Chorismate transition state inhibitor

Adamantane has an extra methylene bridge (the asterisk in the diagram) linked to the six-membered ring, thus stabilizing a cagelike structure. The authors indeed subsequently showed that some adamantane derivatives are potent inhibitors of chorismate mutase thus, these are examples of transition-state analogs. 

The transition state for the enzymatic reaction has been shown to have a chairlike geometry as well [61], and conformationally constrained compounds that mimic this structure, such as the oxabicyclic dicarboxylic acid 1 (Fig. 3.6), are good inhibitors of chorismate mutase enzymes [62 - 64], How a protein might stabilize this high-energy species has been a matter of some debate. Recently, heavy atom isotope effects were used to characterize the structure of the transition state bound to BsCM [65]. A very... 

Fig. 3.6. Chorismate prefers a pseudodiequatorial conformation in solution. It must adopt a disfavored pseudodiaxial conformation to reach the pericyclic transition state. The conformationally constrained oxabicyclic dicarboxylic acid 1, which mimics the transition state, is a potent inhibitor of natural chorismate mutases [62], Antibodies raised against this compound also catalyze the reaction, albeit 100 to 10,000-times less efficiently than their natural counterparts [39, 41].

Although chorismate mutase does provide a rate enhancement of 2 X 10 (147), this uni-molecular reaction readily occurs without enzyme, under mild conditions. The reaction was expected to pass through a chairlike transition state (59)(Fig. 17.25) but early molecular orbital calculations indicated that the boatlike transition state (60) was not out of the question (147). In an attempt to define the transition-state structure, several compounds, each designed to mimic a putative transition state, were synthesized and tested as chorismate mutase inhibitors (147). The enzyme was found to be inhibited by the exo-carboxy nonane (61), with an apparent value of 3.9 X 10 M Conversely, the endo-carboxy nonane (62) did not inhibit the enzyme. The apparent K- value of the adaman-... 

It has been shown that both the catalyzed and the uncatalyzed reaction proceed through a chairlike transition state, stabilized in polar media59 60-143 262-263. Compound 1, an analog of the transition-state structure, proved to be a potent inhibitor of E. coli chorismate mutase-prephenate dehydrogenase204-255. For a discussion of the mechanism and structural requirements of the enzyme see refs 266 and 267. 

Use of chorismate mutase inhibitors to define the transition state structure. Biochemistry 16 4848-4852. 

This realization has not escaped the bioorganic community, and a number of research groups, notably those of Andrews and Berchtold, have synthesized molecules that are designed to mimic the presumed bicyclic transition state. A truly potent inhibitor has eluded our grasp, however, as reflected by the fact that most compounds investigated bind more weakly to chorismate mutase/prephenate dehydrogenase than does chorismate (as reflected by the substrate Km value). 1-Adamantyl phosphonic acid is the most potent inhibitor previously reported, with an I50 value twenty-fold less than chorismate Km under comparable conditions. 

Andrews, P.R., Cain, E.N., Rizzardo, E. and Smith, G.D. (1977) Rearrangement of Chorismate to Prephenate. Use of Chorismate Mutase Inhibitors to Define the Transition State Structure, Biochemistry, 16,4848-4852. 

Bartlett, P.A., Nakagawa, Y., Johnson, C.R., Reich, S. and Luis, A. (1988) Chorismate Mutase Inhibitors Synthesis and Evaluation of Some Potential Transition State Analogs, J. Org. Chem., 53, 3195-3210. 

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/ ... 

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