Allosteric enzyme

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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.

Contents

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.

Kinetic properties

Hemoglobin, though not an enzyme, is the canonical example of an allosteric protein molecule - and one of the earliest to have its crystal structure solved (by Max Perutz). More recently, the E. coli enzyme aspartate carbamoyltransferase (ATCase) has become another good example of allosteric regulation.

The kinetic properties of allosteric enzymes are often 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. These structurally distinct enzyme forms have been shown to exist in several known allosteric enzymes.

However the molecular basis for conversion between the two states is not well understood. Two main models have been proposed to describe this mechanism: the "concerted model" of Monod, Wyman, and Changeux, [1] and the "sequential model" of Koshland, Nemethy, and Filmer. [6]

In the concerted model, the protein is thought to have two “all-or-none” global states. This model is supported by positive cooperativity where binding of one ligand increases the ability of the enzyme to bind to more ligands. The model is not supported by negative cooperativity where losing one ligand makes it easier for the enzyme to lose more.

In the sequential model there are many different global conformational/energy states. Binding of one ligand changes the enzyme so it can bind more ligands more easily, i.e. every time it binds a ligand it wants to bind another one.

Neither model fully explains allosteric binding, however. The recent 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) may improve our understanding of allostery.

Related Research Articles

G protein-coupled receptor Class of cell surface receptors coupled to G-Protein associated intracelular signaling

G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related proteins that are cell surface receptors that detect molecules outside the cell and activate cellular responses. Coupling with G proteins, they are called seven-transmembrane receptors because they pass through the cell membrane seven times. Ligands can bind either to extracellular N-terminus and loops or to the binding site within transmembrane helices. They are all activated by agonists although a spontaneous auto-activation of an empty receptor can also be observed.

Molecular binding is an interaction between molecules that results in a stable physical association between those molecules. Cooperative binding occurs in binding systems containing more than one type, or species, of molecule and in which one of the partners is not mono-valent and can bind more than one molecule of the other species.

Allosteric regulation Regulation of enzyme activity

In biochemistry, allosteric regulation is the regulation of an enzyme by binding an effector molecule at a site other than the enzyme's active site.

Active site Active region of an enzyme

In biology and biochemistry, the active site is the region of an enzyme where substrate molecules bind and undergo a chemical reaction. The active site consists of amino acid residues that form temporary bonds with the substrate and residues that catalyse a reaction of that substrate. Although the active site occupies only ~10–20% of the volume of an enzyme, it is the most important part as it directly catalyzes the chemical reaction. It usually consists of three to four amino acids, while other amino acids within the protein are required to maintain the tertiary structure of the enzymes.

Cooperativity is a phenomenon displayed by systems involving identical or near-identical elements, which act dependently of each other, relative to a hypothetical standard non-interacting system in which the individual elements are acting independently. One manifestation of this is enzymes or receptors that have multiple binding sites where the affinity of the binding sites for a ligand is apparently increased, positive cooperativity, or decreased, negative cooperativity, upon the binding of a ligand to a binding site. For example, when an oxygen atom binds to one of hemoglobin's four binding sites, the affinity to oxygen of the three remaining available binding sites increases; i.e. oxygen is more likely to bind to a hemoglobin bound to one oxygen than to an unbound hemoglobin. This is referred to as cooperative binding.

Binding site Molecule-specific coordinate bonding area in biological systems

In biochemistry and molecular biology, a binding site is a region on a macromolecule such as a protein that binds to another molecule with specificity. The binding partner of the macromolecule is often referred to as a ligand. Ligands may include other proteins, enzyme substrates, second messengers, hormones, or allosteric modulators. The binding event is often, but not always, accompanied by a conformational change that alters the protein's function. Binding to protein binding sites is most often reversible, but can also be covalent reversible or irreversible.

A transcriptional activator is a protein that increases transcription of a gene or set of genes. Activators are considered to have positive control over gene expression, as they function to promote gene transcription and, in some cases, are required for the transcription of genes to occur. Most activators are DNA-binding proteins that bind to enhancers or promoter-proximal elements. The DNA site bound by the activator is referred to as an "activator-binding site". The part of the activator that makes protein–protein interactions with the general transcription machinery is referred to as an "activating region" or "activation domain".

Receptor (biochemistry) Protein molecule receiving signals for a cell

In biochemistry and pharmacology, receptors are chemical structures, composed of protein, that receive and transduce signals that may be integrated into biological systems. These signals are typically chemical messengers which bind to a receptor and cause some form of cellular/tissue response, e.g. a change in the electrical activity of a cell. There are three main ways the action of the receptor can be classified: relay of signal, amplification, or integration. Relaying sends the signal onward, amplification increases the effect of a single ligand, and integration allows the signal to be incorporated into another biochemical pathway.

GABA<sub>A</sub> receptor Ionotropic receptor and ligand-gated ion channel

The GABAA receptor (GABAAR) is an ionotropic receptor and ligand-gated ion channel. Its endogenous ligand is γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. Upon opening, the GABAA receptor on the postsynaptic cell is selectively permeable to chloride ions (Cl−) and, to a lesser extent, bicarbonate ions (HCO3−). Depending on the membrane potential and the ionic concentration difference, this can result in ionic fluxes across the pore. If the membrane potential is higher than the equilibrium potential (also known as the reversal potential) for chloride ions, when the receptor is activated Cl− will flow into the cell. This causes an inhibitory effect on neurotransmission by diminishing the chance of a successful action potential occurring at the postsynaptic cell. The reversal potential of the GABAA-mediated inhibitory postsynaptic potential (IPSP) in normal solution is −70 mV, contrasting the GABAB IPSP (-100 mV).

