Emil Fischer’s Lock-and-Key Hypothesis

Cramer, Friedrich, Emil Fischer s Lock-and-Key Hypothesis after 100 Years - Towards a Supracellular Chemistry, 1, 1. 

The region of the enzyme that interacts with substrates is referred to as the active site. For reaction to occur there must be an appropriate fit between the three-dimensional structure of this site and the geometry of the reactant molecule so that an enzyme-substrate complex may form (Emil Fischer s lock and key hypothesis). Enzymes are relatively labile species and when subjected to unfavorable conditions of temperature, pH, pressure, chemical environment, etc., they can lose their catalytic activity. In these situations, deactivation of the enzyme can usually be attributed to changes in the geometric configuration of the active site. 

Just one year after Ostwald s hypothesis about the existence of catalysts in 1893, when nobody yet had a clear idea of the structure and composition of enzymes, Emil Fischer voiced the idea for the first time that a substrate molecule fits into the pocket of an enzyme, the lock-and-key hypothesis (Fischer, 1894). Both the lock (enzyme) as well as the key (substrate) were regarded as rigid. 

The specificity of enzymes is far greater than that shown by most chemical catalysts. In the enzymatic synthesis of proteins, for example (through reactions that take place on ribosomes. Section 25.5E), polypeptides consisting of well over 1000 amino acid residues are synthesized virtually without error. It was Emil Fischer s discovery, in 1894, of the ability of enzymes to distinguish between a- and jS-glycosidic linkages (Section 22.12) that led him to formulate his lock-and-key hypothesis for enzyme specificity. 

An enzyme is typically a large protein molecule that contains one or more active sites where interactions with substrates take place. These sites are structurally compatible with specific substrate molecules, in much the same way as a key fits a particular lock. In fact, the notion of a rigid enzyme structure that binds only to molecules whose shape exactly matches that of the active site was the basis of an early theory of enzyme catalysis, the so-called lock-and-key theory developed by the German chemist Emil Fischer in 1894 (Figure 13.28). Fischer s hypothesis accounts for the specificity of enzymes, but it contradicts research evidence that a single enzyme binds to substrates of different sizes and shapes. Chemists now know that an enzyme molecule (or at least its active site) has a fair amount of structural flexibility and can modify its shape to accommodate more than one type of substrate. Figure 13.29 shows a molecular model of an enzyme in action. 

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