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    Topic review

    Fusarium Cyclodepsipeptide Mycotoxins

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    Most of the fungi from the Fusarium genus are pathogenic to cereals, vegetables, and fruits, and the products of their secondary metabolism mycotoxins may accumulate in foods and feeds. Non-ribosomal cyclodepsipeptides are one of the main mycotoxin groups and include beauvericins (BEAs), enniatins (ENNs), and beauvenniatins (BEAEs).

    1. Introduction

    Fungi belonging to the Fusarium genus produce a wide range of secondary metabolites, including the non-ribosomal depsipeptide mycotoxins, such as beauvericins (BEAs), beauvenniatins (BEAEs), enniatins (ENNs), and their analogues [1][2][3][4]. BEAs, BEAEs, and ENNs were included in the cyclodepsipeptide group of compounds, often found in high concentrations in grains, crops, vegetables, fruits, and even eggs, as a result of fungal infection [5][6][7][8][9]. They are involved in plant-pathogen interaction and may lead to many plants′ diseases, which can be very dangerous for animals′ health, including humans [10][11][12][13][14]. For example, ENNs produced by Fusarium species may act synergistically as a phytotoxin complex, which causes wilt and necrosis of plant tissue [15]. Moreover, ENN B affects mouse embryo development by inducing the dosage-related apoptosis or necrosis in mouse blastocytes [16]. On the other hand, BEA demonstrated neurotoxic properties in mice. In higher concentrations (7.5 and 10 µM), it affected the skeletal muscle fibers [17].

    Additionally, BEA has a harmful influence on the reproductive system. The progesterone synthesis in cumulus cells was decreased when exposed to BEA [18]. Moreover, BEA inhibited estradiol and progesterone synthesis in bovine granulosa cells [19]. Also, ENN B reduced progesterone, testosterone, and cortisol secretion in human adrenocortical carcinoma cells and modulated the expression of genes involved in steroidogenesis [20]. The cytotoxicity of cyclodepsipeptides (BEAs, BEAEs, ENNs) is related to their ionophoric properties [21][22][23]. Even at low concentrations, they possess the capacity of perforation of the cell membrane, which is associated with the induction of apoptotic cell death and disruption of extracellular regulated protein kinase (ERK) activity [24][25][26][27]. However, this ability does not exclude the capability of promoting the transport of cations such as K+, Na+, Mg2+, and Ca2+ through the membranes, which leads to the disturbance of cellular ionic homeostasis [28]. This cytotoxic effect on various human cancer cell lines also suggests the potential use of cyclodepsipeptides as anti-cancer drugs [22][29][30][31][32]. All cyclodepsipeptides (BEAs, BEAEs, ENNs) have been shown as compounds exhibiting numerous biological activities, such as antimicrobial, insecticidal, and antibiotic activity, towards Mycobacterium tuberculosis and Plasmodium falciparum (human malaria parasite) because of their potential to inhibit the cholesterol acyltransferase of microbial origin [30][33]. Furthermore, BEA can be used as a co-drug for fungal infections in humans because the combination of BEA and ketoconazole (an anti-fungal drug) enhances its antifungal activities [29][33][34][35]. BEA has been reported as a growth inhibitor of human-pathogenic bacteria, such as Escherichia coli, Enterococcus faecium, Salmonella enterica, Shigella dysenteriae, Listeria monocytogenes, Yersinia enterocolitica, Clostridium perfringens, and Pseudomonas aeruginosa. The chemical properties of cyclodepsipeptides may allow for the emergence of new pharmaceutical products with anti-inflammatory and antibiotic properties [33][36][37]. The studies have shown the divergent impact of cyclodepsipeptides on human health; still, further studies are needed to indicate the potential effects of BEAs, BEAEs, and ENNs on human health. Moreover, it is imperative to study new compounds of the cyclodepsipeptide group, along with their analogues, to better understand the relationships between their structure, diversity, and toxicity.

