Lock-and-key hypothesis

To explain substrate specificity, E. Fischer proposed a hypothesis a century ago in which he depicted the substrate as being analogous to a key and the enzyme as its lock. According to this model, the active site has a geometry which is complementary only to its substrate (Fig. 2.10). In contrast, there are many possibilities for a bad substrate to be bound to the enzyme, but only one provides the properly positoned enzyme-substrate complex, as illustrated in Fig. 2.10, which is converted to the product. 

The proteinases chymotrypsin and trypsin are two enzymes for which secondary and tertiary structures have been elucidated by x-ray analysis and which have structures supporting the lock and key hypothesis to a certain extent. The binding site in chymotrypsin and trypsin is a three-dimensional hydrophobic pocket (Fig. 2.11). Bulky amino acid residues such as aromatic amino acids fit neatly into the pocket (chymotrypsin. Fig. 2.11a), as do substrates with lysyl or arginyl residues (trypsin. Fig. 2.11b). Instead of Ser, the trypsin peptide chain has Asp which is present in the deep cleft in the form of a carboxylate anion and which attracts the positively charged lysyl or arginyl residues of the substrate. Thus, the substrate is stabilized and realigned by its peptide bond to face the enzyme s Ser which participates in hydrolysis (transforming locus). 

The peptide substrate is hydrolyzed by the enzyme elastase by the same mechanism as for chymotrypsin. However, here the pocket is closed to such an extent by the side chains of Val and Thr that only the methyl group of alanine can enter the cleft (Fig. 2.11c). Therefore, elastase has specificity for alanyl peptide bonds or alanyl ester bonds. 

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First law of thermodynamics, 24 645-648 First limiting amino acid, 2 601 First-order irreversible chemical kinetics, 25 286-287, 292-293 First-principle approach, in particle size measurement, 13 153 First sale doctrine, 7 793 Fischer, Emil, 16 768 Fischer carbene reaction, 24 35-36 Fischer esterification, 10 499 Fischer formula, 4 697 Fischer-Indole synthesis, 9 288 Fischer lock and key hypothesis, 24 38 Fischer-Tropsch (FT) synthesis, 6 791, 827 12 431... 

The initial steps in enzyme-catalysed reactions involve the binding of the reactants to the enzyme surface and one of the functions of the enzyme is to orientate these reactants relative to each other. This idea was suggested by Fischer as a lock-and-key hypothesis, where the enzyme is the lock and the... 

Various mechanisms of reversible inhibition have been proposed. Competitive inhibition is conceptually the easiest to understand. Recall that the active site of an enzyme is complementary in shape to the shape of the substrate (crudely, the lock and key hypothesis). Suppose a compound which is not the true substrate, but structurally similar to it blocks the active site by binding to it. The true substrate cannot bind and so no reaction will occur. Hence, there is competition between the true substrate and the inhibitor for binding at the active site. 

The understanding of three-dimensional molecular structure and the explanation of ligand-site affinity on hand of shape and functional group complementarity ( lock and key hypothesis) naturally lead to the introduction of the pharmacophore concept in medicinal chemistry and implicitly in computational chemistry see [6] and references therein. The specific physicochemical mechanisms controlling the macromolecule-ligand interactions could be, in principle, understood on a purely... 

Liver alcohol dehydrogenase—see alcohol dehydrogenase Lock-and-key hypothesis 354, 369 Loops 20, 51... 

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. 

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

Figure 4.1 The above diagram illustrates the "lock and key" hypothesis of enzyme action. The approaching substrate fits perfectly into the enzyme—like a key going into a lock. The enzyme-substrate complex is then formed, and products form out of the substrate. The products no longer fit the "lock" of the active site and are released.

Molecular recognition, defined as the favored binding of a molecule (i.e., a substrate) to a specific site in a receptor over other structurally and chemically related molecules, is at the forefront of science.1 s Long before man walked on this earth, nature had succeeded in the creation of a series of biologically based recognition elements with unmatched specificity antibodies, enzymes, and receptors. Perhaps the simplest well-known example of this concept is the lock and key hypothesis that has been used to describe protein-substrate interactions in biological systems.5-7... 

Protein-protein interactions are of immense importance and yet are not well understood. It is probable that these involve the same principles as appear to regulate enzyme activity. The first attempt to understand how protein enzymes can have such great specificity for their targets was proposed by Fischer in 1894 in his conceptually groundbreaking lock and key hypothesis [5], Over half a century later Koshland proposed a modification to this theory arguing that it did not adequately explain the conformational rearrangements that must occur as the enzyme binds the target... 

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. 

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. 

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