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Siderophore Electrochemistry: Relation to Intracellular Iron Release Mechanism (Bacterial Iron Transport/Enterobactin/Hydroxamates/Reduction Potential) STEPHEN R

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Siderophore Electrochemistry: Relation to Intracellular Iron Release Mechanism (Bacterial Iron Transport/Enterobactin/Hydroxamates/Reduction Potential) STEPHEN R Proc. Nati. Acad. Sci. USA Vol. 75, No. 8, pp. 3551-3554, August 1978 Chemistry Siderophore electrochemistry: Relation to intracellular iron release mechanism (bacterial iron transport/enterobactin/hydroxamates/reduction potential) STEPHEN R. COOPER, JAMES V. MCARDLE, AND KENNETH N. RAYMOND Departrrment of Chemistry, University of California, Berkeley, California 94720 Communicated by Melvin Calvin, May 15,1978 ABSTRACT Previous studies have shown that there is a amate and catecholate functional groups. Ferrichrome, isolated major difference between the iron release mechanism of en- from Ustilago sphaerogena (5), and ferrioxamine B, e.g., from terobactin, a catechol-based siderophore, and that of the hy- Streptomyces pilosus (8), are typical of the hydroxamate class. droxamate-based siderophores such as ferrichrome. For ferric enterobactin there is an esterase that hydrolyzes the ligand Ferrichrome is a cyclic hexapeptide that includes a tripeptide during iron release. In contrast, iron is released by the hydrox- sequence of b-N-acetyl-L-6-N-hydroxyomithine, each residue amate-based siderophores and the ligands are reused in subse- of which binds to ferric ion via the bidentate hydroxamate quent iron transport. It has been suggested that release of iron [-N(OH)-CO-] group, forming a hexacoordinate complex (7) by hydroxamates occurs by reduction to the ferrous complex, (Fig. 1). Ferrioxamine B is a linear conjugate of alternating a process that does not occur for ferric enterobactin. Cyclic succinate and 1-amino-5-hydroxyaminopentane constituents vo tammograms of ferrichrome A and ferrioxamine B exhibit (7) (Fig. 2). Among fungi, yeasts, and molds-such as U. reversible one-electron waves with pH-independent formal potentials (Ef vs. the normal hydrogen electrode) -446 and -454 sphaerogena-are found primarily hydroxamic acid-based mV, respectively, within the range of physiological reductants. siderophores. Among the true bacteria, however, chelates based Ferric enterobactin also shows a reversible one-electron wave on catechol (o-dihydroxybenzene) are also found, of which (at pH > 10) with Ef = -986 mV vs. the normal hydrogen elec- enterobactin [from, e.g., E. coli (9) or Salmonella typhimurilum trode. From the pH dependence of this potential we estimate (10)] is the salient example. Enterobactin consists of a cyclic a reduction potential of -750 mV at pH 7. In sharp contrast to triester of 2,3-dihydroxybenzoylserine and binds iron via three the value for the ferric hydroxamates, this value is well below once a hexacoordinate the range of physiological reducing agents. The results dem- bidentate catechol groups, again yielding onstrate that the observed hydrolysis of enterobactin is a nec- ferric complex (7) (Fig. 3). essary prerequisite to in vivo release of iron from the sidero- Both classes of ligands are secreted into the medium only by phore via ferric ion reduction. organisms growing under low-iron stress; evidently under normal conditions only very small amounts of these sidero- Clinical studies have shown that the pathogenicity of some phores are synthesized and the uncharged ligands are retained bacteria is closely related to the availability of iron (1), and that in the cell wall to scavenge adventitious iron. Under low iron one defense against infection in mammals is the denial of iron concentrations, siderophore synthesis is derepressed and the to bacteria. Sequestration of serum iron by proteins such as chelators are secreted into the medium (7). transferrin (2, 3) reduces the ferric ion activity to levels well Despite the similarity in function and regulation, there is a below those required for optimal microbial growth. Over- basic difference in the mechanism of intracellular iron release coming this defense mechanism by saturating serum transferrin from the complexes of the hydroxamates and enterobactin. The with exogeneous iron increases dramatically the virulence of hydroxamate chelates are reused by the cell-after intracellular certain bacterial infections (1). For example, intraperitoneal iron release the iron-free ligand is once again secreted into the injection of 5 mg of iron per kg of body weight decreases the medium. Intracellular release of iron from the hydroxamate number of Escherichia coli cells necessary to kill rats by five chelates probably occurs by reduction to the ferrous state, orders of magnitude (4). Thus the means by which microor- converting the tightly bound ferric complex to the loosely ganisms acquire iron has significant clinical ramifications. bound ferrous complex,* from which the iron