Allosteric enzyme
Allosteric enzymes are enzymes that change their conformational ensemble upon binding of an effector, which results in an apparent change in binding affinity at a different ligand binding site. This "action at a distance" through binding of one ligand affecting the binding of another at a distinctly different site, is the essence of the allosteric concept. Allostery plays a crucial role in many fundamental biological processes, including but not limited to cell signaling and the regulation of metabolism. Allosteric enzymes need not be oligomers as previously thought[1], and in fact many systems have demonstrated allostery within single enzymes [2].
Whereas enzymes without coupled domains/subunits display normal Michaelis-Menten kinetics, most allosteric enzymes have multiple coupled domains/subunits and show cooperative binding. Generally speaking, such cooperativity results in allosteric enzymes displaying a sigmoidal dependence on the concentration of their substrates in positively cooperative systems. This allows most allosteric enzymes to greatly vary catalytic output in response to small changes in effector concentration. Effector molecules, which may be the substrate itself (homotropic effectors) or some other small molecule (heterotropic effector), may cause the enzyme to become more active or less active by redistributing the ensemble between the higher affinity and lower affinity states. The binding sites for heterotropic effectors, called allosteric sites, are usually separate from the active site yet thermodynamically coupled.
[edit] Kinetic properties
The kinetic properties of allosteric enzymes have been explained in terms of a conformational change between a low-activity, low-affinity "tense" or T state and a high-activity, high-affinity "relaxed" or R state. Although these structurally distinct enzyme forms have been shown to exist in several known allosteric enzymes, what is less well understood is the molecular basis for the conversion between the two states. Two main models have been proposed to describe the mechanistic basis of enzyme allostery. In the concerted model of Monod, Wyman, and Changeux [3], the protein is thought to have only two “all-or-none” global states, while the sequential model of Koshland, Nemethy, and Filmer [4] allows for a number of different global conformational/energy states. Recently, the combined use of physical techniques (for example, x-ray crystallography and solution small angle x-ray scattering or SAXS) and genetic techniques (site-directed mutagenesis or SDM) has enabled researchers to investigate more deeply the molecular basis of allostery. The Escherichia coli enzyme aspartate carbamoyltransferase (ATCase) has established itself as one of the model system's for allosteric regulation. However, it is irrefutable that the canonical allosteric system that has shaped our current understanding of allostery is tetrameric vertebrate Hemoglobin. This is mostly in part due to the fact that it was the first biological macromolecule that had its crystal structure solved by Max Perutz.
[edit] References
- ^ Monod, J., Wyman, J, Changeux, J.P. (1965). On the nature of allosteric transitions: a plausible model. J Mol Biol. 12:88-118.
- ^ Gohara, D.W., Di Cera, E. (2011). Allostery in trypsin-like proteases suggests new therapeutic strategies. "Trends Biotechnol".
- ^ Monod, J., Wyman, J, Changeux, J.P. (1965). On the nature of allosteric transitions: a plausible model. J Mol Biol. 12:88-118.
- ^ Koshland DE Jr, Némethy G, Filmer D. (1966). Comparison of experimental binding data and theoretical models in proteins containing subunits. Biochemistry 5(1):365-85.
