, although not statistically significant, a 35% inhibition of OTA produced by A. westerdijkiae. To further investigate the bioactivity of FER and COUM, their metabolic fate was characterized in fungal broths. The capacity of P. verrucosum to metabolize FER and COUM through a C2-clivage type degradation was demonstrated. Overall, our data support the potential use of FER to prevent OTA contamination and reduce the use of synthetic pesticides. Full article
(This article belongs to the Special Issue Molecular Biology and Chemistry of Mycotoxins and Phytotoxins)
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Article
Aspergillus flavus Exploits Maize Kernels Using an “Orphan” Secondary Metabolite Cluster
Int. J. Mol. Sci. 2020, 21(21), 8213; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218213 - 03 Nov 2020
Cited by 3 | Viewed by 637
Abstract
Aspergillus flavus is a saprophytic cosmopolitan fungus, capable of infecting crops both pre- and post-harvest and exploiting different secondary metabolites, including aflatoxins. Aflatoxins are known carcinogens to animals and humans, but display no clear effect in host plants such as maize. In a [...] Read more.
Aspergillus flavus is a saprophytic cosmopolitan fungus, capable of infecting crops both pre- and post-harvest and exploiting different secondary metabolites, including aflatoxins. Aflatoxins are known carcinogens to animals and humans, but display no clear effect in host plants such as maize. In a previous study, we mined the genome of A. flavus to identify secondary metabolite clusters putatively involving the pathogenesis process in maize. We now focus on cluster 32, encoding for fungal effectors such as salicylate hydroxylase (SalOH), and necrosis- and ethylene-inducing proteins (npp1 domain protein) whose expression is triggered upon kernel contact. In order to understand the role of this genetic cluster in maize kernel infection, mutants of A. flavus, impaired or enhanced in specific functions (e.g., cluster 32 overexpression), were studied for their ability to cause disease. Within this frame, we conducted histological and histochemical experiments to verify the expression of specific genes within the cluster (e.g., SalOH, npp1), the production of salicylate, and the presence of its dehydroxylated form. Results suggest that the initial phase of fungal infection (2 days) of the living tissues of maize kernels (e.g., aleuron) coincides with a significant increase of fungal effectors such as SalOH and Npp1 that appear to be instrumental in eluding host defences and colonising the starch-enriched tissues, and therefore suggest a role of cluster 32 to the onset of infection. Full article
(This article belongs to the Special Issue Molecular Biology and Chemistry of Mycotoxins and Phytotoxins)
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Communication
Heterologous Expression of the Core Genes in the Complex Fusarubin Gene Cluster of Fusarium Solani
Int. J. Mol. Sci. 2020, 21(20), 7601; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207601 - 14 Oct 2020
Cited by 3 | Viewed by 934
Abstract
Through stepwise recreation of the biosynthetic gene cluster containing PKS3 from Fusarium solani, it was possible to produce the core scaffold compound of bostrycoidin, a red aza-anthraquinone pigment in Saccharomyces cerevisiae. This was achieved through sequential transformation associated recombination (TAR) cloning [...] Read more.
Through stepwise recreation of the biosynthetic gene cluster containing PKS3 from Fusarium solani, it was possible to produce the core scaffold compound of bostrycoidin, a red aza-anthraquinone pigment in Saccharomyces cerevisiae. This was achieved through sequential transformation associated recombination (TAR) cloning of FvPPT, fsr1, fsr2, and fsr3 into the pESC-vector system, utilizing the inducible bidirectional galactose promoter for heterologous expression in S. cerevisiae. The production of the core metabolite bostrycoidin was investigated through triplicate growth cultures for 1–4 days, where the maximum titer of bostrycoidin was achieved after 2 days of induction, yielding 2.2 mg/L. Full article
(This article belongs to the Special Issue Molecular Biology and Chemistry of Mycotoxins and Phytotoxins)
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Article
The brlA Gene Deletion Reveals That Patulin Biosynthesis Is Not Related to Conidiation in Penicillium expansum
Int. J. Mol. Sci. 2020, 21(18), 6660; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186660 - 11 Sep 2020
Cited by 2 | Viewed by 1039
Abstract
Dissemination and survival of ascomycetes is through asexual spores. The brlA gene encodes a C2H2-type zinc-finger transcription factor, which is essential for asexual development. Penicillium expansum causes blue mold disease and is the main source of patulin, a mycotoxin [...] Read more.
