The allosterism or allosteric regulation is defined as the process of inhibition or activation of enzyme mediated by a regulatory molecule different from its substrate and which acts at a specific site of its structure, different from the active site thereof.
The term "allosteric" or "allosterism" comes from the Greek roots "allos", which means "other" and "stereós", which means "form" or "place"; so it is literally translated as "another space", "another place" or "another structure".
Graphic diagram of an allosteric regulation. (A) Active site. (B) Allosteric site. (C) Substrate. (D) Inhibitor. (E) Enzyme. (Source: Isaac Webb Via Wikimedia Commons)
Some authors describe allosterism as a process by which remote sites in a system (the structure of an enzyme, for example) are energetically coupled to produce a functional response, which is why it can be assumed that a change in a region can affect any other in it.
This type of regulation is typical of enzymes that participate in multiple known biological processes, such as signal transduction, metabolism (anabolism and catabolism), regulation of gene expression, among others.
The first ideas about allosterism and its participation in the control of cellular metabolism were postulated in the 1960s by F. Monod, F. Jacob and J. Changeux, while they studied the biosynthetic pathways of different amino acids, which were inhibited after the accumulation of final products.
Although the first publication in this regard had to do with genetic regulation, shortly thereafter Monod, Wyman and Changeux expanded the concept of allosterism to proteins with enzymatic activity and proposed a model based on multimeric proteins, based mainly on the interactions between subunits. when any of these were attached to an effector.
Many of the later concepts had their foundations in the theory of "induced fit" that was introduced by Koshland a few years earlier.
General features
In general, all enzymes have two different sites for ligand binding: one is known as the active site, to which the molecules that function as a substrate (responsible for the biological activity of the enzyme) bind, and the other is known as the allosteric site, which is specific for other metabolites.
These "other metabolites" are called allosteric effectors and can have positive or negative effects on the rate of enzyme-catalyzed reactions or the affinity with which they bind to their substrates at the active site.
Usually, the binding of an effector in the allosteric site of an enzyme causes an effect in another site of the structure, modifying its activity or its functional performance.
Graphic scheme of the reaction of an allosteric enzyme (Source: File: Enzyme allostery en.png: File: Enzyme allostery.png: Allostery.png: Nicolas Le Novere (talk). Lenov at en.wikipediaderivative work: TimVickers (talk) derivative work: Retama (talk) derivative work: KES47.
Although there are thousands of examples of allosterism or allosteric regulation in nature, some have been more prominent than others. Such is the case of hemoglobin, which was one of the first proteins described in depth in the structural aspect.
Hemoglobin is a very important protein for many animals, as it is responsible for the transport of oxygen through the blood from the lungs to the tissues. This protein presents homotropic and heterotropic allosteric regulation at the same time.
The homotropic allosterism of hemoglobin has to do with the fact that the binding of an oxygen molecule to one of the subunits that compose it directly affects the affinity with which the adjacent subunit binds to another oxygen molecule, increasing it (positive regulation or cooperativism).
Heterotropic allosterism
Heterotropic allosterism, on the other hand, is related to the effects that both the pH and the presence of 2,3-diphosphoglycerate have on the binding of oxygen to the subunits of this enzyme, inhibiting it.
Aspartate transcarbamylase or ATCase, which participates in the pyrimidine synthesis pathway, is also one of the "classic" examples of allosteric regulation. This enzyme, which has 12 subunits, of which 6 are catalytically active and 6 are regulatory, is heterotropically inhibited by the end product of the pathway it leads, cytidine triphosphate (CTP).
Lactose operon
The fruit of the first ideas of Monod, Jacob and Changeux was an article published by Jacob and Monod related to the lactose operon of Escherichia coli i, which is one of the typical examples of heterotropic allosteric regulation at the genetic level.
The allosteric regulation of this system is not related to the ability of a substrate to convert into a product, but to the binding affinity of a protein to the operator DNA region.
References
- Changeux, JP, & Edelstein, SJ (2005). Allosteric mechanisms of signal transduction. Science, 308 (5727), 1424-1428.
- Goldbeter, A., & Dupont, G. (1990). Allosteric regulation, cooperativity, and biochemical oscillations. Biophysical chemistry, 37 (1-3), 341-353.
- Jiao, W., & Parker, EJ (2012). Using a combination of computational and experimental techniques to understand the molecular basis for protein allostery. In Advances in protein chemistry and structural biology (Vol. 87, pp. 391-413). Academic Press.
- Kern, D., & Zuiderweg, ER (2003). The role of dynamics in allosteric regulation. Current opinion in structural biology, 13 (6), 748-757.
- Laskowski, RA, Gerick, F., & Thornton, JM (2009). The structural basis of allosteric regulation in proteins. FEBS letters, 583 (11), 1692-1698.
- Mathews, CK, Van Holde, KE, & Ahern, KG (2000). Biochemistry, ed. San Francisco, Calif.