Biological Applications and Evolutionary Origins of Ionophores

Abstract

The structure and physical chemical properties are reviewed of various ionophores, small molecules which transport cations across biological membranes. The subclass of carboxylic ionophores has dramatic pharmacological properties, dilating the coronary arteries and increasing cardiac contractility, which make them especially interesting. They share related structures containing a terminal carboxyl group hydrogen bonded to the opposite end of the molecule in a cyclic conformation. A variety of oxygen atoms, in heterocyclic rings or linear ether configurations, hydroxyls, and/or ketonic carbonyls as well as carboxyls, focus upon a sphere which can ligand to appropriately fitting cations via ion-dipole interaction. Extreme dependency of liganding energy on fit confers striking ion selectivity upon ionophores. It is speculated that carboxylic ionophores originated as prosthetic groups of ion carriers and represent a natural experiment by the streptomyces genus in the construction of non-proteinaceous binding sites. Ultimately production of these prosthetic groups hypertrophied and subsequently they were elaborated as antibiotics to provide their producers with a survival advantage over competitors. Analogous ionophores have now been synthesized. Unique applications for these compounds are emerging, based either on their selective toxicity or ability to modify physiological processes by altering membrane gradients.