Chemistry and Biology of Mycotoxins and Related Fungal Metabolites
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Chem. Rev. 2009, 109, 3903–3990 3903 Chemistry and Biology of Mycotoxins and Related Fungal Metabolites Stefan Bra¨se,* Arantxa Encinas,† Julia Keck,‡ and Carl F. Nising§ Institut fu¨r Organische Chemie, Karlsruhe Institute of Technology, Fritz-Haber-Weg 6, D-76131 Karlsruhe, Germany Received October 1, 2007 Contents 1. Introduction 1. Introduction 3903 Nature produces a variety of different species, prokaryotes 1.1. Occurrence of Mycotoxins 3905 and eukaryotes. Among them, fungi play a very important, 1.2. Toxicology/Mycotoxicoses/Risks 3905 but yet mostly unexplored role. Their widespread occurrence 1.2.1. Aflatoxins 3906 on land and in marine life makes them a challenge and a risk for humans. 1.2.2. Ochratoxins 3906 1.2.3. Trichothecenes 3906 During their lifespan, fungi metabolize and produce a broad range from simple to very complex organic com- 1.2.4. Fumonisins 3906 pounds. Most of them exhibit certain biological activities. 1.2.5. Patulin 3907 However, a specific characteristic is the production of toxins. 2. Total Synthesis 3907 Mycotoxins (from “myco” fungus and toxin) are nonvolatile,1 2.1. Aflatoxins 3935 relatively low-molecular weight,2 fungal3 secondary meta- 2.2. Citrinin 3938 bolic products that may affect exposed vertebrates such as 2.3. Ergot Alkaloids 3939 animals in a variety of ways. In contrast, other metabolites 2.4. Fumonisins 3939 such as penicillins, only (or mainly) affecting prokaryotes 2.5. Ochratoxin 3942 or other eukaryotes, are in general not classified as mycotoxins. 2.6. Patulin 3945 Mycotoxins are considered secondary metabolites because 2.7. Trichothecenes 3946 they are not necessary for fungal growth and are simply a 2.7.1. Introduction 3946 product of primary metabolic processes. The functions of 2.7.2. Total Syntheses of the Sesquiterpenoid 3948 mycotoxins have not been clearly established, but they are Core believed to play a role in eliminating other microorganisms 2.7.3. Macrocyclic Trichothecenes 3949 competing in the same environment. They are also believed 4 2.7.4. Other Small Trichothecenes 3952 to help parasitic fungi invade host tissues. The amount of 2.8. Zearalenone and Related Macrolactones 3952 toxins needed to produce adverse health effects varies widely among toxins, as well as within each person’s immune 2.9. Other mycotoxins 3956 system. 2.9.1. Alternaria metabolites 3956 2.9.2. Skyrins 3958 Some mycotoxins are carcinogenic, some are vasoactive, and some cause central nervous system damage. Often, a 2.9.3. Xanthones 3960 single mycotoxin can cause more than one type of toxic 2.9.4. Cytochalasans 3961 effect. We will discuss this briefly in section 1.2. 2.9.5. Peptidic Mycotoxins 3963 Fungi that produce mycotoxins are referred to as toxigenic 3. Biosynthesis 3964 fungi. The most frequently studied mycotoxins (see Table 3.1. Polyketide-Derived Mycotoxins 3964 2) are produced by species of Aspergillus, ClaViceps,5 3.2. Terpenoid Mycotoxins 3968 Fusarium, Penicillium,6 Stachybotrys, and Myrothecium.7 3.3. Mycotoxins Incorporating Amino Acids 3968 However, toxins have been detected from many other fungi 3.3.1. Mixed Biosynthesis 3969 under certain growth conditions. An important and steadily 3.3.2. Directed Biosynthesis 3970 increasing number of natural products have been isolated 4. Structure-Activity Relationships 3970 from marine8 and pathogenic insecticidal fungi.9 In most 5. Mycotoxins and Related Compounds As Potential 3974 cases, the toxicology has not yet been fully elaborated, and Therapeutics thus, their status remains unclear. We have included the most 6. Conclusions/Summary 3975 important fungal metabolites in this review. The type and 7. Abbreviations 3975 amount of toxin produced depends on the fungal strain, the 8. Acknowledgments 3975 growing conditions, and the presence or absence of other 9. References 3975 organisms. Fungi may be classified by the humidity, Xerophiles (e.g., Aspergillus restrictus, A. glaucus, A. Versicolor) and Hy- * To whom correspondence should be addressed. Fax +49 721 608 8581. grophiles (e.g., Cladosporium, Fusarium, Mucorales), or by E-mail: [email protected].. temperature, Thermophiles (e.g., Byssochlamys, Aspergillus † New address of A.E.: Elara Pharmaceuticals, Heidelberg, Germany. ‡ New address of J.K.: Evonik Degussa, Rheinfelden, Germany. fumigatus), Thermotolerants (e.g., Aspergillus niger), Me- § New address of C.N.: Bayer Cropscience, Monheim, Germany. sophiles (e.g., Penicillium chrysogenum, P. expansum, P. 10.1021/cr050001f CCC: $71.50 2009 American Chemical Society Published on Web 06/17/2009 3904 Chemical Reviews, 2009, Vol. 109, No. 9 Bräse et al. Stefan Bra¨se was born in Kiel, Germany, in 1967. After he studied in Arantxa Encinas Lo´pez was born in Madrid, Spain, in 