Enzyme
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Enzymes (
Enzymes are known to catalyze more than 5,000 biochemical reaction types.
Like all catalysts, enzymes increase the reaction rate by lowering its activation energy. Some enzymes can make their conversion of substrate to product occur many millions of times faster. An extreme example is orotidine 5'-phosphate decarboxylase, which allows a reaction that would otherwise take millions of years to occur in milliseconds.[5][6] Chemically, enzymes are like any catalyst and are not consumed in chemical reactions, nor do they alter the equilibrium of a reaction. Enzymes differ from most other catalysts by being much more specific. Enzyme activity can be affected by other molecules: inhibitors are molecules that decrease enzyme activity, and activators are molecules that increase activity. Many therapeutic drugs and poisons are enzyme inhibitors. An enzyme's activity decreases markedly outside its optimal temperature and pH, and many enzymes are (permanently) denatured when exposed to excessive heat, losing their structure and catalytic properties.
Some enzymes are used commercially, for example, in the synthesis of antibiotics. Some household products use enzymes to speed up chemical reactions: enzymes in biological washing powders break down protein, starch or fat stains on clothes, and enzymes in meat tenderizer break down proteins into smaller molecules, making the meat easier to chew.
Etymology and history
By the late 17th and early 18th centuries, the digestion of meat by stomach secretions[7] and the conversion of starch to sugars by plant extracts and saliva were known but the mechanisms by which these occurred had not been identified.[8]
French chemist
In 1877, German physiologist
The biochemical identity of enzymes was still unknown in the early 1900s. Many scientists observed that enzymatic activity was associated with proteins, but others (such as Nobel laureate Richard Willstätter) argued that proteins were merely carriers for the true enzymes and that proteins per se were incapable of catalysis.[16] In 1926, James B. Sumner showed that the enzyme urease was a pure protein and crystallized it; he did likewise for the enzyme catalase in 1937. The conclusion that pure proteins can be enzymes was definitively demonstrated by John Howard Northrop and Wendell Meredith Stanley, who worked on the digestive enzymes pepsin (1930), trypsin and chymotrypsin. These three scientists were awarded the 1946 Nobel Prize in Chemistry.[17]
The discovery that enzymes could be crystallized eventually allowed their structures to be solved by x-ray crystallography. This was first done for lysozyme, an enzyme found in tears, saliva and egg whites that digests the coating of some bacteria; the structure was solved by a group led by David Chilton Phillips and published in 1965.[18] This high-resolution structure of lysozyme marked the beginning of the field of structural biology and the effort to understand how enzymes work at an atomic level of detail.[19]
Classification and nomenclature
Enzymes can be classified by two main criteria: either amino acid sequence similarity (and thus evolutionary relationship) or enzymatic activity.
Enzyme activity. An enzyme's name is often derived from its substrate or the chemical reaction it catalyzes, with the word ending in -ase.[1]: 8.1.3 Examples are lactase, alcohol dehydrogenase and DNA polymerase. Different enzymes that catalyze the same chemical reaction are called isozymes.[1]: 10.3
The International Union of Biochemistry and Molecular Biology have developed a nomenclature for enzymes, the EC numbers (for "Enzyme Commission"). Each enzyme is described by "EC" followed by a sequence of four numbers which represent the hierarchy of enzymatic activity (from very general to very specific). That is, the first number broadly classifies the enzyme based on its mechanism while the other digits add more and more specificity.[20]
The top-level classification is:
- EC 1, oxidation/reduction reactions
- EC 2, Transferases: transfer a functional group (e.g. a methyl or phosphate group)
- EC 3, Hydrolases: catalyze the hydrolysis of various bonds
- EC 4, Lyases: cleave various bonds by means other than hydrolysis and oxidation
- EC 5, Isomerases: catalyze isomerization changes within a single molecule
- EC 6, Ligases: join two molecules with covalent bonds.
- EC 7, Translocases: catalyze the movement of ions or molecules across membranes, or their separation within membranes.
These sections are subdivided by other features such as the substrate, products, and
Sequence similarity. EC categories do not reflect sequence similarity. For instance, two ligases of the same EC number that catalyze exactly the same reaction can have completely different sequences. Independent of their function, enzymes, like any other proteins, have been classified by their sequence similarity into numerous families. These families have been documented in dozens of different protein and protein family databases such as Pfam.[22]
Non-homologous isofunctional enzymes. Unrelated enzymes that have the same enzymatic activity have been called non-homologous isofunctional enzymes.[23] Horizontal gene transfer may spread these genes to unrelated species, especially bacteria where they can replace endogenous genes of the same function, leading to hon-homologous gene displacement.
