Structural investigations, at atomic level, of three enzymes comprising steps three, four and five of the mevalonate-independant pathway for isoprenoid biosynthesis

• Antragstellerin: Dr. Florence Pojer
• Fachliche Zuordnung: Pharmazie
• Förderung: Förderung von 2003 bis 2007
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 5422756

The objective of this proposal is to understand the structural and mechanistic features governing the biosynthesis of isoprenoids and their chemical precursors in bacteria. Isoprenoids are the most structurally diverse family of compounds found in nature. More than 23.000 isoprenoid molecules are know to date [1]. Many isoprenoids have biotechnological applications as drugs, flavours, pigments, perfumes or agrochemicals. In living beings, isoprenoids have important roles in processes as diverse electron transport, reproduction, growth regulation, signal transduction and defence. I propose to use protein x-ray crystallography in an integrated fashion with functional experiments including site-directed mutagenesis and steady state kinetic analysis to address the stereochemical and kinetic basis for isoprenoid biosynthesis through the so-called mevalonate-independent or methyl-D-erythritol (MEP) pathway at atomic resolution [2]. This research proposal will focus on the structural elucidation of substrates complexed with kinetically impaired mutants of three enzymes comprising steps three, four, and five of the MEP pathway for isoprenoid biosynthesis. Since the MEP pathway is absent in humans and has been shown to be essential in bacteria, its enzymes are excellent candidates for new drug targets, for the treatment of both bacterial and parasitic infections.

• DFG-Verfahren: Forschungsstipendien