Enniatins

The enniatins belong to the class of complexones (ionophores) they transport metal ions through membranes including those in bacterial cell walls and have, therefore, antibiotic properties (see Chap. 9). 

Fischer, E. Foumeau, Uber einige Derivate des Glykokolls Ber. dtsch. Chem. Ges. 34 2868-2879 

Sanger, The arrangement of amino acids in proteins, Advan. Protein Chem. 7 1-67 (1952) 

Fruton, Early theories of protein structure, Annals New York Acad. Sci. 325 1-18 (1979) 

Troensegard, Uber die Struktur des Proteinmolekiils eine chemische Untersuchung, E. Munksgaard, Kopenhagen, 1942 

---

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). 

Enniatin A [11113-62-5] M 681.9, m 122-122.5", [a]Jj -92 (c 0.9, CHCI3). A cyclic peptidic ester antibiotic which is recrystd from EtOH/water but is deactivated in alkaline soln. [Ovchinnikov and Ivanov in The Proteins (Neurath and Hill eds) Academic Press, NY, Vol V pp. 365 and 516 7952.]... 

With respect to the carrier mechanism, the phenomenology of the carrier transport of ions is discussed in terms of the criteria and kinetic scheme for the carrier mechanism the molecular structure of the Valinomycin-potassium ion complex is considered in terms of the polar core wherein the ion resides and comparison is made to the Enniatin B complexation of ions it is seen again that anion vs cation selectivity is the result of chemical structure and conformation lipid proximity and polar component of the polar core are discussed relative to monovalent vs multivalent cation selectivity and the dramatic monovalent cation selectivity of Valinomycin is demonstrated to be the result of the conformational energetics of forming polar cores of sizes suitable for different sized monovalent cations. 

Fig. 23. Space filling model of the Enniatin B—K + complex after the crystal structure 103). Since the carbonyl moieties coordinating the cation are similar for Enniatin B and Valinomycin, the difference in selectivities must arise due to the energetics of the conformations required to achieve coordination of the cation...

A. lCBr titration of Enniatin B in methanol. Since exchange of cation between solution and carrier is relatively rapid only one signal is seen per chemically distinct carbonyl. The titration shows the magnitude of the chemical shift observed. Since Enniatin B may be considered a cyclic analogue of Gramicidin A, these chemical shifts indicate the magnitudes of chemical shifts that can be expected in the Gramicidin A channel (see Fig. 6 and 13) for direct interaction of carbonyl with cation. 

Fig. 16. The antibiotic ligands (a) monensin, which binds Na+ selectively, and (b) valinomycin and (c) enniatin-B, which bind K+ selectively.

Nicholson P, Simpson D R, Wilson A H, Chandler E and Thomsett M (2004), Detection and differentiation of trichothecene enniatin-producing Fusarium species on small-grain cereals , Europ. J. Plant Pathol., 110, 503-514. 

The symmetrical ring enniatin (304) forms a potassium complex (Figure 9.3) whose crystal structure indicates that the cation is contained in the macrocyclic cavity and is coordinated by the six carbonyl oxygen atoms which are orientated such that three lie above and three lie below the main plane of the molecule (Dobler, Dunitz Krajewski, 1969). Apart from those just discussed, it needs to be noted that a range of other structures of antibiotic molecules and their metal complexes have been determined (Hilgenfeld Saenger, 1982). 

Figure 9.3. The potassium complex of enniatin B (from Fenton, 1977).

Stability constants, measured in methanol solution, for alkaline earth complexes of a number of ionophores are given in Table XVI (280,289,571-577).8 The values for the complexes of valinomycin and enniatin B lie between the values for the crown ethers 15C5 and 18C6 (cf. Section II.C.5 above), for the middle four entries the values are slightly higher. Stabilities of enniatin B complexes show a modest maximum for Ca2+, and of valinomycin complexes show stabilities increasing up to Ba2+ (281). LogAi values for the Ca2+ complexes of acetate, benzoate, and salicylate are between 4.5 and 4.7 in methanol (578) - the... 

Similarly, iterative NRPSs operate in a linear fashion but utilize at least one domain or module multiple times for the synthesis of a single NRP product. Thus, peptides assembled by iterative synthetases contain short, repeating units of peptide building blocks. In such systems, the terminal PCP-TE (or infrequendy PCP-C) didomain is responsible for both condensation of the repeating peptide units and chain release from the assembly line. NRPs biosynthesized in this manner include enniatin, enterobactin, bacillibactin, " gramicidin and the depsi-peptides valinomycin and cereulide. Of these examples, condensation of the precursor peptides for both enterobactin and gramicidin S has been extensively studied and will be discussed in detail. 

In a limited number of NRPSs, the final module terminates in a specialized C domain that catalyzes chain release through amide bond formation. Modules of this type are found in the synthetases involved in the biosynthesis of enniatin, vibriobactin, cyclosporin/ HC-toxin/ and PF1032A. Unlike TE termination, this method of chain release does not utilize an acyl-ester intermediate. Most likely, the chain termination precursor is presented to the C domain as an aminoacyl-5-PCP substrate. Most of these specialized C domains... 

Another molecule selective for potassium is enniatin B, a cydohexa-depsipeptide with an eighteen-atom ring, (VII). In the crystals of the potassium iodide complex KI, (VII) (62), the disordered iodide ions are... 

The alkali metal cation complexes of compounds of the valino-mycin group (valinomycin, enniatins, macrotetrolides, beauveridn, antamanide) are positively charged. 

Of the neutral ligands described in Section 2, the macrotetrolides and the macroheterobicyclic ligands form nearly spherical complexes and the depsipeptides valinomycin and enniatin B approximately cylindrical ones (Table l)6). Calculations of AGk-values for both kinds of complex show that the discrimination between mono- and divalent cations is dependent not only on the coordination number but also on the overall size and shape of the complexed ligand, because the electrostatic interaction of the complex with the surrounding medium (term AGs in Eq. 

---