    2. Chemistry

    BEAs, ENNs, BEAEs, and allobeauvericins (ALLOBEAs) represent a family of regular cyclodepsipeptides, consisting of three N-methyl amino acids and three hydroxy acid groups [4][38][39][40][41]. Characterization of all cyclodepsipeptides produced by Fusarium fungi, their elemental composition, molecular weights (used for their identification), and chemical structures are presented in Table 1 and Figure 1. Most of the BEAs contain three groups of N-methyl-phenylalanine, except for BEAs J, K, and L, which contain one, two, or three groups of N-methyl-tyrosine, respectively [2][26]. However, BEA D and E have demethylated amino acids-phenylalanine and leucine in their structures [42]. Moreover, BEAs differ in hydroxy acids possession. BEA and BEA D, E, J, K, and L possess D-2-hydroxyisovaleric acid (D-Hiv) (Figure 2a) and BEA A/F, B, and C possess D-2-hydroxy-3-methylpentanoic acid (D-Hmp) (Figure 2b), whereas BEA G1 and G2 possess D-2-hydroxybutyric acid (D-Hbu) (Figure 2c) [2][3][31][33][42]. ALLOBEAs A, B, and C are diastereomeric to BEAs A, B, and C, respectively. These compounds differ in the D-Hmp groups’ configuration [33]. Some of the BEAs, such as BEA B, C, J, K, L, G1, G2, and all ALLOBEAs, were known from previous publications as precursor-directed compounds, detected inside in vitro cultures of fungi belonging to Beauveria, Acremonium, and Paecilomyces genera [26][31][33]. It was proven that phytopathogenic fungi from the Fusarium genus naturally produce all BEAs and ALLOBEAs [2][3][42]. The structures of BEAs have been described in many articles, where they were determined by a variety of chemical methods, including liquid chromatography-mass spectrometry (LC-MS) and nuclear magnetic resonance (NMR).

    Figure 1. Chemical structures of beauvericin, enniatin, allobeauvericin, and beauvenniatin analogues produced by Fusarium species.

    Figure 2. Chemical structures of D-2-hydroxyisovaleric acid (D-Hiv) (a), D-2-hydroxy-3-methylpentanoic acid (D-Hmp) (b), and D-2-hydroxybutyric acid (D-Hbu) (c) groups.

    Table 1. Elemental composition and molecular weights of beauvericins, enniatins, and their analogues.

    Compound MW MW + NH4+ (18) MW + Na+ (23) MW + K+ (39) Elemental Composition
    Beauvericin 783 801 806 822 C45H57N3O9
    Beauvericin A/F/Allobeauvericin A 797 815 820 836 C46H59N3O9
    Beauvericin B/Allobeauvericin B 811 829 834 850 C47H61N3O9
    Beauvericin C/Allobeauvericin C 825 843 848 864 C48H63N3O9
    Beauvericin D 769 787 792 808 C44H55N3O9
    Beauvericin E 735 753 758 774 C41H57N3O9
    Beauvericin G1 769 787 792 808 C44H55N3O9
    Beauvericin G2 755 773 778 794 C43H53N3O9
    Beauvericin J 799 817 822 838 C45H57N3O10
    Beauvericin K 815 833 838 854 C45H57N3O11
    Beauvericin L 831 849 854 870 C45H57N3O12
    Beauvenniatin A 735 753 758 774 C41H57N3O9
    Beauvenniatin B 687 705 710 726 C37H57N3O9
    Beauvenniatin G1/G2/G3 715 733 738 754 C39H61N3O9
    Beauvenniatin L 749 767 772 788 C42H59N3O9
    Enniatin A/F/MK 1688 681 699 704 720 C36H63N3O9
    Enniatin A1/E/I 667 685 690 706 C35H61N3O9
    Enniatin A2 681 699 704 720 C35H61N3O9
    Enniatin B 639 657 662 678 C33H57N3O9
    Enniatin B1/B4/D/H 653 671 676 692 C34H59N3O9
    Enniatin B2/J2/J3/K1 625 643 648 664 C32H55N3O9
    Enniatin B3/J1 611 629 634 650 C31H53N3O9
    Enniatin P1 641 659 664 680 C33H57N3O10
    Enniatin P2 655 673 678 694 C34H59N3O10

    ENNs are typically composed of N-methyl-leucine, N-methyl-isoleucine and/or N-methyl-valine [1][10][41]. However, two of the ENNs: ENN P1 and P2 also possess N-methyl-tyrosine in their structures [21]. ENN J1, J2, and J3 are another group of ENNs that differ from the common ENNs. These cyclodepsipeptides consist of one N-methyl-isoleucine, one N-methyl-valine, and N-methyl-alanine [43]. Most ENNs contain three groups of D-2-hydroxyisovaleric acid (D-Hiv) and only three ENNs: ENN H, I, and MK 1688, containing one, two, or three groups of D-2-hydroxy-3-methylpentanoic acid (D-Hmp), respectively [44]. Some of the reported ENNs are isomers, with the same amino acid composition but in different positions, e.g., ENN J1, J2, J3 or ENN A and F [39][43][45]. On the other hand, even though the ENNs are not isomers, they share the same molecular weight. Therefore, the MS/MS technique with acid hydrolysis or NMR is sometimes necessary during the detection of cyclodepsipeptides for their correct identification.

