The Enniatin Ionophores. Conformation and Ion Binding Properties

Abstract

The ability of enniatins to bind alkali metal, alkaline earth metal and certain transition metal ions in solution has been investigated. The complexes have been shown to form in 1:1, 2:1 and 3:2 macrocycle:cation ratios; their stability constants have been determined, and the conditions favoring their formation have been established. The enniatins were shown to be complexones of very wide spectrum, displaying low metal ion selectivity in alcoholic solutions. Two basic spatial forms, the non‐symmetric N3 form (in nonpolar solvents) and the symmetric P form (in polar solvents) have been disclosed and proposals made as to their conformational parameters. The molecular structure of the enniatin complexes has been established. Independent of the complexed ion species, of the complex stoichiometry, or of the type of solvent, the enniatin backbone of the complex is in the P form. In the 1:1 complexes, the ion is accommodated in the molecular cavity, forming iondipole bonds with all the amide and ester carbonyls. The depsipeptide chain of the enniatins is flexible, permitting “adaptation” of the complexone to the size of the ion, and thus explaining the low selectivity of these complexones. In the 2:1 and 3:2 complexes the cation is sandwiched in between two molecules of the antibiotic at the symmetry axis and interacts mainly with the N‐methylamide carbonyls. In these “sandwich” complexes the cation is much better screened from the anion and solvent than in the equimolar complexes and is highly soluble in organic solvents. The data presented here may serve as basis for interpreting the dependence between the structure, metal complexing behavior and membrane‐affecting properties in the series of the naturally occurring enniatin ionophores and their synthetic analogs.

Optimization of Enniatin Production by Solid-Phase Fermentation of Fusarium tricinctum

“…Due to ionophoric properties, enniatins have been shown to have insecticidal activity as well as antimycobacterial activity, one of the most potent being enniatin B (Ovchinnikov et al, 1974;Lifson et al, 1984;Visconti et al, 1992;Doebler, 2000;Firáková et al, 2007). They inhibit various enzymes, e.g.…”

Effects of the anthelmintic drug PF1022A on mammalian tissue and cells

“…This was based on a significant depolarisation of the mitochondrial membrane potential, which is an important step to trigger programmed cell death, after 48 h PF1022A treatment with 10 µM [50]. Moreover, several characteristics of programmed cell death like cell shrinkage, chromatin condensation and apoptotic body formations were observed after 48 h drug treatment with 10 µM PF1022A.…”

“…This strongly suggests that PF1022A is a potential channelforming ionophore. Moreover, formation of a sandwich complex can be postulated similar to the cyclohexadepsipeptides beauvericin [49] and enniatin [50]. Through such PF1022A-induced membrane spanning pores, ions are able to diffuse at both directions following their electrochemical gradient.…”

Experimental and theoretical study on complexation of the ammonium cation with enniatin B

“…They appear in nature as mixtures of cyclic depsipeptides -the main variants are enniatins A, A1, B, and B1, together with minor amounts of enniatins C, D, E, and F. Enniatins function as ionophores by their incorporation into the cellular membrane to form dimeric structures. They transport monovalent ions across the membrane, especially the mitochondrial membranes, affecting oxidative phosphorylation uncoupling [5][6][7][8]. It has been demonstrated that enniatins have a cytotoxic effect on human cancer cells [9].…”