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Isoprenoid Biosynthesis in Pathogenic Bacteria: Nuclear Resonance Vibrational Spectroscopy Provides Insight into the Unusual [4Fe-4S] Cluster of the E. coli LytB/IspH Protein.
Angew Chem Int Ed Engl. 2015 Oct 19; 54(43):12584-7.AC

Abstract

The LytB/IspH protein catalyzes the last step of the methylerythritol phosphate (MEP) pathway which is used for the biosynthesis of essential terpenoids in most pathogenic bacteria. Therefore, the MEP pathway is a target for the development of new antimicrobial agents as it is essential for microorganisms, yet absent in humans. Substrate-free LytB has a special [4Fe-4S](2+) cluster with a yet unsolved structure. This motivated us to use synchrotron-based nuclear resonance vibrational spectroscopy (NRVS) in combination with quantum chemical-molecular mechanical (QM/MM) calculations to gain more insight into the structure of substrate-free LytB. The apical iron atom of the [4Fe-4S](2+) is clearly linked to three water molecules. We additionally present NRVS data of LytB bound to its natural substrate, (E)-4-hydroxy-3-methylbut-2-en-1-yl diphosphate (HMBPP) and to the inhibitors (E)-4-amino-3-methylbut-2-en-1-yl diphosphate and (E)-4-mercapto-3-methylbut-2-en-1-yl diphosphate.

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Authors+Show Affiliations

Faus I
Fachbereich Physik, TU Kaiserslautern, Erwin-Schrödinger-Strasse 46, 67653 Kaiserslautern (Germany).
Reinhard A
Fachbereich Physik, TU Kaiserslautern, Erwin-Schrödinger-Strasse 46, 67653 Kaiserslautern (Germany).
Rackwitz S
Fachbereich Physik, TU Kaiserslautern, Erwin-Schrödinger-Strasse 46, 67653 Kaiserslautern (Germany).
Wolny JA
Fachbereich Physik, TU Kaiserslautern, Erwin-Schrödinger-Strasse 46, 67653 Kaiserslautern (Germany).
Schlage K
P01, Petra III, DESY, Notkestrasse 85, D-22607 Hamburg (Germany).
Wille HC
P01, Petra III, DESY, Notkestrasse 85, D-22607 Hamburg (Germany).
Chumakov A
ESRF - The European Synchrotron, CS40220, 38043 Grenoble Cedex 9 (France).
Krasutsky S
Department of Chemistry, University of Utah, 315 South 1400 East RM 2020, Salt Lake City, UT 84112 (USA).
Chaignon P
Université de Strasbourg, UMR 7177 CNRS, Institut Le Bel, 4 rue Blaise Pascal, CS 90032, 67081 Strasbourg Cedex (France).
Poulter CD
Department of Chemistry, University of Utah, 315 South 1400 East RM 2020, Salt Lake City, UT 84112 (USA).
Seemann M
Université de Strasbourg, UMR 7177 CNRS, Institut Le Bel, 4 rue Blaise Pascal, CS 90032, 67081 Strasbourg Cedex (France). mseemann@unistra.fr.
Schünemann V
Fachbereich Physik, TU Kaiserslautern, Erwin-Schrödinger-Strasse 46, 67653 Kaiserslautern (Germany). schuene@physik.uni-kl.de.

MeSH

Biosynthetic PathwaysCrystallography, X-RayDiphosphatesEscherichia coliEscherichia coli InfectionsEscherichia coli ProteinsHumansModels, MolecularNuclear Magnetic Resonance, BiomolecularOxidoreductasesTerpenes

Pub Type(s)