    BEAEs possess hybrid structures between the aliphatic (enniatin-type) and aromatic (beauvericin-type) cyclodepsipeptides [2][3][26][30]. Moieties of N-methyl-phenylalanine, N-methyl-leucine, and/or N-methyl-valine are the parts of BEAEs’ structures. BEAE A contains one N-methyl-valine, whereas BEAE B, G1, G2, and G3 have two. BEAE L has one N-methyl-leucine in its structure. Apart from the D-2-hydroxyisovaleric acid (D-Hiv) group, three of the BEAE isomers, namely BEAE G1, G2, and G3, contain two D-2-hydroxy-3-methylpentanoic acid (D-Hmp) groups in different combinations. At first, all BEAEs were described as cyclodepsipeptides from Acremonium sp., however further research revealed that Fusarium species are also able to produce these compounds [2][3][26][30].

    3. Biosynthesis

    Cyclodepsipeptides are biosynthesized by a multi-domain non-ribosomal peptide synthase (NRPS) that is composed of enzymatic modules used to elongate the proteinogenic and non-proteinogenic amino acids, as well as carboxyl and hydroxy acids [48][49]. The modules respond to the order and number of the precursors incorporated into the chain. Separate NRPS modules are required to assemble the product and a minimal module consists of the three core domains: adenylation (A) domain, thiolation or peptidyl-carrier protein (T or PCP) domain, and condensation (C) domain. Moreover, each module and each active site domain is used only once for the recognition and activation of the precursors through adenylation with ATP (A: adenylation domain), covalent thioester tethering (T: thiolation or PCP: peptidyl carrier protein domain), which tethers the activated precursor to a 4′-phosphopantetheine (PP) cofactor through a thioester bond and transport substrates to the active sites of the domains, and condensation (C domain) of the precursors via catalyzing the peptide bond (C-N) formation between the elongated chain and the activated amino acid. The main domains may be supported by additional domains of the NRPS, such as the epimerization (E) domain, which catalyzes the transformation of an L-amino acid into a D-amino acid, or the dual/epimerization (E/C) domains, which catalyze the epimerization and condensation. NRPSs contain an additional reductase (R) domain, which is responsible for reducing the final peptide, the methylation (MT) domain, which catalyzes N-methylation of the amino acid substrate, the cyclization (Cy) domain that catalyzes the formation of oxazoline or thiazoline rings by internal cyclization of cysteine, serine, or threonine residues, and the oxidation (Ox) domain, which catalyzes the formation of an aromatic thiazol through oxidation of a thiazoline ring. The last domains (TE–thioesterase domains), mostly located at the final NRPS module, are responsible for releasing the full-length NRPS product from the enzyme through cyclization or hydrolysis [48][49][50][51][52].

    Enniatin biosynthesis is catalyzed by the 347 kDa multienzyme enniatin synthase (ESYN1) purified for the first time from Fusarium oxysporum and further characterized by Zocher and coworkers [53]. Extensive molecular research revealed the basis of cyclic oligopeptide biosynthesis and allowed us to identify esyn1, a gene encoding enniatin synthase, as the essential enzyme of the metabolic pathway [39][54][55][56][57]. The biochemical characterization revealed that the enzyme possesses two substrate activation modules EA and EB, composed of approximately 420 amino acid residues. The EA module activates and participates in binding the α-D-hydroxy acids, while the EB module activates the amino acids. These two modules consist of a conserved 4-phosphopantetheine binding site at the C-terminus, with a highly conserved serine residue. An additional 4-phosphopantetheine group and N-methyltransferase domain M are present in the EB module. Also, a putative condensation (C) domain exists between the EA and EB modules. The M domain is highly conserved among N-methyl peptide synthases of prokaryotic and eukaryotic origin, thus it represents only local sequence similarities to the structural elements of other AdoMet-dependent methyltransferases. A dipeptidol unit is formed due to the interaction between the EA and EB modules and later, it is transferred and condensed into a thiol group. Three such successive condensations of the enzyme-bound dipeptidols are followed by the ring′s closure into the enniatin (ENN) molecule [4][58][59][60][61] (Figure 3A,B).

    Figure 3. Mechanism of enniatin B formation according to Hornbogen et al. [4]. (A) Scheme of partial reactions leading to the formation of ENN B, P1, P2, P3 = 4′-phosphopantetheine. (B) Model of the arrangement of catalytic sites in enniatin synthase; Cy: cyclization cavity; EA: D-Hiv-activation module; EB: L-valine-activation module; M: N-methyltransferase domain.