Structure
Enzymes are generally globular proteins, acting alone or in larger complexes. The sequence of the amino acids specifies the structure which in turn determines the catalytic activity of the enzyme.[24] Although structure determines function, a novel enzymatic activity cannot yet be predicted from structure alone.[25] Enzyme structures unfold (denature) when heated or exposed to chemical denaturants and this disruption to the structure typically causes a loss of activity.[26] Enzyme denaturation is normally linked to temperatures above a species' normal level; as a result, enzymes from bacteria living in volcanic environments such as hot springs are prized by industrial users for their ability to function at high temperatures, allowing enzyme-catalysed reactions to be operated at a very high rate.
Enzymes are usually much larger than their substrates. Sizes range from just 62 amino acid residues, for the monomer of 4-oxalocrotonate tautomerase,[27] to over 2,500 residues in the animal fatty acid synthase.[28] Only a small portion of their structure (around 2–4 amino acids) is directly involved in catalysis: the catalytic site.[29] This catalytic site is located next to one or more binding sites where residues orient the substrates. The catalytic site and binding site together compose the enzyme's active site. The remaining majority of the enzyme structure serves to maintain the precise orientation and dynamics of the active site.[30]
In some enzymes, no amino acids are directly involved in catalysis; instead, the enzyme contains sites to bind and orient catalytic
A small number of
Mechanism
Substrate binding
Enzymes must bind their substrates before they can catalyse any chemical reaction. Enzymes are usually very specific as to what
Some of the enzymes showing the highest specificity and accuracy are involved in the copying and expression of the genome. Some of these enzymes have "proof-reading" mechanisms. Here, an enzyme such as DNA polymerase catalyzes a reaction in a first step and then checks that the product is correct in a second step.[33] This two-step process results in average error rates of less than 1 error in 100 million reactions in high-fidelity mammalian polymerases.[1]: 5.3.1 Similar proofreading mechanisms are also found in RNA polymerase,[34] aminoacyl tRNA synthetases[35] and ribosomes.[36]
Conversely, some enzymes display
"Lock and key" model
To explain the observed specificity of enzymes, in 1894
Induced fit model
In 1958,
Catalysis
Enzymes can accelerate reactions in several ways, all of which lower the activation energy (ΔG‡, Gibbs free energy)[45]
- By stabilizing the transition state:
- Creating an environment with a charge distribution complementary to that of the transition state to lower its energy[46]
- By providing an alternative reaction pathway:
- Temporarily reacting with the substrate, forming a covalent intermediate to provide a lower energy transition state[47]
- By destabilising the substrate ground state:
- Distorting bound substrate(s) into their transition state form to reduce the energy required to reach the transition state[48]
- By orienting the substrates into a productive arrangement to reduce the reaction entropy change[49] (the contribution of this mechanism to catalysis is relatively small)[50]
Enzymes may use several of these mechanisms simultaneously. For example, proteases such as trypsin perform covalent catalysis using a catalytic triad, stabilise charge build-up on the transition states using an oxyanion hole, complete hydrolysis using an oriented water substrate.[51]
Dynamics
Enzymes are not rigid, static structures; instead they have complex internal dynamic motions – that is, movements of parts of the enzyme's structure such as individual amino acid residues, groups of residues forming a
Substrate presentation
This section needs additional citations for verification. (October 2023) |
Substrate presentation is a process where the enzyme is sequestered away from its substrate. Enzymes can be sequestered to the plasma membrane away from a substrate in the nucleus or cytosol. Or within the membrane, an enzyme can be sequestered into lipid rafts away from its substrate in the disordered region. When the enzyme is released it mixes with its substrate. Alternatively, the enzyme can be sequestered near its substrate to activate the enzyme. For example, the enzyme can be soluble and upon activation bind to a lipid in the plasma membrane and then act upon molecules in the plasma membrane.
