STUDIES IN THE SHIKIMATE-CHORISMATE PATHWAY

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Continuation of a broadly based bioorganic program to study some of the key enzymes in the shikimate-chorismate pathway is proposed. The major elements are the following: 1.5-Enolpyruvylshikimate-3-phosphate Synthase. We propose to continue our work on the synthesis of stabilized analogs of the tetrahedral intermediate and on the synthesis of this species itself; we will also study the mechanism and stereochemistry of the elimination step. 2.Chorismate Synthase. Through the use of isotopically labeled substrate analogs and of 5-deazaflavin, we will study the role of the flavin cofactor and the mechanism of the 1,4-elimination reaction catalyzed by this enzyme. 3.Chorismate Mutase. We expect to complete our study of this enzyme with the synthesis of ammonium and aziridinium inhibitor analogs and an investigation of an electronically perturbed substrate analog. 4.Dehydroquinate Synthase. We propose to resolve the remaining mechanistic issue, namely the extent of enzymatic involvement in the final step of the transformation, and to synthesize some potential suicide inhibitors of the enzyme. 5.Dehydroquinase. We will initiate a program to develop suicide inhibitors for this early enzyme in the pathway. 6.Isochorismate Synthase and Isochorismatase. We will initiate programs to develop inhibitors and reaction intermediate analogs for these enzymes of a branch pathway.