The Lock and Key Concept

A number of glycosides were available to Fischer by way of the Koenigs-Knorr reaction and his own glycoside synthesis, which involves treatment of 

The Selective Fermentation of Natural Sugars by Pure Yeasts 

These present observations are undoubtedly in favor of the assumption that the yeast 

Of course, it is now established that the glycolysis of glucose to carbon dioxide and ethanol occurs by way of a complex pathway involving 10 different enzymes acting on a variety of sugar phosphate intermediates. The extracellular enzyme preparation that Fischer used was termed invertin, the origin of the term for the enzyme we now know as invertase. He termed the intracellular enzyme yeast-glucase (31) and this enzyme is of the type we now refer to as an amylase. 

The research with Thierfelder (30) had led to the hypothesis that the active chemical agents of yeast cells can react only with those sugars that are configurationally related. It was this stereochemical assessment of the fermentation process that, in turn, now led to the question (32)  

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HOW EMIL FISCHER WAS LED TO THE LOCK AND KEY CONCEPT FOR ENZYME SPECIFICITY1... 

Enzymic methods in preparative carbohydrate chemistry, 49, 175-237 Enzyme specificity, how Emil Fischer was led to the lock and key concept for, 50, 1-20... 

When students learn about enzymes, it is nearly always stated, very dogmatically, that enzymes will act on only one chemical—they have very narrow substrate specificity. Indeed, when introducing the concept of enzyme action at an elementary level, the analogy of the lock and key is often used to illustrate the concept of specificity. In other words, students are told that for every product found in a cell, there will be one enzyme that has made that product and that enzyme will make no other product. This idea was extended to the idea of one gene-one enzyme-one reaction. There is indeed a considerable body of evidence to support the view that many enzymes do have narrow substrate specificity. However, exceptions were known to this rule . But more importantly, the types of enzymes used as good examples of the lock and key concept were drawn... 

Impressed by the specificity of enzymatic action, biochemists early adopted a "lock-and-key" theory which stated that for a reaction to occur the substrate must fit into an active site precisely. Modem experiments have amply verified the idea. A vast amount of kinetic data on families of substrates and related competitive inhibitors support the idea and numerous X-ray structures of enzymes with bound inhibitors or with very slow substrates have given visual evidence of the reality of the lock-and-key concept. Directed mutation of genes of many enzymes of known three-dimensional structure has provided additional proof. 

Figure 25-18 Illustration of the lock-and-key concept of enzyme-substrate Interaction (top) and of the induced-fit theory, whereby the enzyme molds to the substrate through conformational changes (bottom)...

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. 

R. U. lemieux and U. Spohr, How Emil Fisher was led to the lock and key concept for enzyme specificity, Tldv. Carbohydr. Chem Biochem. 50 1(1994). 

A description of the pioneering work of Emil Fischer in the period around 1890, especially relating to his elucidation of the molecular configuration of glucose and aspects of his philosophical view of chemistry, has appeared. Lemieux and Spohr have looked in detail at how Fischer was led to the "lock and key" concept for enzyme specificity. An animated 386-based PC program with VGA graphics has been produced to assist visualization of the relationship between Fischer and Haworth projections of monosaccharides. ... 

The lock-and-key concepts at present are considered in drug design. Samples of protein targets were isolated and X-ray crystallography discovered their molecular structural design. Molecules are conceived either on the basis of similarities with recognized reference structures or on the basis of their complementarily with the three dimensional (3D) structure of well-known active sites. 

We have left this discussion until after description of the Eyring transition-state theory because there are many similarities. The main difference is that usually the active site pocket of an enzyme has two main geometrical attributes. First, there is the lock and key analogy, which notes that usually the entrance to the active site is stereospecific to a particular substrate molecule or a class of molecules. We see that in Figure 8.6 with catechol oxidase for substituted phenols. Much has been made of the lock-and-key concept in pharmaceutical research since that is how substrate specificity is achieved and many medicinal dmg molecules are designed with a specific shape and... 

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