Allosteric modulation
Allosteric sites are pockets on the enzyme, distinct from the active site, that bind to molecules in the cellular environment. These molecules then cause a change in the conformation or dynamics of the enzyme that is transduced to the active site and thus affects the reaction rate of the enzyme.[53] In this way, allosteric interactions can either inhibit or activate enzymes. Allosteric interactions with metabolites upstream or downstream in an enzyme's metabolic pathway cause feedback regulation, altering the activity of the enzyme according to the flux through the rest of the pathway.[54]
Cofactors
Some enzymes do not need additional components to show full activity. Others require non-protein molecules called cofactors to be bound for activity.
An example of an enzyme that contains a cofactor is carbonic anhydrase, which uses a zinc cofactor bound as part of its active site.[58] These tightly bound ions or molecules are usually found in the active site and are involved in catalysis.[1]: 8.1.1 For example, flavin and heme cofactors are often involved in redox reactions.[1]: 17
Enzymes that require a cofactor but do not have one bound are called apoenzymes or apoproteins. An enzyme together with the cofactor(s) required for activity is called a holoenzyme (or haloenzyme). The term holoenzyme can also be applied to enzymes that contain multiple protein subunits, such as the DNA polymerases; here the holoenzyme is the complete complex containing all the subunits needed for activity.[1]: 8.1.1
Coenzymes
Coenzymes are small organic molecules that can be loosely or tightly bound to an enzyme. Coenzymes transport chemical groups from one enzyme to another. and closely related compounds (vitamins) must be acquired from the diet. The chemical groups carried include:
- the hydride ion (H−), carried by NAD or NADP+
- the phosphate group, carried by adenosine triphosphate
- the acetyl group, carried by coenzyme A
- formyl, methenyl or methyl groups, carried by folic acidand
- the methyl group, carried by S-adenosylmethionine[59]
Since coenzymes are chemically changed as a consequence of enzyme action, it is useful to consider coenzymes to be a special class of substrates, or second substrates, which are common to many different enzymes. For example, about 1000 enzymes are known to use the coenzyme NADH.[60]
Coenzymes are usually continuously regenerated and their concentrations maintained at a steady level inside the cell. For example, NADPH is regenerated through the
Thermodynamics
As with all catalysts, enzymes do not alter the position of the chemical equilibrium of the reaction. In the presence of an enzyme, the reaction runs in the same direction as it would without the enzyme, just more quickly.[1]: 8.2.3 For example, carbonic anhydrase catalyzes its reaction in either direction depending on the concentration of its reactants:[62]
-
(in tissues; high CO2 concentration)
(1)
-
(in lungs; low CO2 concentration)
(2)
The rate of a reaction is dependent on the activation energy needed to form the transition state which then decays into products. Enzymes increase reaction rates by lowering the energy of the transition state. First, binding forms a low energy enzyme-substrate complex (ES). Second, the enzyme stabilises the transition state such that it requires less energy to achieve compared to the uncatalyzed reaction (ES‡). Finally the enzyme-product complex (EP) dissociates to release the products.[1]: 8.3
Enzymes can couple two or more reactions, so that a thermodynamically favorable reaction can be used to "drive" a thermodynamically unfavourable one so that the combined energy of the products is lower than the substrates. For example, the hydrolysis of ATP is often used to drive other chemical reactions.[63]
Kinetics
Enzyme kinetics is the investigation of how enzymes bind substrates and turn them into products.