Dissemination and survival of ascomycetes is through asexual spores. The brlA gene encodes a C2H2-type zinc-finger transcription factor, which is essential for asexual development. Penicillium expansum causes blue mold disease and is the main source of patulin, a mycotoxin that contaminates apple-based food. A P. expansum PeΔbrlA deficient strain was generated by homologous recombination. In vivo, suppression of brlA completely blocked the development of conidiophores that takes place after the formation of coremia/synnemata, a required step for the perforation of the apple epicarp. Metabolome analysis displayed that patulin production was enhanced by brlA suppression, explaining a higher in vivo aggressiveness compared to the wild type (WT) strain. No patulin was detected in the synnemata, suggesting that patulin biosynthesis stopped when the fungus exited the apple. In vitro transcriptome analysis of PeΔbrlA unveiled an up-regulated biosynthetic gene cluster (PEXP_073960-PEXP_074060) that shares high similarity with the chaetoglobosin gene cluster of Chaetomium globosum. Metabolome analysis of PeΔbrlA confirmed these observations by unveiling a greater diversity of chaetoglobosin derivatives. We observed that chaetoglobosins A and C were found only in the synnemata, located outside of the apple, whereas other chaetoglobosins were detected in apple flesh, suggesting a spatial-temporal organization of the chaetoglobosin biosynthesis pathway. Full article
(This article belongs to the Special Issue Molecular Biology and Chemistry of Mycotoxins and Phytotoxins)
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Article
Aflatoxin B1 Induces Neurotoxicity through Reactive Oxygen Species Generation, DNA Damage, Apoptosis, and S-Phase Cell Cycle Arrest
Int. J. Mol. Sci. 2020, 21(18), 6517; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186517 - 06 Sep 2020
Cited by 10 | Viewed by 928
Abstract
Aflatoxin B1 (AFB1) is a mycotoxin widely distributed in a variety of food commodities and exhibits strong toxicity toward multiple tissues and organs. However, little is known about its neurotoxicity and the associated mechanism. In this study, we observed that brain [...] Read more.
Aflatoxin B1 (AFB1) is a mycotoxin widely distributed in a variety of food commodities and exhibits strong toxicity toward multiple tissues and organs. However, little is known about its neurotoxicity and the associated mechanism. In this study, we observed that brain integrity was markedly damaged in mice after intragastric administration of AFB1 (300 μg/kg/day for 30 days). The toxicity of AFB1 on neuronal cells and the underlying mechanisms were then investigated in the neuroblastoma cell line IMR-32. A cell viability assay showed that the IC50 values of AFB1 on IMR-32 cells were 6.18 μg/mL and 5.87 μg/mL after treatment for 24 h and 48 h, respectively. ROS levels in IMR-32 cells increased significantly in a time- and AFB1 concentration-dependent manner, which was associated with the upregulation of NOX2, and downregulation of OXR1, SOD1, and SOD2. Substantial DNA damage associated with the downregulation of PARP1, BRCA2, and RAD51 was also observed. Furthermore, AFB1 significantly induced S-phase arrest, which is associated with the upregulation of CDKN1A, CDKN2C, and CDKN2D. Finally, AFB1 induced apoptosis involving CASP3 and BAX. Taken together, AFB1 manifests a wide range of cytotoxicity on neuronal cells including ROS accumulation, DNA damage, S-phase arrest, and apoptosis—all of which are key factors for understanding the neurotoxicology of AFB1. Full article
(This article belongs to the Special Issue Molecular Biology and Chemistry of Mycotoxins and Phytotoxins)
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Article
verA Gene is Involved in the Step to Make the Xanthone Structure of Demethylsterigmatocystin in Aflatoxin Biosynthesis
Int. J. Mol. Sci. 2020, 21(17), 6389; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21176389 - 02 Sep 2020
Cited by 3 | Viewed by 738
Abstract
In the biosynthesis of aflatoxin, verA, ver-1, ordB, and hypA genes of the aflatoxin gene cluster are involved in the pathway from versicolorin A (VA) to demethylsterigmatocystin (DMST). We herein isolated each disruptant of these four genes to determine their [...] Read more.
