Beauvericin

Valinomycin and the Enniatins. Neutral ionophores such as the cycHc dodecadepsipeptide valinomycin [2001-95-8] C H QN O g, (Fig. 8) from StreptomjcesJulvissimus (179), and the cycHc hexadepsipeptides enniatin [11113-62-5] and beauvericin [26048-05-5] from fungi (180—182),... 

Fig. 8. Stmcture of (a) valinomycin and (J3) and enniatins and beauvericin. Hov = a-hydroxy-isovaleric acid and Lac = lactic acid. The /V-methylamino acid for enniatin A is isoleucine enniatin B, valine enniatin C, leucine and beauvericin, phenylalanine.

The enniatins enniatin A [2503-13-17, C gH N Og, enniatin B [917-13-5] C23H yN202, enniatin C [19893-23-3], C Hg N Og, and beauvericin (Fig. 8) are 700—800 molecular weight cycHc hexadepsipeptides. They form valinomycinlike hydrophilic cavities surrounded by outer lipophilic regions, but they have more flexible stmctures than those seen with valinomycin and therefore have less specificity for potassium over sodium ion than valinomycin (186,187). 

C domains can display functions that deviate from typical amide bond formation. Several C domains are postulated to act as ester synthases, catalyzing ester formation instead of amide formation. NRPS modules containing C domains that display this activity are present in the biosynthetic pathways for the kutznerides, cryptophycins, " cereulide, valinomycin, hectochlorin, and beauvericin. Each of these C domains likely utilizes a PCP-bound a-hydroxyl acceptor in the condensation reaction. Another NRPS C domain that catalyzes ester bond formation is involved in the biosynthesis of the polyketide-derived mycotoxins known as the fiimonisins. Du and coworkers have shown that a recombinant PCP-C didomain of an NRPS involved in the biosynthetic pathway of the fnmonisins can catalyze ester bond formation between hydroxyfumonisins and the A-acetylcysteamine thioester of tricarballylic acid, even though PCP-bound tricarballylic acid is not... 

Recently, bacterial NRPS modules with the organization of A-KR-PCP have been discovered in the valino-mycin and cereulide synthetases. The A domains of these modules selectively activate a-keto acids. After the resulting adenylate is transferred to the PCP domain, the a-ketoacyl- -PCP intermediate is reduced to a PCP-bound, a-hydroxythioester by the KR domain. These domains use NAD(P)H as a cofactor and are inserted into A domains between two conserved core motifs analogous to MT domains. Their substrate specificity differs from that of polyketide synthase KR domains, which reduce /3-ketoacyl substrates. Similar fungal NRPSs, such as beauvericin synthetase, utilize A domains that selectively activate a-hydroxy acids. These molecules are thought to be obtained using an in trans KR domain, which directly reduces the necessary, soluble a-keto acid. 

Fumonisins, fusaric RAPD marker PCR acid, fusarin C, moniliformin, naphdioquinone pigments, beauvericin... 

Fumonisins, beauvericin, moniliformin, naphthoquinone pigments, fusaric acid, fusarin C, gibebyrones see fumonisin producers... 

Enniatins belong to the class of A-mcthylatcd cyclopeptides which are produced by various strains of the genus Fusarium [12], As shown in Figure 1, enniatins consist of alternating residues of D-2-hydroxyisovaleric acid (D-Hiv) and a branched chain A-methyl-L-amino acid, linked by peptide and ester bonds. In the case of beauvericin the branched chain L-amino acid is substituted by L-phenylalanine (Fig. 1). 

Figure 1 Structures of enniatins and beauvericin. Enniatin A, R, = R2 = R3 = sec-butyl enniatin Al, Ri = isopropyl, R2 = R3 =. sec-butyl enniatin B, R3 = R2 = R3 = isopropyl enniatin Bl, Ri = R2 = isopropyl, R3 =. sec-butyl beauvericin, Ri = R2 = R3 = benzyl.

Beauvericin is a structural homolog of enniatins in which the branched-chain L-amino acid is substituted by the aromatic amino acid L-phenylalanine. Beauvericin synthetase, which has been isolated from the fungus Beauveria bassiana [54] and various strains of Fusaria [55], strongly resembles Esyn with respect to its molecular size and the reaction mechanism. In contrast to Esyn, which is only able to incorporate aliphatic amino acids, beauvericin synthetase exhibits high substrate specificity for aromatic amino acids such as phenylalanine. This capability is obviously caused by mutational alterations in the adenylation domain of this enzyme. 

Recently, two new beauvericins were discovered [56], These beauvericins are composed of L-phenylalanine, D-2-hydroxy-3-methyl-valerate, and D-2-hydroxyisovalerate, yielding mixed-type structures. 

Cyclosporins, produced by the filamentous fungus Tolypocladium niveum and by numerous strains of Fusaria and Neocosmospora, are a class of cyclic undecapep-tides which are composed of hydrophobic aliphatic amino acids [73-75], They exhibit antiinflammatory, immunosuppressive, antifungal, and antiparasitic properties [74], The main metabolite, cyclosporin A, is in clinical use worldwide under the trade name SANDIMMUN to prevent allograft rejection [77,78], Besides cyclosporin A, there are 24 naturally occuring cyclosporins which have substitutions of amino acids in positions 1, 2, 4, 5, 7, and 11 and/or contain unmethylated peptide bonds in positions 1,4,6,9,10, or 11 [79-82], Cyclosporin A contains three nonproteinogenic amino acids D-alanine in position 8, L-a-aminobutyric acid in position 2, and, in position 1, the unusual amino acid 4(R)-4-[(E)-2-butenyl]-4-methyl-L-threonine (Bmt) (Fig. 8). All three amino acids have to be synthesized by a pathway independent of the primary metabolism. In addition, several peptide bonds of the cyclosporin molecule are A -mcthylated similar to the depsipeptides enniatin, beauvericin and PF1022A-related peptides. 

JF Grove, M Pople. The insecticidal activity of beauvericin and the enniatin complex. Mycopathologia 70 103-105, 1980. 

H Peeters, R Zocher, N Madry, PB Oelrichs, H Kleinkauf, G Kraepelin. Cell-free synthesis of the depsipeptide beauvericin. J Antibiot 36 1762-1766, 1983. 

A Logrieco, A Moretti, G Castella, M Kostecki, P Golinski, A Ritieni, J Chelkow-ski. Beauvericin production by Fusarium species. Appl Environ Microbiol 64 3084-3088, 1998. 

S Gupta, C Montilor, Y Hwang. Isolation of novel beauvericin analogues from the fungus Beauveria bassiana. J Natural Prod 58 733-738, 1995. 

A. Logrieco A. Moretti A. Ritieni M. F. Caiatfa L. Macchia, Beauvericin Chemistry, Biology and Significance. In Advances in Microbial Toxin and Its Biotechnological Exploitation R. K. Upadhyay, Ed. Kluwer Academic, Plenum Publishers New York, 2002 pp 23-30. 

Pocsfalvi, G., Dilanda, G., Ferranti, P. et al. (1997) Observation of non-covalent interactions between beauvericin and oligonucleotides using electrospray ionization mass spectrometry. Rapid Commun. Mass Spectrom., 11 (3), 265-72. 

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