Enzyme rates depend on solution conditions and substrate concentration. To find the maximum speed of an enzymatic reaction, the substrate concentration is increased until a constant rate of product formation is seen. This is shown in the saturation curve on the right. Saturation happens because, as substrate concentration increases, more and more of the free enzyme is converted into the substrate-bound ES complex. At the maximum reaction rate (Vmax) of the enzyme, all the enzyme active sites are bound to substrate, and the amount of ES complex is the same as the total amount of enzyme.[1]: 8.4
Vmax is only one of several important kinetic parameters. The amount of substrate needed to achieve a given rate of reaction is also important. This is given by the
The efficiency of an enzyme can be expressed in terms of kcat/Km. This is also called the specificity constant and incorporates the
Michaelis–Menten kinetics relies on the law of mass action, which is derived from the assumptions of free diffusion and thermodynamically driven random collision. Many biochemical or cellular processes deviate significantly from these conditions, because of macromolecular crowding and constrained molecular movement.[68] More recent, complex extensions of the model attempt to correct for these effects.[69]
Inhibition
Enzyme reaction rates can be decreased by various types of enzyme inhibitors.[70]: 73–74
Types of inhibition
Competitive
A
Non-competitive
A non-competitive inhibitor binds to a site other than where the substrate binds. The substrate still binds with its usual affinity and hence Km remains the same. However the inhibitor reduces the catalytic efficiency of the enzyme so that Vmax is reduced. In contrast to competitive inhibition, non-competitive inhibition cannot be overcome with high substrate concentration.[70]: 76–78
Uncompetitive
An
Mixed
A mixed inhibitor binds to an allosteric site and the binding of the substrate and the inhibitor affect each other. The enzyme's function is reduced but not eliminated when bound to the inhibitor. This type of inhibitor does not follow the Michaelis–Menten equation.[70]: 76–78
Irreversible
An
Functions of inhibitors
In many organisms, inhibitors may act as part of a feedback mechanism. If an enzyme produces too much of one substance in the organism, that substance may act as an inhibitor for the enzyme at the beginning of the pathway that produces it, causing production of the substance to slow down or stop when there is sufficient amount. This is a form of negative feedback. Major metabolic pathways such as the citric acid cycle make use of this mechanism.[1]: 17.2.2
Since inhibitors modulate the function of enzymes they are often used as drugs. Many such drugs are reversible competitive inhibitors that resemble the enzyme's native substrate, similar to
Factors affecting enzyme activity
As enzymes are made up of proteins, their actions are sensitive to change in many physio chemical factors such as pH, temperature, substrate concentration, etc.
The following table shows pH optima for various enzymes.[81]
Enzyme | Optimum pH | pH description |
---|---|---|
Pepsin | 1.5–1.6 | Highly acidic |
Invertase | 4.5 | Acidic |
Lipase (stomach) | 4.0–5.0 | Acidic |
Lipase (castor oil) | 4.7 | Acidic |
Lipase (pancreas) | 8.0 | Alkaline |
Amylase (malt) | 4.6–5.2 | Acidic |
Amylase (pancreas) | 6.7–7.0 | Acidic-neutral |
Cellobiase | 5.0 | Acidic |
Maltase | 6.1–6.8 | Acidic |
Sucrase | 6.2 | Acidic |
Catalase | 7.0 | Neutral |
Urease | 7.0 | Neutral |
Cholinesterase | 7.0 | Neutral |
Ribonuclease | 7.0–7.5 | Neutral |
Fumarase | 7.8 | Alkaline |
Trypsin | 7.8–8.7 | Alkaline |
Adenosine triphosphate | 9.0 | Alkaline |
Arginase | 10.0 | Highly alkaline |
Biological function
Enzymes serve a wide variety of
An important function of enzymes is in the
Metabolism
Several enzymes can work together in a specific order, creating metabolic pathways.[1]: 30.1 In a metabolic pathway, one enzyme takes the product of another enzyme as a substrate. After the catalytic reaction, the product is then passed on to another enzyme. Sometimes more than one enzyme can catalyze the same reaction in parallel; this can allow more complex regulation: with, for example, a low constant activity provided by one enzyme but an inducible high activity from a second enzyme.[87]
Enzymes determine what steps occur in these pathways. Without enzymes, metabolism would neither progress through the same steps and could not be regulated to serve the needs of the cell. Most central metabolic pathways are regulated at a few key steps, typically through enzymes whose activity involves the hydrolysis of ATP. Because this reaction releases so much energy, other reactions that are
Control of activity
There are five main ways that enzyme activity is controlled in the cell.[1]: 30.1.1
Regulation
Enzymes can be either activated or inhibited by other molecules. For example, the end product(s) of a metabolic pathway are often inhibitors for one of the first enzymes of the pathway (usually the first irreversible step, called committed step), thus regulating the amount of end product made by the pathways. Such a regulatory mechanism is called a negative feedback mechanism, because the amount of the end product produced is regulated by its own concentration.[88]: 141–48 Negative feedback mechanism can effectively adjust the rate of synthesis of intermediate metabolites according to the demands of the cells. This helps with effective allocations of materials and energy economy, and it prevents the excess manufacture of end products. Like other homeostatic devices, the control of enzymatic action helps to maintain a stable internal environment in living organisms.[88]: 141
