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Enterobactin: an Archetype for Microbial Iron Transport Enterobactin: An archetype for microbial iron transport Kenneth N. Raymond*, Emily A. Dertz, and Sanggoo S. Kim Department of Chemistry, University of California, Berkeley, CA 94720-1460 Bacteria have aggressive acquisition processes for iron, an essential nutrient. Siderophores are small iron chelators that facilitate cel- lular iron transport. The siderophore enterobactin is a triscatechol derivative of a cyclic triserine lactone. Studies of the chemistry, regulation, synthesis, recognition, and transport of enterobactin make it perhaps the best understood of the siderophore-mediated iron uptake systems, displaying a lot of function packed into this small molecule. However, recent surprises include the isolation of corynebactin, a closely related trithreonine triscatechol derivative lactone first found in Gram-positive bacteria, and the crystal struc- ture of a ferric enterobactin complex of a protein identified as an antibacterial component of the human innate immune system. arious aspects of iron regula- rioxamine (17, 21). A similar effect is function be packed into this small tion, transport, storage, and seen if desferrioxamine is supplied dur- molecule? utilization appear in several ing infections of Klebsiella and Salmo- articles in this issue of PNAS. nella (15), whereas direct correlation FeEnt Structure V The isolation of enterobactin (or entero- As often noted (1–4) iron is needed in between the LD50 of Vibrio vulnificans organisms in relatively large amounts. A and iron availability has been demon- chelin) in 1970 resulted in the first of 70-kg adult human has Ϸ5 g of iron strated (22). many controversies about this molecule. Ϫ (Ϸ10 3 M for body volume), whereas a Bacteria have consequently evolved Pollack and Neilands (28), who isolated Ϫ bacterial cell of 10 9 cm3 requires 105 to aggressive iron acquisition processes. the compound from Salmonella typhi- 106 ferric ions per generation to main- murium, named it enterobactin, whereas Ϫ Powerful and selective iron chelators tain the required 10 6 M internal con- (siderophores) are produced and se- O’Brien and Gibson (29), who isolated centration (5). creted specifically in response to iron the compound from E. coli, called it en- deficiency. The regulator protein Fur terochelin. Although the O’Brien and Iron: Can’t Live With It, Can’t Live (ferric uptake regulation) (23–25) or Gibson paper was submitted first, the Without It Fur-like proteins, regulate iron uptake Pollack and Neilands paper was printed While iron’s abundance in the Earth’s in many bacterial species. Some Gram- first, resulting in the widespread use of crust, spin state, and redox tuneability positive bacteria (such as streptomyces, both names. makes it the most versatile of the transi- corynebacteria, and mycobacteria) use Characterization of enterobactin proved challenging, with many flawed tion elements, the insolubility of ferric the DtxR (diphtheria toxin regulator) analyses published over the years. The hydroxide at pH 7.4 limits the concen- protein (26). Regulation of iron up- 3ϩ coordination mode of FeEnt involves a tration of [Fe ] (the free aqueous ion) take and siderophore production has Ϸ Ϫ18 hexadentate triscatecholate geometry to 10 M (1). However, even below recently been the subject of an excellent with a ⌬ configuration at the metal cen- this concentration, free ferric ion is review (27). toxic. To avoid toxicity and regulate ter, as shown in Fig. 1 Lower Right (30, Spectacular advances have taken place iron transport, the human serum iron 31). Iron release is through the action of in the last 10 years in understanding the transport protein, transferrin, maintains the cytoplasmic esterase (32, 33). How- recognition and transport processes in- the free ferric ion concentration at ever, synthetic analogs of enterobactin, Ϫ volved in siderophore-mediated iron ac- Ϸ10 24 M (6–8). Pathogenic bacteria which are not susceptible to hydrolysis, quisition. The structural characterization must compete against this thermody- are Ϸ5% as effective in delivering iron of proteins and identification of genes namic limit to obtain iron from the se- (34), implying a secondary pathway of rum or tissues of its human host. have elucidated the steps involved in iron release. Unfortunately, perhaps be- It is difficult to overestimate the sig- siderophore-mediated iron transport in cause of previous errors, there continues nificance of iron as a limiting nutrient in several different systems. The general to be confusion on this subject. Even a microbial growth. Excess iron increases mechanism is initiated when the ferric recent major microbiological review (35) the virulence of organisms as diverse as siderophore complex binds to the recep- incorrectly assigned the