This proposal outlines six specific objectives, in order of priority, for study in the shikimic acid biosynthetic pathway. This pathway represents the major biosynthetic route to aromatic compounds in plants and microorganisms. By combining sophisticated syntheses of complex molecules with biochemical assays on key enzymes, important information on crucial intermediates and processes along the pathway may be gained. (1) Studies on anthranilate synthase and p-aminobenzoate synthase will attempt to elucidate what mechanistic relationships follow from apparent evolutionary relationships in the genetics of these enzymes. Findings may also clarify the biosynthesis of isochorismic acid and several meta-carboxyaromatic amino acids. Work on (2) chorismate mutase, (3) dehydroquinate synthase and (4) chorismate synthase will focus on the nature of catalysis by each enzyme and the design of specific inhibitors or inactivators of each protein. (5) Arylamine synthase, which catalyzes a Claisen rearrangement similar to chorismate mutase, will also be studied using synthetic 4amino- 4-deoxychorismic acid. This substrate can also be used to probe key mechanistic and stereochemical questions about the biosynthesis of L-p-aminophenylalanine and of chloramphenicol. (6) A long range objective will focus on the mechanism and structure of chorismate lyase, which converts chorismate to p-hydroxybenzoate on the biosynthetic pathway to coenzyme Q (ubiquinone).
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