Global InformationAllosteric enzyme information
Allosteric enzymes are enzymes that change their conformational ensemble upon binding of an effector (allosteric modulator) 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] In biochemistry, allosteric regulation (or allosteric control) is the regulation of a protein by binding an effector molecule at a site other than the enzyme's active site.
The site to which the effector binds is termed the allosteric site. Allosteric sites allow effectors to bind to the protein, often resulting in a conformational change involving protein dynamics. Effectors that enhance the protein's activity are referred to as allosteric activators, whereas those that decrease the protein's activity are called allosteric inhibitors. [citation needed]
Allosteric regulations are a natural example of control loops, such as feedback from downstream products or feedforward from upstream substrates. Long-range allostery is especially important in cell signaling.[3] Allosteric regulation is also particularly important in the cell's ability to adjust enzyme activity.
The term allostery comes from the Greek allos (ἄλλος), "other," and stereos (στερεὀς), "solid (object)." This is in reference to the fact that the regulatory site of an allosteric protein is physically distinct from its active site.
The protein catalyst (enzyme) may be part of a multi-subunit complex, and/or may transiently or permanently associate with a Cofactor (e.g. adenosine triphosphate). Catalysis of biochemical reactions is vital due to the very low reaction rates of the uncatalysed reactions. A key driver of protein evolution is the optimization of such catalytic activities via protein dynamics.[4]
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. Allosteric Database (ASD, http://mdl.shsmu.edu.cn/ASD) [5] provides a central resource for the display, search and analysis of the structure, function and related annotation for allosteric molecules, including allosteric enzymes and their modulators. Each enzyme is annotated with detailed description of allostery, biological process and related diseases, and each modulator with binding affinity, physicochemical properties and therapeutic area.
- ^ Monod J, Wyman J, Changeux JP (May 1965). "On the nature of allosteric transitions: a plausible model". Journal of Molecular Biology. 12: 88–118. doi:10.1016/s0022-2836(65)80285-6. PMID 14343300.
- ^ Gohara DW, Di Cera E (November 2011). "Allostery in trypsin-like proteases suggests new therapeutic strategies". Trends in Biotechnology. 29 (11): 577–85. doi:10.1016/j.tibtech.2011.06.001. PMC 3191250. PMID 21726912.
- ^ Bu Z, Callaway DJ (2011). "Proteins MOVE! Protein dynamics and long-range allostery in cell signaling". Advances in Protein Chemistry and Structural Biology. 83: 163–221. doi:10.1016/B978-0-12-381262-9.00005-7. ISBN 9780123812629. PMID 21570668.
- ^ Kamerlin, S. C.; Warshel, A (2010). "At the dawn of the 21st century: Is dynamics the missing link for understanding enzyme catalysis?". Proteins: Structure, Function, and Bioinformatics. 78 (6): 1339–75. doi:10.1002/prot.22654. PMC 2841229. PMID 20099310.
- ^ Huang Z, Zhu L, Cao Y, Wu G, Liu X, Chen Y, Wang Q, Shi T, Zhao Y, Wang Y, Li W, Li Y, Chen H, Chen G, Zhang J (January 2011). "ASD: a comprehensive database of allosteric proteins and modulators". Nucleic Acids Research. 39 (Database issue): D663–9. doi:10.1093/nar/gkq1022. PMC 3013650. PMID 21051350.