Transition-state analogues changes

Lysozyme catalyzes the hydrolysis of the polysaccharide component of plant cell walls and synthetic polymers of j8(l — 4)-linked units of A-acetylglucosamine (NAG) (Chapter 1). It is expected from studies on nonenzymatic reactions that one of the intermediates in the hydrolytic reaction is a oxocarbenium ion in which the conformation of the glucopyranose ring changes from a full-chair to a sofa (half-chair) conformation (Chapter 1). The transition state analogue I, in which the lactone ring mimics the carbonium ion-like transition state n, binds tightly to lysozyme = 8.3 X 10 8M.10... 

Antibodies raised to the transition state analogue (Fig. 7.3) will bind to the transition state of the hydrolysis reaction, lowering the activation energy and therefore catalyzing the reaction. These antibodies were trapped at the surface of a pH electrode using a dialysis membrane [Fig. 7.4(a)]. The reaction (Eq. 7.17) produces a change in local pH at the surface of the electrode, since acetic acid is one of the products. The measured pH therefore decreases as the phenyl acetate concentration increases in the external solution, since the steady-state concentration of acetic acid in the reaction layer increases [Fig. 7.4(b)]. 

Slow binding and even slower release are often found with inhibitors with well above nM levels, and this is usually interpreted in terms of slow protein conformational changes or loss of water, particularly to accommodate a poorly analogous transition state analogue (see Section 5.3.2). Such systems are described by Scheme 5.6. 

The induced-fit model assumes that the enzyme and substrate must both move and change to conform to each other perfectly. Thus, the true fit is not between the enzyme and substrate but between the enzyme and the transition state of the substrate on its way to product A transition-state analogue fits the enzyme nicely in this model. 

Y = OMe and 1.18 for 115, Y = Ph, in accordance with the change in hybridization at the benzylic position in the transition state (118). Furthermore, in H2 0, the Diels-Alder product (120) from cyclopentadiene and 119 was unlabelled while benzyl alcohol (122), formed from 121 and water, was enriched in 0. Methyl and nitro analogues (115,... 

---