Receptor mapping with artificial siderophores

In order to guarantee adequate supply of iron, which is essential for growth, microbial organisms have developed ingenious vehicles, the siderophores. These low molecular weight compounds bind and transport iron from the environment into the cell in a receptor driven mechanism. In an attempt to simulate the properties of one of the siderophoresferrichrome, with artificial binders, tripod-like hydroxamates that bind iron(II1) in the same configuration as the natural counterpart with equal growth promotion activity were prepared. In vivo tests of these compounds established that three of them approach and even equal the activity of genuine ferrichrome BS growth promoters of Arthrobacter flavescens. A. flavescens is completely dependent on ferrichrome for growth and previously failed to respond to any synthetic compounds. The biomimetic iron carriers described here are thus the first examples that are active towards this mutant and are taken up by a receptor driven mechanism. The implications of these findings in mapping the surface of siderophore receptors are discussed. INTRODUCTION Model building with synthetic structures is a valuable method to examine biological phenomena at a molecular level and deduce the underlying principles. tiate between They enable systematic development of ever superior synthetic analogs till optimal match with the biological systems is reached. This approach proved successful in the study of ionophore mediated ion transport through biological membranes [l]. erparts, are capable to selectively bind and transport specific metal ions through lipid membranes. success of the biomimetic approach in the study of ionophores encouraged us to apply it to a related, but more complex problem, the problem of microbial iron uptake [4]. Continuous supply of iron is essential for the maintenance of living systems. Yet, adequate iron supply is hindered by the low solubility of iron hydroxide in water and by the negligible permeability of cell membranes to charged species. vehicles, siderophores (Fig. l), that s'electively bind and transport iron from the environment into the cell. Siderophore mediated iron uptake is not a diffusion controlled process (like ionophore mediated ion uptake), but involves a series of steps that necessitate specific interactions with membranal proteins and membranal receptors 151. This iron uptake mechanism has been shown to be highly specific and only the natural isomers, but not their enantiomers are active. In the case of enterobactin it is the natural righthanded complex (A-cis) that is recognized, while in the case of ferrichrome the left-handed one (A-cis) [S]. Models can serve as "sounding boards" to differenthe essential and the superfluous, between the understood, and the still obscure. It led to the synthesis of artificial ion carriers [2,3], that similarly to the natural countThe In order to overcome this problem, nature has devised ingenious chemical A-cis Enterobactin F f Fig. 1. Examples of natural ferric ion carriers (siderophores).