structure of Escherichia (9), Klebsiella (10), Listeria tor protein on the microbial cell surface. FeEnt and its major route of iron (11), Neisseria (12), Pasteurella (11), Shi- Translocation of the complex requires release. gella (13), Salmonella (14, 15), Vibrio active transport, ending with iron re- Enterobactin is predisposed for metal (16), and Yersinia (17). Iron dextran in- lease and metabolism inside the cell. binding (31, 36–38). The conformation jections in children, originally intended Enterobactin (Fig. 1) coordinates iron of the neutral catecholamide free ligand to prevent iron deficiencies, enhanced through three catecholate functionalities has the ortho-hydroxy proton hydrogen- Escherichia coli bacteremia and meningi- that are linked to a triserine macrocycle. bonded to the amide oxygen atom. tis (18). As early as the 1850s, Dr. Ar- The remarkable stability of the ferric Upon deprotonation this conformation mand Trousseau, a Parisian professor of enterobactin (FeEnt) complex, the role changes to the trans form (Fig. 1 Upper clinical medicine, warned his students of its stereochemistry in recognition and Right), in which the amide proton hydro- against administering an iron prepara- transport, and the significance of the gen-bonds to the ortho-hydroxy oxygen Ϸ tion, then widely used, to tuberculosis trilactone ring for iron release are all atom. At physiological pH 50% of the patients (19). Nonlethal injections of E. now understood. Although many differ- three catecholate units have their hy- coli in guinea pigs become lethal by the ent siderophores and several types of droxy oxygen atoms oriented in the concomitant addition of either heme or transport systems are known, it seems same direction as the amide proton. If enough iron to saturate the transferrin timely to take a retrospective look at we view the siderophores as both iron (9, 20). The virulence of Yersinia entero- enterobactin as perhaps the best under- colitica is enhanced 10 million-fold by stood of the siderophore-mediated iron *To whom correspondence should be addressed. E-mail: the peritoneal injection of ferric desfer- transport systems. How can so much [email protected]. 3584–3588 ͉ PNAS ͉ April 1, 2003 ͉ vol. 100 ͉ no. 7 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0630018100 Downloaded by guest on October 1, 2021 SPECIAL FEATURE PERSPECTIVE lyzed by EntD, EntE, EntF, and a C- terminal aryl carrier of EntB, which is a bifunctional protein (46). Serine is acti- vated by adenylation and subsequently binds onto a peptidyl carrier protein do- main of EntF as an acyl-S-pantetheine intermediate (47). The terminal thioes- terase domain of EntF later releases enterobactin after the hydrolysis of three molecules of DHB-Ser by inter- molecular cyclization (48) (Scheme 1 Upper). Chemical Syntheses of Enterobactin The first chemical synthesis of enter- obactin was reported by Corey and Bhattacharya (49). Their procedure gave enterobactin with a relatively low yield (Ϸ1%). Subsequent syntheses for both enterobactin and its mirror image, enan- Fig. 1. Schematic and space filling structures of enterobactin and its ferric complex. (Upper) The catechol, amide linkage and triserine ring components of enterobactin, and the conformation charge, driven by tioenterobactin (50), have steadily im- hydrogen bonding, following deprotonation (or metal complexation). (Lower Right) The structure of the proved the yield (51). A single-step syn- V(IV) complex (30), considered to be a close model of the Fe(III) complex. (Lower Left) A computer- thesis of the triserine lactone (52) generated structure of uncomplexed enterobactin based on the trilactone structure of Seebach et al. (52) (Scheme 1 Lower) provides an overall and appended catecholamide groups as seen in the crystal structure of an enterobactin analog (79). Note yield of Ϸ50% and also enables the how hydrogen bonding locks the catechol group into one of two rigid conformations, the interconversion functionalization of the trilactone by of which is triggered by deprotonation͞metal complexation. attaching chelating groups other than catecholamides (53, 54). prospecting and sequestering agents, this synthetases. Walsh and coworkers (39, Enterobactin Recognition and Transport dynamic conformation of free enter- 40), Earhart and coworkers (41, 42), and The low concentration and large size of obactin seems optimally tuned to per- McIntosh and coworkers (43, 44) have form both tasks: the free ligand confor- ferric siderophore complexes require shown that enterobactin is synthesized active transport (Fig. 2). Recognition mation favors rapid initial binding of an from a fork in the aromatic amino acid iron atom, whereas the conformation and incorporation of the ferric sid- pathway in a two-step process (40, 41, change that results from
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