Enzyme mechanisms, free energy relationships

Hydrolysis of phosphate esters is one of the fundamental biochemical reactions and a vast amount of research has been devoted to the study of phosphoryl transfer reactions [57-60], both in solution and in enzymes. Despite these efforts there are still ambiguities regarding the interpretation of experimental data (e.g., linear free energy relationships, kinetic isotope effects, crystal structures of enzyme-inhibitor complexes etc.) in terms of detailed reaction mechanisms [21,25,59,60]. Of particular interest has been to determine... 

Application of linear free energy relationships to enzyme mechanisms has, naturally, been attempted but the influence of the substituent may... 

Variation of Substrate Structure. Whereas linear free energy relationships play a central role in the determination of non-enzymic mechanisms, they are much less important for enzymes, for two reasons. First, enzymes have evolved to bind their natural substrates, and substituents introduced in an attempt merely to alter electron demand at the transition state may have many other interactions with the enzyme protein. The result is very noisy Hammett and Bronsted plots. Whereas conclusions can be drawn from non-enzymic rates varying over a factor of 3, with enzyme reactions, to see any trend above the noise it is usually necessary to have rates ranging over several orders of magnitude. 

The existence of a linear free energy relationship between two enzymes acting on the same library of substrates can give an indication of common mechanism. Thus, a plot of log(kcat/Ani) for hydrolysis of a series of p-nitrophenyl glycosides and aryl glucosides by the GH 1 enzyme from the mesophile Agrobacterium... 

Shifts in AE° on complex formation reflect a difference between the internal equilibrium constant K2 and the overall equilibrium constant Attention has focused on the relationship between K2 and in connection with the optimal free energy profile for an enzyme-catalyzed reaction (117, 118). In a sequential reaction mechanism, the greatest flux of material occurs along pathways lacking both large kinetic barriers and highly stable intermediates (119). in terms of a... 

Enzymes, so often popular for explaining the mechanism of drug action and detoxification, form the subject matter of chapter 3. The present state of knowledge of the relationship of chemical structure of polycyclic hydrocarbons to the likelihood of carcinogenicity is reviewed in chapter 4. The recently developed application of free energy calculations to the action of chemicals on biological systems often leaves the average medicinal chemist bewildered, and chapter 5 aims to introduce and explain the physical chemical concepts involved so that the reader who is interested may be better equipped to read the specialised reviews which are available. In the last chapter, a very active facet of synthetic medicinal chemistry — the synthesis of nitriles - is reviewed. 

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