In the biosynthesis of aflatoxin, verA, ver-1, ordB, and hypA genes of the aflatoxin gene cluster are involved in the pathway from versicolorin A (VA) to demethylsterigmatocystin (DMST). We herein isolated each disruptant of these four genes to determine their functions in more detail. Disruptants of ver-1, ordB, and hypA genes commonly accumulated VA in their mycelia. In contrast, the verA gene disruptant accumulated a novel yellow fluorescent substance (which we named HAMA) in the mycelia as well as culture medium. Feeding HAMA to the other disruptants commonly caused the production of aflatoxins B1 (AFB1) and G1 (AFG1). These results indicate that HAMA pigment is a novel aflatoxin precursor which is involved at a certain step after those of ver-1, ordB, and hypA genes between VA and DMST. HAMA was found to be an unstable substance to easily convert to DMST and sterigmatin. A liquid chromatography-mass spectrometry (LC-MS) analysis showed that the molecular mass of HAMA was 374, and HAMA gave two close major peaks in the LC chromatogram in some LC conditions. We suggest that these peaks correspond to the two conformers of HAMA; one of them would be selectively bound on the substrate binding site of VerA enzyme and then converted to DMST. VerA enzyme may work as a key enzyme in the creation of the xanthone structure of DMST from HAMA. Full article
(This article belongs to the Special Issue Molecular Biology and Chemistry of Mycotoxins and Phytotoxins)
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Review

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Review
Regulation of Secondary Metabolism in the Penicillium Genus
Int. J. Mol. Sci. 2020, 21(24), 9462; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21249462 - 12 Dec 2020
Viewed by 1137
Abstract
Penicillium, one of the most common fungi occurring in a diverse range of habitats, has a worldwide distribution and a large economic impact on human health. Hundreds of the species belonging to this genus cause disastrous decay in food crops and are [...] Read more.
Penicillium, one of the most common fungi occurring in a diverse range of habitats, has a worldwide distribution and a large economic impact on human health. Hundreds of the species belonging to this genus cause disastrous decay in food crops and are able to produce a varied range of secondary metabolites, from which we can distinguish harmful mycotoxins. Some Penicillium species are considered to be important producers of patulin and ochratoxin A, two well-known mycotoxins. The production of these mycotoxins and other secondary metabolites is controlled and regulated by different mechanisms. The aim of this review is to highlight the different levels of regulation of secondary metabolites in the Penicillium genus. Full article
(This article belongs to the Special Issue Molecular Biology and Chemistry of Mycotoxins and Phytotoxins)
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Review
Secondary Metabolites of the Rice Blast Fungus Pyricularia oryzae: Biosynthesis and Biological Function
Int. J. Mol. Sci. 2020, 21(22), 8698; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228698 - 18 Nov 2020
Cited by 2 | Viewed by 1047
Abstract
Plant pathogenic fungi produce a wide variety of secondary metabolites with unique and complex structures. However, most fungal secondary metabolism genes are poorly expressed under laboratory conditions. Moreover, the relationship between pathogenicity and secondary metabolites remains unclear. To activate silent gene clusters in [...] Read more.
Plant pathogenic fungi produce a wide variety of secondary metabolites with unique and complex structures. However, most fungal secondary metabolism genes are poorly expressed under laboratory conditions. Moreover, the relationship between pathogenicity and secondary metabolites remains unclear. To activate silent gene clusters in fungi, successful approaches such as epigenetic control, promoter exchange, and heterologous expression have been reported. Pyricularia oryzae, a well-characterized plant pathogenic fungus, is the causal pathogen of rice blast disease. P. oryzae is also rich in secondary metabolism genes. However, biosynthetic genes for only four groups of secondary metabolites have been well characterized in this fungus. Biosynthetic genes for two of the four groups of secondary metabolites have been identified by activating secondary metabolism. This review focuses on the biosynthesis and roles of the four groups of secondary metabolites produced by P. oryzae. These secondary metabolites include melanin, a polyketide compound required for rice infection; pyriculols, phytotoxic polyketide compounds; nectriapyrones, antibacterial polyketide compounds produced mainly by symbiotic fungi including endophytes and plant pathogens; and tenuazonic acid, a well-known mycotoxin produced by various plant pathogenic fungi and biosynthesized by a unique NRPS-PKS enzyme. Full article
(This article belongs to the Special Issue Molecular Biology and Chemistry of Mycotoxins and Phytotoxins)
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