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Munich researchers discover new target for tailored antibiotics
Date:7/14/2009

ay open a potent line of attack for custom-tailored antibiotics.

Research into the bacterial synthesis of isoprene building blocks was initiated as early as 12 years ago by Professor Adelbert Bacher in collaboration with Drs. Wolfgang Eisenreich and Felix Rohdich in Organic Chemistry and Biochemistry. Over the years, the team discovered most of the reaction steps of the new metabolic pathway. Yet the structure of the terminal step catalyzed by the IspH enzyme remained stubbornly elusive. Earlier measurements suggested that the active core must be an iron-sulfur cluster with three iron and four sulfur atoms. But other researchers questioned the results, and for many years the crystal structure of the enzyme that would provide the proof could not be determined.

The main problem was the oxygen sensitivity of the enzyme, which degenerates very quickly in air, thus losing both its structure and its function. Only recently a group from the Justus-Liebig University in Giessen managed to determine the X-ray crystal structure of the enzyme's open state. However, this structure provides hardly any information on the mutation process catalyzed by the enzyme. The research team of Professor Groll, Dr. Eppinger, and Dr. Grwert has now succeeded in cracking the closed-state X-ray structure that shows the precise folding pattern of the protein chain and the chemical environment of the active site cavity.

The crystal structure opened the door to a detailed examination of the reaction mechanism using computer simulation and mutagen experiments, in which E. coli bacteria are coerced into synthesizing defective IspH enzymes. Thus, the X-ray structure, kinetic measurements, and mutagenic analyses ultimately confirmed the unusual arrangement of three iron and four sulfur atoms in the central cavity, just as proposed years ago.

"Now that the location, the chemical process, and the helpers involved in the IspH reaction have been identified," expla
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Contact: Dr. Andreas Battenberg
battenberg@zv.tum.de
49-892-891-2890
Technische Universitaet Muenchen
Source:Eurekalert

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