can be easily Although the importance of iron to living systems can extracted and the intact ligand can be recycled (11). Thus one scarcely be overemphasized, the means by which bacteria ac- siderophore molecule can shuttle more than one iron ion into quire this vital element received little attention prior to the the organism. By contrast, the cyclic triester linkages of ferric discovery by Neilands of ferrichrome, an iron-transporting enterobactin are cleaved by an esterase specific for the ferric chelate (siderophore), in 1952 (5). Aerobic microorganisms have complex (12, 13). Esterase-deficient mutants are colored pink a particularly severe problem acquiring iron, because in oxi- due to intracellular ferri-enterobactin (in contrast to the white dizing environments iron is available only as ferric ion, for cells of the parent strain) but grow poorly under iron stress, which a saturated solution is about 10(18 molar at physiological establishing that esterase activity is vital to enterobactin-me- pH (Ksp = [Fe3+][OH-]3 - 10-39) (6). This problem has been diated transport. Furthermore, the bacteria are unable to use circumvented in many prokaryotes by the evolution of ferri- the cleavage product, 2,3-dihydroxybenzoylserine, as a substrate chrome and other siderophores, ligands that bind ferric ion with for enterobactin synthesis, which occurs instead via conden- extreme avidity and selectivity, thereby solubilizing it for sation of 2,3-dihydroxybenzoic acid and serine. (12). Thus each metabolic incorporation (7). molecule of enterobactin yields one iron atom to the cell and The two most common siderophore classes contain hydrox- then is destroyed. The enormous waste of metabolic energy The costs of publication of this article were defrayed in part by the Abbreviations: SCE, saturated calomel electrode; NHE, normal hy- payment of page charges. This article must therefore be hereby marked drogen electrode. "advertisement" in accordance with 18 U. S. C. §1734 solely to indicate * K. Abu-Dari, S. R. Cooper, and K. N. Raymond, unpublished this fact. data. - 3551 Downloaded by guest on October 1, 2021 3552 Chemistry: Cooper et al. Proc. Natl. Acad. Sci. USA 75 (1978) R'R CONH-CH CONH- H-CONHNH /0 99 > C H~~~~~2 CH-NHCO-CH-NHCO-CH-NHCO CH-CH2-O- -CH-CH20-C-CH.; NH NH NHI (CH2)3 (CH2)3 II N--OH -OH N-OH == H I ~~~_== (O H iO H R R R FIG. 1. Structure of desferriferrichrome. For ferrichrome, R' = FIG. 3. Structure of enterobactin. H, R = H3. For ferrichrome A, R' = CH20H, CH3 RESULTS R= \ Cyclic voltammograms of ferrichrome A and ferrioxamine B H CH2CO0H are shown in Fig. 4 top and middle. These complexes exhibit reversible one-electron oxidation-reduction waves with E1/2 entailed in synthesis and subsequent degradation of entero- values of -690 mV and -698 mV, respectively, vs the SCE or bactin after one iron transport cycle suggests that such de- -446 and -454 mV vs. the normal hydrogen electrode (NHE). struction must be necessary. Previous workers (12) have sug- A similar value for ferrioxamine B from polarographic data has gested that enterobactin cleavage is necessitated by the inor- been reported by Keller-Schierlein and coworkers (8). A sepa- dinately low reduction potential of the ferric complex, so much ration between extrema in the cyclic voltammogram of 59/n lower than that physiologically available that the reductive iron mV is expected for a reversible n-electron process at 25°. The release mechanism of the hydroxamates is unavailable to the observed separation of 60 mV, its scan rate independence, and bacteria. This hypothesis was supported by the work of of the ratio of peak cathodic to anodic currents of nearly unity are O'Brien et al. (12), who were unable to observe ferric entero- all consistent with electrochemical reversibility for both ferri- bactin reduction electrochemically to -1.8 V vs. the saturated chrome A and ferrioxamine B. The half-wave potentials for calomel electrode (SCE). On the other hand, the cleavage reversible couples can be equated to the thermodynamic products of enterobactin, in particular the ferric tris (2,3- midpoint potential within an excellent approximation. The dihydroxybenzoylserine) complex, are readily reduced elec- midpoint potentials of the two hydroxamates are essentially trochemically at potentials well within the physiological range. independent of pH over the region 8-12, as expected for a redox In order to consider this hypothesis more thoroughly we have process involving no protons. examined the electrochemical behavior of ferric enterobactin Ferric enterobactin, like ferrichrome A and ferrioxamine B, and the representative hydroxamates ferrichrome A and fer- yields a reversible one-electron wave, as evidenced by the scan rioxamine B. rate-independent 60-mV separation between extrema and the peak current ratio. In sharp contrast to the hydroxamate com- METHODS AND MATERIALS plexes, however, is the much lower midpoint potential for this Ferrichrome
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