    The primary precursors of the ENNs are valine, leucine or isoleucine, D-2-hydroxyisovaleric acid, and S-adenosylmethionine and their synthesis is entirely dependent on the cyclization reaction of linear hexadepsipeptide. The amino acid specificity of ESYN1 contributes to the chemical diversity of ENNs and this is why different types of ENNs are produced by Fusarium scirpi, F. lateritium, and F. sambucinum. The Esyn domains activating L-valine in F. scirpi and preferably activating L-isoleucine in F. sambucinum are nearly identical, with an exception of the three regions showing significant differences in their structures. This difference in the activation can be accredited to the mutations that eventually occurred in the amino acid recognition sites of various enniatin synthases. In spite of the variability in amino acid units, certain ENNs can only be isolated from specific Fusarium strains, in which the enniatin synthase prefers some amino acids over others during biosynthesis [4][53][62][63][64][65].

    BEAs are also formed as cyclic trimers assembled from three D-Hiv-N-methyl-L-amino acid dipeptidol monomers (Figure 4A) [50][51]. Similarly, they are also produced by a thiol template mechanism and synthesized by beauvericin synthase (BEAS) enzyme, which consists of a single polypeptide chain of about 351 kD [41][50]. For the first time, the 250 kDa BEAS enzyme was characterized by Peeters et al. [66] from the entomopathogenic fungus Beauveria bassiana, although Xu et al. [50], who conducted a more in-depth analysis, described a 33,475 bp beauvericin gene cluster including a 9570 bp bbBeas gene. Five years later, Zhang and coworkers [51] cloned and characterized 9413 bp beauvericin synthase gene (fpBeas) from Fusarium proliferatum.

    Figure 4. Biosynthesis of fungal cyclodepsipeptides (A) and model of beauvericins (BEAS) synthase structure with domain roles (domains not to scale) (B) according to Xu et al. [50][52].

    The C1, A1, and T1 domains within the first module of FpBEAS and ESYN (EA module) synthases have the same role in cyclodepsipeptide formation [51]. Nevertheless, the two depsipeptide synthases differ in A2 domain substrate specificity within module 2 (ESYN EB module), i.e., apart from that of enniatin synthase, beauvericin synthase preferably accepts N-methyl-L-phenylalanine and some other aliphatic hydrophobic amino acids (e.g., leucine or isoleucine) [50]. Furthermore, their incorporation efficiency reduces with the length of side chains, where ortho-, meta-, and para-fluoro-substituted phenylalanine derivatives and N-methyl-L-leucine, N-methyl-L-norleucine, and N-methyl-L-isoleucine residues could replace N-methyl-L-phenylalanine. Domains C2, T2a;b, M2, and C3 within module 2 of BEAS and ESYN play the same role in both synthases (Figure 4B) [50][56].

    The depsipeptides, including BEAs, have a common 2-hydroxycarboxylic acid ingredient–D-2-hydroxyisovalerate (D-Hiv) that is formed from 2-ketoisovalerate (2-Kiv) by a highly specific chiral reduction reaction catalyzed by 2-ketoisovalerate reductase (KIVR) enzyme [50][52][67][68][69][70]. KIVR has a significant role in the biosynthesis of BEAs as was clearly understood when BEA production was inhibited in a KIVR knock-out B. bassiana mutant [67]. Kiv is formed from pyruvate during the biosynthesis of valine and it is the key intermediate in several metabolic pathways, including pantothenate biosynthesis in fungi, bacteria, and plants. It is also involved in producing phosphopantetheinyl prosthetic groups of acyl or peptidyl carrier proteins and co-enzyme A (Figure 5) [50][52][67][69][70].

    Figure 5. Synthesis of 2-ketoisovalerate (Kiv), a substrate used in the formation of D-2-hydroxyisovaleric acid (D-Hiv) moiety by 2-ketoisovalerate reductase (KIVR) according to Xu et al. [67]. BCAAT: branched-chain amino acid aminotransferase.

    Significant sequence homologies were identified for certain Fusarium enzymes, which shows a common genetic background for the synthesis of both depsipeptide compounds. Zhang et al. [51] revealed in their analysis that FpBEAS (GenBank acc. no. JF826561.1) has 64% identity to ESYN (GenBank acc. no. CAA79245) as it was proven that some Fusarium species, like F. poae, F. proliferatum, or F. oxysporum were found to produce ENNs and BEA simultaneously. This is justified by the fact that both toxins share a metabolic pathway [1][44][71][72]. Reports suggest that there is a high probability that the single PCR based esyn1- and/or BEAS- specific marker can detect potential BEAs and ENNs-producing fungi from contaminated soil and plant material [39][55][73].

