Chorismic acid from 5-enolpyruvylshikimate 3-phosphate

Research in David Sprinson s laboratory at Columbia University, in part contemporary with the research outlined in the preceding pages, has unraveled the earliest stages of the sequence and the derivation of the first, non-cyclic intermediate, DAMP. In the same laboratory, Judith Levin discovered 5-enolpyruvylshikimate 3-phosphate and predicted the existence and correct structure of the next, and last one, of the common intermediates, the compound from which the pathways to the individual primary aromatic products branch off. Isolation and structure proof of this branchpoint intermediate, chorismic acid, by the Australian workers F. Gibson, L.M. Jackman, and J.M. Edwards completed the elucidation of the general pathway. 

The information obtained from the application of glyphosate to complex systems strongly pointed to one of the following three enzymes as the target of the inhibitor in the shikimate pathway shikimate kinase (EC 2.7.1.71), 5-enolpyruvylshikimate 3-phosphate (EPSP) synthase (EC 2.5.1.19), and chorismate synthase (EC 4.6.1.4). Jointly, these three enzymes convert shikimic acid to chorismic acid in a series of interesting reactions >(Fig. 2). A defined system" had therefore to be found in which the conversion of shikimic acid to chorismic acid could be conveniently studied. 

Anthranilic acid (or o-amino-benzoic acid) is an aromatic acid with the formula C H NO, which consists of a substituted benzene ring with two adjacent, or "ortho- functional groups, a carboxylic acid, and an amine (Fig. 14.1). Anthranilic acid is biosynthesized from shikimic acid (for shikimic acid biosynthesis, see Chapter 10) following the chorismic acid-mediated pathway [1]. Based on its biosynthetic mechanism, shikimate is transformed to shikimate 3-phosphate with the consumption of one molecule of ATP, catalyzed by shikimate kinase. 5-Enolpyruvylshikimate-3-phosphate (EPSP) synthase is then catalyze the addition of phosphoenolpyruvate to 3-phospho-shikimate followed by the elimination of phosphate, which leads to EPSP. EPSP is further transformed into chorismate by chorismate synthase. Chorismate reacts with glutamine to afford the final product anthranilate and glutamate pyruvate catalyzed by anthranilate synthase (Fig. 14.1). 

When we began our synthetic program, shikimic acid had been prepared by a number of routes, and the groups of Danishefsky and Plieninger had reported syntheses of prephenic acid. The intervening intermediates, shikimate-3-phosphate (S-3-P), 5-enolpyruvylshikimate-3-phosphate (EPSP), and chorismate, were only available from natural sources or by enz)onatic transformations. 

The synthesis of compound (44) as a potential transition-state analogue inhibitor of isochorismate synthase (IS) has been reported/ Compounds (45) and (46) have been synthesized from the known 6-fluoroshikimic acids (J. Chem. Soc., Chem. Commun., 1989, 1386) by treatment first with shikimate kinase then 5-enolpyruvylshikimate-3-phosphate (EPSP) synthase and shown to be competitive inhibitors of chorismate synthase/ ... 

---