Journal Article

Language

eng

PubMed ID

26118554

Citation

Faus, Isabelle, et al. "Isoprenoid Biosynthesis in Pathogenic Bacteria: Nuclear Resonance Vibrational Spectroscopy Provides Insight Into the Unusual [4Fe-4S] Cluster of the E. Coli LytB/IspH Protein." Angewandte Chemie (International Ed. in English), vol. 54, no. 43, 2015, pp. 12584-7.
Faus I, Reinhard A, Rackwitz S, et al. Isoprenoid Biosynthesis in Pathogenic Bacteria: Nuclear Resonance Vibrational Spectroscopy Provides Insight into the Unusual [4Fe-4S] Cluster of the E. coli LytB/IspH Protein. Angew Chem Int Ed Engl. 2015;54(43):12584-7.
Faus, I., Reinhard, A., Rackwitz, S., Wolny, J. A., Schlage, K., Wille, H. C., Chumakov, A., Krasutsky, S., Chaignon, P., Poulter, C. D., Seemann, M., & Schünemann, V. (2015). Isoprenoid Biosynthesis in Pathogenic Bacteria: Nuclear Resonance Vibrational Spectroscopy Provides Insight into the Unusual [4Fe-4S] Cluster of the E. coli LytB/IspH Protein. Angewandte Chemie (International Ed. in English), 54(43), 12584-7. https://doi.org/10.1002/anie.201502494
Faus I, et al. Isoprenoid Biosynthesis in Pathogenic Bacteria: Nuclear Resonance Vibrational Spectroscopy Provides Insight Into the Unusual [4Fe-4S] Cluster of the E. Coli LytB/IspH Protein. Angew Chem Int Ed Engl. 2015 Oct 19;54(43):12584-7. PubMed PMID: 26118554.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Isoprenoid Biosynthesis in Pathogenic Bacteria: Nuclear Resonance Vibrational Spectroscopy Provides Insight into the Unusual [4Fe-4S] Cluster of the E. coli LytB/IspH Protein. AU - Faus,Isabelle, AU - Reinhard,Annegret, AU - Rackwitz,Sergej, AU - Wolny,Juliusz A, AU - Schlage,Kai, AU - Wille,Hans-Christian, AU - Chumakov,Aleksandr, AU - Krasutsky,Sergiy, AU - Chaignon,Philippe, AU - Poulter,C Dale, AU - Seemann,Myriam, AU - Schünemann,Volker, Y1 - 2015/06/26/ PY - 2015/03/18/received PY - 2015/6/30/entrez PY - 2015/6/30/pubmed PY - 2016/8/6/medline KW - LytB(IspH) KW - inhibitors KW - metalloenzymes KW - methylerythritol phosphate pathway KW - nuclear resonance vibrational spectroscopy SP - 12584 EP - 7 JF - Angewandte Chemie (International ed. in English) JO - Angew Chem Int Ed Engl VL - 54 IS - 43 N2 - The LytB/IspH protein catalyzes the last step of the methylerythritol phosphate (MEP) pathway which is used for the biosynthesis of essential terpenoids in most pathogenic bacteria. Therefore, the MEP pathway is a target for the development of new antimicrobial agents as it is essential for microorganisms, yet absent in humans. Substrate-free LytB has a special [4Fe-4S](2+) cluster with a yet unsolved structure. This motivated us to use synchrotron-based nuclear resonance vibrational spectroscopy (NRVS) in combination with quantum chemical-molecular mechanical (QM/MM) calculations to gain more insight into the structure of substrate-free LytB. The apical iron atom of the [4Fe-4S](2+) is clearly linked to three water molecules. We additionally present NRVS data of LytB bound to its natural substrate, (E)-4-hydroxy-3-methylbut-2-en-1-yl diphosphate (HMBPP) and to the inhibitors (E)-4-amino-3-methylbut-2-en-1-yl diphosphate and (E)-4-mercapto-3-methylbut-2-en-1-yl diphosphate. SN - 1521-3773 UR - https://www.unboundmedicine.com/medline/citation/26118554/Isoprenoid_Biosynthesis_in_Pathogenic_Bacteria:_Nuclear_Resonance_Vibrational_Spectroscopy_Provides_Insight_into_the_Unusual_[4Fe_4S]_Cluster_of_the_E__coli_LytB/IspH_Protein_ DB - PRIME DP - Unbound Medicine ER -