Acting as a suicide inhibitor, TPCK alkylates a critical residue and halts the function of chymotrypsin. In the gut-bound protease chymotrypsin, studies with the radio-labeled substrate analog Tosyl phenylalanyl chloromethyl ketone (TPCK) has identified some of the catalytic amino acid residues. This method of crystallography has become an indispensable resource in the study of changes in quaternary structure during enzymatic catalysis, provided the enzyme in question has a know substrate analog.Īnalogs that have an effect on their target can be used to identify properties of the enzyme's primary structure. This highlights the academically compelling properties of substrate analogs they resemble the natural substrate enough to bind and affect the enzyme, but not enough to be processed as the natural substrate would. Substrate analogs have made it possible to visualize the short-lived conformational change in N-acetyltransferase when it binds its substrate. When coupled with X-ray crystallography, bound analogs have provided crucial insight into the mechanisms of enzymes. Suicide inhibitor analogs have also made it possible to determine the structural features of various enzymes. Analogs that act as a suicide inhibitor are useful in drug design, the most famous of which is penicillin (see Beta-lactam antibiotic for mechanism). Substrate analogs can have a variety of academic and medical applications.
It is not enough to simply possess a few functional groups in common with the substrate, as enzyme-substrate interaction often involves multiple points of contact. To mimic a substrate's transition state is no small task, however. For example, the analog N-(Phosphonacetyl)-L-aspartate (PALA) differs from the natural transition state by only a few functional groups.
The specific mechanism varies from one analog to another, but the general ability for enzymatic analogs to do this stems from their structural similarity to the transition state of an enzyme's substrate. While an incredibly large number of non-substrate molecules may enter the active site of an enzyme, only a very small number of these, analogs, will be able to elicit affection from the enzyme. Many enzyme inhibitors are substrate analogs. This change in transition-state free energy increases the reaction rate according to the Arrhenius equation. Most enzymes stabilize the transition state, thus lowering the free energy associated with it. All substrates must pass though the transition state, a high energy conformation that normally prevents the spontaneous conversion of substrate to product. An enzyme is a molecule that binds a specific substrate and increases the rate at which the substrate is converted into a specific product.
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