1977. She studied Go¨ttingen, Bangor (U.K.), and Marseille, he received his Ph.D. in 1995, at the Autonoma University of Madrid and received her Ph.D. in 2006 at after working with Armin de Meijere in Go¨ttingen. After postdoctoral the Medicinal Chemistry Institute of CSIC in Madrid (Ana Castro). After a appointments at Uppsala University (Jan E. Ba¨ckvall) and The Scripps postdoctoral appointment at Karlsruhe University (Stefan Bra¨se), she joined Research Institute, La Jolla (K. C. Nicolaou), he began his independent as a postdoctoral fellow in the Chemical Biology core department of EMBL research career at the RWTH Aachen, Germany, in 1997 (associated to in Heidelberg (Joe Lewis). Since January 2009, she is working as medicinal Dieter Enders). In 2001, he finished his Habilitation and moved to the chemist in Elara pharmaceuticals GmbH on the design and synthesis of University of Bonn as professor for organic chemistry. Since 2003, he is pharmacologically active compounds as novel and efficacious medicines full professor at the University of Karlsruhe, Germany. He is recipient for the treatment of cancer. Her research focuses on medicinal chemistry, (among other awards) of the OrChem award of the GDCh and the Lilly including the synthesis of natural products and small molecules with award. His research interests include methods in drug discovery (including biological activity and combinatorial chemistry. drug delivery), combinatorial chemistry towards the synthesis of biologically active compounds, and total synthesis of natural products and nanotechnology. Carl Nising was born in 1979 in Troisdorf, Germany. He studied chemistry at the University of Bonn, where he received his diploma degree in 2003. He then moved to the University of Karlsruhe (TH), where he obtained Julia Keck, née Gall, was born 1980 in Ludwigshafen/Rhein, Germany, his Ph.D. under the supervision of Stefan Bra¨se in 2006. After performing in 1980. She studied chemistry at the University of Karlsruhe, where she postdoctoral studies at Harvard University with Andrew G. Myers, he joined received her diploma degree in 2004. During her graduate studies in the Bayer CropScience AG in late 2007, where he is currently head of research group of Stefan Bra¨se, she worked on the total synthesis of laboratory in fungicide research. His research interests are natural product pharmacologically active natural products. After completing her Ph.D. work chemistry, heterocyclic chemistry, and the development of new synthetic in 2007, she joined Evonik Degussa GmbH as R&D scientist (Innovation methods. His research was supported by fellowships of the Studienstiftung Management Silanes). Her research interests include asymmetric catalysis, des Deutschen Volkes and the Scheringstiftung. Additionally, he was natural product chemistry, and synthesis of organometallic compounds. recipient of the Klaus Grohe Prize and the Wolff&Sohn Award. In this review, the chemistry such as the total synthesis cyclopium, Aspergillus Versicolor, A. flaVus, A. nidulans, A. and semisynthesis of the most important mycotoxins is fumigatus), and Cryophiles (e.g., Cladosporium, Alternaria). discussed.12 Some aspects have been reviewed earlier.13-17 Mycotoxins accumulate on fungal spores, cell fragments, Many secondary metabolites have been isolated from and substrates (nutrient sources). Although the toxic effects fungi; however, since mycotoxins are always affiliated with of fungal metabolites have been known for centuries (St. biological activity, this is a requirement to be considered in Anthony’s fire), nowadays the threat of adverse effects from this review. If a member of a structural class is recognized mycotoxins has gained dramatic importance due to the as a mycotoxin, the whole group is mentioned (e.g., reduced application of antifungal treatment on food.10 anthraquinones). While mycotoxins with particular signifi- cance in terms of food safety18 and human health are According to the literature, far more than 400 mycotoxins discussed in detail, less abundant and rare mycotoxins are are produced by some 350 species of fungi.11 However, we only mentioned briefly. Since the biosynthesis of mycotoxins found a significantly higher number of relevant bioactive/ is an important issue, we will outline the current status toxic fungal metabolites: around 1000 compounds are (section 3). Recent studies (by Hertweck and colleagues) presented in this review. have demonstrated that some mycotoxins (rhizoxin and Mycotoxins and Related Fungal Metabolites Chemical Reviews, 2009, Vol. 109, No. 9 3905 To illustrate the variety of mycotoxins produced by fungi, Table 2 shows the mycotoxins produced by Aspergillus sp. As a general overview, Table 3 includes all relevant mycotoxins and some related fungal metabolites (with alternate name, putative stereochemistry/sign