Transition state complementarity

A new model for enzyme catalysis that challenges the long-standing concept of transition state complementarity as the sole source of enzymatic catalytic efficacy. This shifting model states that (a) enzymes evolved to bind substrates (b) enzyme-substrate complexes have evolved to bind transition states and (c) stronger interactions of substrate with the enzyme facilitate rapid conversion to product. This model questions the concept that strong interactions of enzyme and substrate reduce catalytic efficiency. 

The role of transition state complementarity in enzyme catalysis is further explored in Box 6-3. 

The transition state of a reaction is difficult to study because it is so short-lived. To understand enzymatic catalysis, however, we must dissect the interaction between the enzyme and this ephemeral moment in the course of a reaction. Complementarity between an enzyme and the transition state is virtually a requirement for catalysis, because the energy hill upon which the transition state sits is what the enzyme must lower if catalysis is to occur. How can we obtain evidence for enzyme-transition state complementarity Fortunately, we have a variety of approaches, old and new, to address this problem, each providing compelling evidence in support of this general principle of enzyme action. 

The idea of complementarity in enzyme - substrate interactions was introduced by E. Fischer with his famous lock and key analogy.7 In modem terminology this would represent enzyme-substrate complementarity. The currently favored concept of enzyme-transition state complementarity was introduced by Haldane1 and elaborated by L. Pauling.2... 

B Experimental evidence for the utilization of binding energy in catalysis and enzyme transition state complementarity... 

The effects of enzyme-transition state complementarity on the binding of transition state analogues may be masked by extraneous binding artifacts. Chapter... 

The side chains of amino acid residues in a protein may be changed at will by protein engineering (Chapter 14) and the consequent effects on binding and catalysis studied directly. This is the subject of Chapter 15, where it will be seen how the equations derived so far actually hold in practice and are used to analyze the data. There is direct evidence for enzyme-transition state complementarity. 

Although enzyme-transition state complementarity maximizes kcJKM, this is not a sufficient criterion for the maximization of the overall reaction rate. The reason is that the maximum reaction rate for a particular concentration of substrate depends on the individual values of cat and KM. It can be seen in Table 12.3, where some rates are calculated for various values of kcaX and KM (subject to kc.JKM being kept constant), that maximum rates are obtained for KM greater... 

We have discussed in general terms the catalytic advantages of enzyme-transition state complementarity combined with high KM s, and have seen that this combina-... 

Specificity between competing substrates depends on the relative binding of their transition states to the enzyme. Enzyme-transition state complementarity maximizes specificity because it ensures the optimal binding of the desired transition state. This is also the criterion for the optimal value of kcatIKM, which is not surprising, since specificity is determined by kcatIKM. Maximization of rate... 

Table 1.2 provides an overview of historic events in biocatalysis and biotechnology. It demonstrates that biotechnology is an old science, or even an old art. The big ideas and driving forces for biocatalysis in the 20th century were twofold first, the idea of catalysis as transition-state complementarity in 1944 and second, the development of molecular biology after 1978 to allow the design of enzymes and their production vehicles. 

Linus Pauling Caltech, Pasadena, CA, USA 1st attempt to explain catalysis as transition-state complementarity... 

The X-ray diffraction experiment on the lysozyme-inhibitor complex40 is a well-known example which gave evidence for the transition state complementarity. 

It is a major challenge to elucidate the mechanisms responsible for the efficiencies of enzymes. Jencks (1) offered the following classification of the mechanisms by which enzymes achieve transition state stabilization and the resulting acceleration of the reactions proximity and orientation effects of reactants, covalent catalysis, general acid-base catalysis, conformational distortion of the reactants, and preorganization of the active sites for transition state complementarity. 

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