    4. Fusarium Species and Cyclodepsipeptide Mycotoxins in Food and Feed

    Plant crops are critical mainly in terms of yield and diverse use for foods and feeds. They suffer from a range of fungal diseases and Fusarium species are among the most damaging pathogens, producing toxic secondary metabolites, such as cyclodepsipeptides. Cyclodepsipeptides biosynthesis has been observed for 44 Fusarium species (Table 2) and F. acuminatum, F. concentricum, F. proliferatum, F. verticillioides, F. oxysporum, and F. tricinctum produce a broad spectrum of ENN, BEA, and BEAE analogues. The remaining Fusarium species formed only individual mycotoxin groups, such as BEA, ENNs, or a mixture of these. However, in a few research papers, it was not specified which Fusarium species produced ENNs and the presence of mycotoxins was described as a “mix of ENNs” (Table 2).

    Table 2. Cyclodepsipeptides mycotoxins produced by various Fusarium species.

    Fusarium species can cause many plant diseases and one of them is Fusarium head blight (FHB), which is devastating for cereal species, particularly as it is a major problem regarding wheat production in many countries. Usually, one or more Fusarium species (F. graminearum, F. culmorum, F. avenaceum, F. poae, and F. sporotrichioides) are involved as causal agents [74]. The occurrence of many Fusarium species may increase the accumulation of mycotoxins in grains or plants and introduce them into the food chain [71][75][76]. Humidity and temperature determine the disease severity, but geographical conditions, plant genotype, and local pathogen populations also play essential roles [54][77].

    Available literature data relate both to identifying Fusarium fungi isolated from various hosts and analyzing their mycotoxin biosynthesis capacity (Table 3). Efforts are also being made to assess contamination levels with these toxins of raw plant materials and food and feed products (Table 4). Mainly, the content of BEA and four ENNs (ENN A, ENN A1, ENN B, ENN B1) has been investigated [8][25]. BEA and ENNs are common contaminants and were detected in plant crops and grains throughout the world. The occurrence of BEA, ENN A, ENN A1, ENN B, and ENN B1 in naturally contaminated crops has been studied much more extensively than the occurrence of other cyclodepsipeptides [1][39]. Table 3 summarizes the most effective producers of depsipeptides among Fusarium fungi isolated from different crops and geographical areas. F. avenaceum, F. equiseti, F. proliferatum, and F. sporotrichioides were the most common species isolated from plants. The best producer of BEA was F. proliferatum (FPG61_CM), isolated from garlic in Spain, with the concentration reaching 671.80 μg/g [6]. The highest yielding producers of ENNs were F. avenaceum (KF1330), isolated from wheat in Poland, and F. tricinctum (3405), isolated from wheat in Finland [5][39]. Both strains produced in the highest amounts ENN B (895.46 μg/g, 690 μg/g) and ENN B1 (452.46 μg/g, 1200 μg/g) [5][39].

    Table 3. The strains of Fusarium species from different origins and hosts, producing the highest amounts of cyclodepsipeptides [μg/g].

    Table 4. Maximum levels [μg/g] of naturally occurring depsipeptides in foods and feeds from different countries.

    “ND”—not detected; “NA”—not analyzed.

    Table 4 presents the maximum amounts of BEA and ENNs in naturally contaminated plant crops described in the literature. The highest contamination level of BEA was found to be 1731.55 μg/g in Polish maize [95]. When compared to other cyclodepsipeptides, it was also the highest concentration of mycotoxin in crops. In Tunisian sorghum, maximum concentrations of ENN A (95.6 μg/g) and ENN B1 (120.1 μg/g) were detected [96]. The highest amount of ENN A1 was 813.01 μg/g and 814.42 μg/g in Spanish maize and rice, respectively [97]. ENN B was found with a maximum level of 180.6 μg/g in Tunisian wheat [96]. The data show very high variability of investigated cyclodepsipeptides and it can be concluded that each strain of Fusarium species possesses a unique ability to biosynthesize these compounds. In addition to crops, cyclodepsipeptides are also found in food and feed [98][99][100][101][102][103]. Cyclodepsipeptides were identified mainly in cereal food, with very high levels of ENN A1 and B1 in breakfast cereals from Morocco (668 and 795 μg/g, respectively) [99]. In feed samples, ENNs and BEA levels were very low and did not exceed 0.48 μg/g for BEA (poultry feed) and 2.19 μg/g for ENNs (poultry feed) [101].

    The entry is from 10.3390/toxins12120765


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