Induced-fit: Function, Tasks, Role & Diseases

The induced-fit theory originated with Koshland and corresponds to an extension of the lock-and-key principle, which assumes that anatomical structures fit together. Induced-fit refers to enzymes such as kinase that change their conformation to form an enzyme-ligand complex. In enzyme defects, the induced-fit principle may be affected by perturbations.

What is induced-fit?

There is binding specificity between enzymes and substrates. This binding specificity implies the lock-and-key principle. A special form of the lock-and-key principle is present with induced-fit. Many processes in the body function according to the lock-and-key or hand-in-glove principle. This applies, for example, to articulated joints. The joint head engages in the joint socket like a key in a lock or a hand in a glove. The door does not open until the key fits precisely in the lock. In the same context, certain functions of the body are opened only when structures fit together precisely. A special form of the key-in-lock principle is Induced-fit. This is a theory for the formation of protein-ligand complexes, such as an enzyme-substrate complex in the context of enzyme-catalyzed reactions. Daniel E. Koshland is considered the first to describe the theory and first postulated it in 1958. Unlike the lock-and-key principle, the induced-fit theory does not assume two static structures. Thus, especially in the case of protein-ligand complexes, only a conformational change of the protein involved should allow the complex to form. Koshland considered ligand and protein, or better enzyme, to be dynamic and spoke of an interaction that induces both partners, for the sake of complex formation, to undergo a conformational change.

Function and task

There is binding specificity between enzymes and substrates. This binding specificity implies the lock-and-key principle. Each enzyme carries an active site. This center is shaped to form a complex with a ligand in a way that fits almost perfectly with the spatial shape of the substrate intended for it. In many enzymes, however, the respective active site is present in a less than perfect form as long as it is not bound to a substrate. This observation seems to contradict the lock-and-key principle, because in the case of enzymes and their ligands, shape matching seems to occur first. Thus, as soon as the enzyme attaches to a ligand, intermolecular interactions are induced. These interactions at the intermolecular level cause a conformational change of the enzyme. Conformation refers to the different arrangement possibilities of individual atoms of a molecule that result from simple rotation about an axis. Thus, the conformational change of enzymes corresponds to a change in the spatial arrangement of their molecules and is what enables the formation of an enzyme-substrate complex in the first place. For example, the hexokinase catalyze as enzymes the first step of glycolysis. As soon as these enzymes encounter the substrate glucose, an induced-fit can be observed in the sense of the formation of an “induced fit”. The enzyme hexokinase phosphorylates its ligand glucose to a glucose-6-phosphate with the consumption of ATP. The structure of water resembles that within the alcoholic group of the C6 atom that the enzyme phosphorylates during the reaction. Because of its small size, water molecules could attach to the active site of the enzyme, so hydrolysis of ATP would be produced. However, induced-fit allows the hexokinase to catalyze glucose conversion with high specificity, so ATP hydrolysis must occur at a small scale. Thus, with the induced-fit mechanism, substrate specificity increases. The principle is particularly observable on kinases within the human organism. Induced-fit does not apply to every ligand-receptor complex, because in many cases there are natural limits to the conformational change of both partners.

Diseases and disorders

Disturbed is the induced-fit principle in different enzyme defects. In phenylketonuria, for example, enzymes are restricted in their activity or fail completely. This is usually due to a genetic defect. In phenylketonuria, the enzyme phenylalanine hydroxylase is defective. Phenylalanine is no longer converted into tyrosine and accumulates accordingly.Neurotoxic substances are produced, so that in addition to mental retardation, the patients have a tendency to seizures. Enzyme defects are usually genetically determined and are caused by a defectively coded amino acid sequence in the DNA. Metabolic diseases caused by enzyme defects and such a disturbed induced-fit principle are known as enzymopathies. Pyruvate kinase defects are present, for example, in a defectively coding PKLR gene. This gene is located on gene locus 1q22 of chromosome 1. Different mutations are known from the PKLR allele of pyruvate kinase, which show up as defects in the R form. Hers disease is in turn called glycogenosis type VI and belongs to the group of glycogen storage diseases. It is an autosomal recessive or X-linked inherited metabolic disorder due to enzyme defects. More precisely, the cause lies in various enzyme defects of the phosphorylase kinase system within the liver and muscles. Known in this context are for example the X-linked phosphorylase-b-kinase defect in the liver, the liver phosphorylase defect of autosomal recessive inheritance and the combined failure of phosphorylase-b-kinase within the liver and the musculature. In the context of liver phosphorylase, the causative mutations have been localized to the PYGL gene and are thus located at chromosome 14q21 to q22. The combined liver-muscle phosphorylase deficiency is associated with mutations in the PHKB gene at locus 16q12-q13. Causative mutations in the PHKA2 gene at locus Xp22.2-p22.1 have been identified for the X-linked liver phosphorylase kinase defect. Other glycogenoses may also abolish or complicate the induced-fit effect of the corresponding kinase.