Jean-Pierre Changeux French neuroscientist

Jean-Pierre Changeux is a French neuroscientist known for his research in several fields of biology, from the structure and function of proteins, to the early development of the nervous system up to cognitive functions. Although being famous in biological sciences for the MWC model, the identification and purification of the nicotinic acetylcholine receptor and the theory of epigenesis by synapse selection are also notable scientific achievements. Changeux is known by the non-scientific public for his ideas regarding the connection between mind and physical brain. As put forth in his book, Conversations on Mind, Matter and Mathematics, Changeux strongly supports the view that the nervous system functions in a projective rather than reactive style and that interaction with the environment, rather than being instructive, results in the selection amongst a diversity of preexisting internal representations.

A regulatory enzyme is an enzyme in a biochemical pathway which, through its responses to the presence of certain other biomolecules, regulates the pathway activity. This is usually done for pathways whose products may be needed in different amounts at different times, such as hormone production. Regulatory enzymes exist at high concentrations so their activity can be increased or decreased with changes in substrate concentrations.

Ligand (biochemistry) Substance that forms a complex with a biomolecule

In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. The etymology stems from ligare, which means 'to bind'. In protein-ligand binding, the ligand is usually a molecule which produces a signal by binding to a site on a target protein. The binding typically results in a change of conformational isomerism (conformation) of the target protein. In DNA-ligand binding studies, the ligand can be a small molecule, ion, or protein which binds to the DNA double helix. The relationship between ligand and binding partner is a function of charge, hydrophobicity, and molecular structure.

Monod-Wyman-Changeux model Biochemical model of protein transitions

In biochemistry, the Monod-Wyman-Changeux model describes allosteric transitions of proteins made up of identical subunits. It was proposed by Jean-Pierre Changeux in his PhD thesis, and described by Jacques Monod, Jeffries Wyman, and Jean-Pierre Changeux. It contrasts with the sequential model.

Glutamate dehydrogenase 1

GLUD1 is a mitochondrial matrix enzyme, one of the family of glutamate dehydrogenases that are ubiquitous in life, with a key role in nitrogen and glutamate (Glu) metabolism and energy homeostasis. This dehydrogenase is expressed at high levels in liver, brain, pancreas and kidney, but not in muscle. In the pancreatic cells, GLUD1 is thought to be involved in insulin secretion mechanisms. In nervous tissue, where glutamate is present in concentrations higher than in the other tissues, GLUD1 appears to function in both the synthesis and the catabolism of glutamate and perhaps in ammonia detoxification.

Sequential model

The sequential model is a theory that describes cooperativity of protein subunits. It postulates that a protein's conformation changes with each binding of a ligand, thus sequentially changing its affinity for the ligand at neighboring binding sites.

Receptor theory is the application of receptor models to explain drug behavior. Pharmacological receptor models preceded accurate knowledge of receptors by many years. John Newport Langley and Paul Ehrlich introduced the concept of a receptor that would mediate drug action at the beginning of the 20th century. Alfred Joseph Clark was the first to quantify drug-induced biological responses. So far, nearly all of the quantitative theoretical modelling of receptor function has centred on ligand-gated ion channels and GPCRs.

Morpheein Model of protein allosteric regulation

Morpheeins are proteins that can form two or more different homo-oligomers, but must come apart and change shape to convert between forms. The alternate shape may reassemble to a different oligomer. The shape of the subunit dictates which oligomer is formed. Each oligomer has a finite number of subunits (stoichiometry). Morpheeins can interconvert between forms under physiological conditions and can exist as an equilibrium of different oligomers. These oligomers are physiologically relevant and are not misfolded protein; this distinguishes morpheeins from prions and amyloid. The different oligomers have distinct functionality. Interconversion of morpheein forms can be a structural basis for allosteric regulation. A mutation that shifts the normal equilibrium of morpheein forms can serve as the basis for a conformational disease. Features of morpheeins can be exploited for drug discovery. The dice image represents a morpheein equilibrium containing two different monomeric shapes that dictate assembly to a tetramer or a pentamer. The one protein that is established to function as a morpheein is porphobilinogen synthase, though there are suggestions throughout the literature that other proteins may function as morpheeins.

Cell surface receptor Class of ligand activated receptors localized in surface of plama cell membrane

Cell surface receptors are receptors that are embedded in the plasma membrane of cells. They act in cell signaling by receiving extracellular molecules. They are specialized integral membrane proteins that allow communication between the cell and the extracellular space. The extracellular molecules may be hormones, neurotransmitters, cytokines, growth factors, cell adhesion molecules, or nutrients; they react with the receptor to induce changes in the metabolism and activity of a cell. In the process of signal transduction, ligand binding affects a cascading chemical change through the cell membrane.

In pharmacology and biochemistry, allosteric modulators are a group of substances that bind to a receptor to change that receptor's response to stimulus. Some of them, like benzodiazepines, are drugs. The site that an allosteric modulator binds to is not the same one to which an endogenous agonist of the receptor would bind. Modulators and agonists can both be called receptor ligands.

Allostery is the most direct and efficient way for regulation of biological macromolecule function induced by the binding of a ligand at an allosteric site topographically distinct from the orthosteric site. Due to the inherent high receptor selectivity and lower target-based toxicity, it is also expected to play a more positive role in drug discovery and bioengineering, leading to rapid growth on allosteric findings.

References

  1. 1 2 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.
  2. ↑ 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.
  3. ↑ 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.
  4. ↑ 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.
  5. ↑ 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.
  6. ↑ Koshland DE, Némethy G, Filmer D (January 1966). "Comparison of experimental binding data and theoretical models in proteins containing subunits". Biochemistry. 5 (1): 365–85. doi:10.1021/bi00865a047. PMID   5938952.
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