Fischer’s lock and key concept

As already mentioned, the glucoamylase project was chosen to illustrate Emil Fischer s lock and key concept for enzyme specificity. It is seen that his vision has become unequivocally established. Many other developments could have been chosen, as can be appreciated from recent reviews by Hehre (54) and by Svensson (55). Comforth (56) provided a fine overview of asymmetry and enzyme action in his Nobel prize lecture. Noteworthy is the conclusion that stereospecificity is something not just incidental, but essential to enzyme catalysis. In other words, the key must fit the lock. 

Lemieux and Spohr (Alberta) here trace our understanding of enzyme specificity in broad perspective as they assess Emil Fischer s lock and key concept advanced a century ago in relation to current ideas of molecular recognition. It may be noted that the very first article in Volume 1 of Advances, by Claude S. Hudson, was devoted to the Fischer cyanohydrin synthesis and the consequences of asymmetric induction. 

The life and work of one of the greatest carbohydrate scientists of our time, Raymond U. Lemieux, is recalled here in a sensitive account by Bundle (Edmonton). During a remarkably productive career extending over more than half a century, Lemieux pioneered the application of NMR spectroscopy in chemistry, developed rational approaches for glycosidic coupling, made major contributions to our understanding of three-dimensional carbohydrate structures and protein binding, and made important contributions in the biomedical area. His own articles in these Advances include the chemistry of streptomycin in Volume 3, the mechanisms of replacement reactions in Volume 9, and in Volume 50 a consideration of Emil Fischer s lock and key concept of enzyme specificity. 

It was entirely appropriate that the fine statesman of science, Friedrich Cramer (Gottingen) had the last word today. In his own inimitable way he provided for us an overview of the whole area of molecular recognition illustrated simply by Emil Fischer s "Lock and Key" concept. 

This development was important as it gave support to Koshand s induced fit model that had superseded Fischer s lock and key hypothesis. From a mechanistic point of view Koshland argued that the so called induced fit model could account for enzymes structural order which must exist if they can crystallize [8], It also explained the conformational changes essential if reactants were to be bound, reactions occur, and products disgorged. These two iconic concepts are shown in Fig. 4.3. 

Important milestones in the rationalization of enzyme catalysis were the lock-and-key concept (Fischer, 1894), Pauling s postulate (1944) and induced fit (Koshland, 1958). Pauling s postulate claims that enzymes derive their catalytic power from transition-state stabilization the postulate can be derived from transition state theory and the idea of a thermodynamic cycle. The Kurz equation, kaJkunat Ks/Kt, is regarded as the mathematical form of Pauling s postulate and states that transition states in the case of successful catalysis must bind much more tightly to the enzyme than ground states. Consequences of the Kurz equation include the concepts of effective concentration for intramolecular reactions, coopera-tivity of numerous interactions between enzyme side chains and substrate molecules, and diffusional control as the upper bound for an enzymatic rate. 

The study of these biogenetic pathways was much assisted by the use of isotopic labeling, and Harold Urey (1893-1987) at Columbia and Martin D. Kamen (b.1913) at Berkeley were both proto-bioorganic chemists. In more recent years, NMR has come to play an important role in both mechanism and structure studies (see section on physical instrumentation). The concept of a relationship between the structure of a compound and its biochemical functioning goes back to Emil Fischer s model of a lock and key , first formulated in 1894, but many years were to elapse before bioorganic chemists were able to show how the lock and key fitted together. 

If a metaphorical statement can ever reveal how things are , Emil Fischer s static lock-and-key metaphor [31a] ought to be replaced with a dynamic one. This was done by D. E. Koshland s induced-fit concept [31b], which readily produced the self-explanatory hand-and-glove metaphor. Binding of a given effector will bring about a conformational change of the receptor that is favorable for catalytic activity of the formed supermolecule. 

The induced-fit theory first described by Daniel E. Koshland. Jr., in 1958 is one of the most fundamental discoveries of our age and is a development of Emil Fischer s well-known lock and key theory,it should be noted that an important characteristic of the key-lock theory is that the enzyme accommodates the substrate without having to change the shape of the active site however, in the induced-fit model, the enzyme changes shape when it reacts, like a glove into which a hand is thrust. To visualize the concepts of induced fit and keylock, two binding models are illustrated in Fig. 1. 

Multinuclear NMR studies revealed the presence of only a single diastereomer (A or A ) for reactions of EAC with the rhodium complex of the chiral ligand (S,S)-CHIRAPHOS. One might assume that the product chirality is determined by this preferred mode of substrate binding. This would be a form of "lock-and-key" mechanism that has its origins in Fischer s early concepts of enz)unatic stereospecificity. This assumption, however, is incorrect. The predominant enantiomer of the product is actually formed from the minor diastereomer of the catalyst— namely, olefin adduct A. 

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