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Enterobactin 2016 Enterobactin Fig. 1. Computer generated model of the Enterobactin-iron-complex by: Lukas Geisenhof Sina Federmann Simon Greulich Thomas Geiger Enterobactin - Structure and function Enterobactin is a strong iron chelator and possibly the best understood member of the siderophore family. It was isolated first from Salmonella typhimurium in 1970 by Pollack and Neilands.[4] Iron is a significant nutrient for microbial growth. However due to insolubility of ferric hydroxide at physiological pH value and more important owing to the inherent toxicity of free ferric ions its concentration is maintained at 10-24 M in human serum. Therefor a lot of pathogenic bacteria such as Enterobacteria produce siderophores compete against this thermodynamic limit and obtain iron form the environment. These powerful chelators (K = 1052) are especially secreted in response to iron defiency.[2] Enterobactin is composed of three elemental structures (Fig. 2.): The triacetone backbone, the amide linkage and the metal binding unit. Free Enterobaction (Fig. 3.) has its orthohydroxy groups hydrogen bonded to the amide oxygen atom causing a structure where the hydroxy groups are turned outside predisposing it to metal binding. (Fig. 2) Upon deprotonation of the ortho-hydroxy groups the trans form is induced in which the ortho-hydroxy group hydrogen-bonds with the amide proton. At this conformation the hydroxy groups are turned inside. (Fig. 4.). The conformational change is induced by ligand binding and dependent on the pH value. At physiological pH the ratio of both conformations is around 50/50.[2] Fig. 3. A computer generated structure of Fig. 4 Enterobactin-Iron complex[5] uncomplexed Enterobactin based on the triacetone structure of Seebach et al.[5] The ligand free conformation favors rapid ligand binding. Whereas the Enterobactinmetal complex fully encapsulates the ligand. This very stable complex can be seen in the computer generated structure below (Fig. 1.). Transport and release Iron is one of the essential micro nutrients in organisms. A deficiency in bacterial cells causes a formation of a dative bonding Catecholate complex FeEnt[15] (q.v. Structure and function) Because of its large size FeEnt requires active transport across the outer membrane by using the channel protein Fep A (Fig. 5). To regulate the entire transport process the cells express highly specific receptors, which are capable to recognize the iron binding and amide linkage domains of FeEnt. Assisted by the complex TonB–ExbB–ExbD, which is anchored in the cytoplasmic membrane, the ferric enterobactin complex enters the cytoplasm. Thereon Fep B guides it to the cytoplasmic pores composed of FepD and G. Once delivered it is taken up by using the energy of hydrolyzing ATP via the enzyme FepC. The reaction of the intercellular release of iron is pH dependent and due to the high binding affinity enzyme catalyzed. FeEnt esterase, which is encoded by the fes gene, initiates the hydrolytic cleavage of FeEnt. It appears that the reduction of the Fe3+ occurs collaterally.[6] Fig. 5 crystallographic structure of unliganded FepA (Protein Data Bank code 1FEB) Kenneth N. Raymond et al. PNAS 2003;100:3584-3588 Fig. 6:A pictorial scheme shows the transmembrane topology of the FeEnt uptake proteins and how they function. The synthesis of Enterobactin Biosynthesis [6, 11] The biosynthesis of Enterobactin consists of 2 formal steps. Step one is the synthesis of (DHBA) Fig. 7 [1] and the second one is to form the trilactone. Step 1: The basic molecule is Chorisminacid (C10H10O5) Fig.7 [2]. In aquatic environment it is deprotonated. EntC and the isochorismatsynthetase catalyse the formation of Chorismat to Isochorismat. The next step to DHBA is the catalisation to 2,3-dihydro-2,3-dihydroxybenzoat with EntB ( Isochorismat-pyruvat-hydrolase). With EntA this molecule is then catalysed to DHBA. Step 2: DHBA and L-Serin(Ser) react to N-(2,3-Dihydroxybenzoyl)-L-serin (DBS) Fig. 7 [3]. The membrane Proteins EntD[10], EntF and EntE are catalysing the amide linkage. EntG then hydrolises three DBS componets to one Enterobaktin. Each component is linked to a certain domain of EntF when getting hydrolised with the next componet. After the second hydrolisation, EntF is released due to intramolecular cyclation and the Trilacton is formed. EntB ist the same protein as EntG, often named EntB/G for it has a bifunctional character. [1] [2] [3] Fig.7 The biosynthesis has been researched very well, mainly by Walsh, Earhart and McIntosh. Chemical synthesis [3.3] There are different ways to synthesize Enterobactin. The first time Enterobactin has been synthesized was in 1977, done by Corey and Bhattacharyya. The yield tough was only around 1% and the mechanism had 14 stages. Since then, the mechanism has been optimized. One possible way is to use the “Mitsonobu”-reaction to get a β- lactone. From there on, catalyzed with 2,2-dibutyl-1,3,2-dioxastannolan, the trilactone is synthesized by three β-lactones. Fig.8 The last three steps are: 1. Release of -Trt, which is easily cleaved in acid 2. NH2 binds to the marked C-atom an releases HO-Ph-NO2 3. Reduction of the benzyl-protection group. Releasing HBn Sources [1 ]http://www.e-learning.chemie.fu-berlin.de/bioanorganik/eisen/molekuele/siderophore/index.html Enterobactin: An archetype for microbial iron transport (08.06.2016 15:30 Uhr) [2] Kenneth N. Raymond*, Emily A. Dertz, and Sanggoo S. Kim [3] Department of Chemistry, University of California, Berkeley, CA 94720-1460 [4] Pollack, J. R. & Neilands, J. B. (1970) Biochem. Biophys. Res. Commun. 38, 989–992. [5] Seebach, D., Muller, H. M., Burger, H. M. & Plattner, D. A. (1992) Angew. Chem. Int. Ed. Engl. 31,434–435. [6][ Fig. 2,3,4,5,6] http://www.pnas.org/content/100/7/3584.full (08.06.2016 15:30 Uhr) [7] http://www.pnas.org/content/100/7/3584/F1.expansion.html (08.06.2016 15:30 Uhr) [8]Kamil Stelmaszyk , Synthese und Untersuchung artifizieller tripodaler Catechol-Siderophore , 2014 , S. 27- 30 [Fig.8][9] http://www.pnas.org/content/100/7/3584/F2.large.jpg (12.06.2016 13:00 Uhr) [10] http://www.uniprot.org/uniprot/P19925 (12.06.2016 13:00 Uhr) [11] https://opus.bibliothek.uni-wuerzburg.de/files/93/11-diskussion.pdf PDF EBOOK (12.06.2016 13:00 Uhr) [12] Beyer/Walter, Organische Chemie 25., völlig neu bearbeitete Auflage 2015. S.563f [Fig. 7.1] https://de.wikipedia.org/wiki/Chorismins%C3%A4ure#/media/File:Chorismins%C3%A4ure.svg [Fig.7.2] https://en.wikipedia.org/wiki/2,3-Dihydroxybenzoic_acid#/media/File:2,3- Dihydroxybenzoes%C3%A4ure.svg (12.06.2016 13:00 Uhr) [15] http://www.e-learning.chemie.fu- berlin.de/bioanorganik/eisen/molekuele/siderophore/index.html (12.06.2016 13:00 Uhr) .
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