Post-translational modification
Examples of
Quantity
Enzyme production (
Subcellular distribution
Enzymes can be compartmentalized, with different metabolic pathways occurring in different
Organ specialization
In
Involvement in disease
Since the tight control of enzyme activity is essential for homeostasis, any malfunction (mutation, overproduction, underproduction or deletion) of a single critical enzyme can lead to a genetic disease. The malfunction of just one type of enzyme out of the thousands of types present in the human body can be fatal. An example of a fatal genetic disease due to enzyme insufficiency is Tay–Sachs disease, in which patients lack the enzyme hexosaminidase.[98][99]
One example of enzyme deficiency is the most common type of phenylketonuria. Many different single amino acid mutations in the enzyme phenylalanine hydroxylase, which catalyzes the first step in the degradation of phenylalanine, result in build-up of phenylalanine and related products. Some mutations are in the active site, directly disrupting binding and catalysis, but many are far from the active site and reduce activity by destabilising the protein structure, or affecting correct oligomerisation.[100][101] This can lead to intellectual disability if the disease is untreated.[102] Another example is pseudocholinesterase deficiency, in which the body's ability to break down choline ester drugs is impaired.[103] Oral administration of enzymes can be used to treat some functional enzyme deficiencies, such as
Another way enzyme malfunctions can cause disease comes from
Evolution
Similar to any other protein, enzymes change over time through mutations and sequence divergence. Given their central role in metabolism, enzyme evolution plays a critical role in adaptation. A key question is therefore whether and how enzymes can change their enzymatic activities alongside. It is generally accepted that many new enzyme activities have evolved through gene duplication and mutation of the duplicate copies although evolution can also happen without duplication. One example of an enzyme that has changed its activity is the ancestor of methionyl aminopeptidase (MAP) and creatine amidinohydrolase (creatinase) which are clearly homologous but catalyze very different reactions (MAP removes the amino-terminal methionine in new proteins while creatinase hydrolyses creatine to sarcosine and urea). In addition, MAP is metal-ion dependent while creatinase is not, hence this property was also lost over time.[108] Small changes of enzymatic activity are extremely common among enzymes. In particular, substrate binding specificity (see above) can easily and quickly change with single amino acid changes in their substrate binding pockets. This is frequently seen in the main enzyme classes such as kinases.[109]
Artificial (in vitro) evolution is now commonly used to modify enzyme activity or specificity for industrial applications (see below).
Industrial applications
Enzymes are used in the
Application | Enzymes used | Uses |
---|---|---|
Biofuel industry | Cellulases | Break down cellulose into sugars that can be fermented to produce cellulosic ethanol.[113] |
Ligninases
|
Pretreatment of biomass for biofuel production.[113] | |
Biological detergent
|
Proteases, amylases, lipases | Remove protein, starch, and fat or oil stains from laundry and dishware.[114] |
Mannanases
|
Remove food stains from the common food additive guar gum.[114] | |
Brewing industry | Amylase, glucanases, proteases | Split polysaccharides and proteins in the malt.[115]: 150–9 |
Betaglucanases
|
Improve the wort and beer filtration characteristics.[115]: 545 | |
Amyloglucosidase and pullulanases
|
Make low-calorie beer and adjust fermentability.[115]: 575 | |
Acetolactate decarboxylase (ALDC) | Increase fermentation efficiency by reducing diacetyl formation.[116] | |
Culinary uses | Papain | Tenderize meat for cooking.[117]
|
Dairy industry | Rennin | |
Lipases | Produce | |
Food processing | Amylases | Produce sugars from starch, such as in making high-fructose corn syrup.[120] |
Proteases | Lower the protein level of flour, as in biscuit-making.[121] | |
Trypsin | Manufacture hypoallergenic baby foods.[121] | |
Cellulases, pectinases | Clarify fruit juices.[122]
| |
Molecular biology | Nucleases, DNA ligase and polymerases | Use restriction digestion and the polymerase chain reaction to create recombinant DNA.[1]: 6.2 |
Paper industry | hemicellulases and lignin peroxidases
|
Remove kraft pulp.[123]
|
Personal care
|
Proteases | Remove proteins on contact lenses to prevent infections.[124] |
Starch industry | Amylases | Convert starch into glucose and various syrups.[125] |
See also
Enzyme databases
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Further reading
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External links
- Media related to Enzymes at Wikimedia Commons