STUDIES IN THE SHIKIMATE-CHORISMATE PATHWAY

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A broadly based bioorganic program for the study of some of the key enzymes in the shikimate-chorismate pathway is outlined. The key elements are the following: 1. Chorismate mutase: New transition state analog inhibitors will be synthesized and evaluated; a synthesis of chorismic acid itself will be completed. 2. 3-Dehydroquinate synthase: The stereochemistry of the individual steps in the enzymic transformation will be determined by stereoselective synthesis of a key intermediate; blocked-substrate as well as transition state analog inhibitors will be synthesized and evaluated. 3. Chorismate synthetase: An allylic isomer of the natural substrate will be synthesized and evaluated as an alternative substrate or inhibitor. 4. 5-Enolpyruvylshikimate-3-phosphate synthase: The postulated tetrahedral adduct will be synthesized and its enzymatic conversion to product evaluated; transition state and multisubstrate analog inhibitors will also be synthesized. 5. Prephenate dehydratase: A series of sulfoxide and sulfilimine analogs of prephenate will be synthesized and evaluated as transition state analog or suicide inhibitors. 6. A number of other analogs of intermediates in the shikimate-chorismate pathway are proposed as substrates and inhibitors.