Human glyoxalase I. Two zinc ions that are needed for the enzyme to catalyze its reaction are shown as purple sph eres, and an en zy me inhib itor called S-hexylglutathione is shown as a space-filling model, filling the two active sites. Enzyme From Wikipedia, the free encyclopedia (Redirected from Enzym es) Enzymes ( pronounced /ˈɛnzaɪmz/) are proteins that catalyze (i.e., increase the rates of) chemical reactions. [1][2] In enzymatic reac tions, the molecules at the be gi nning of the process, called substrates, are converted into different molecules, called products. Almos t all chemical reactions in a biolog ical cell need enzymes in order to occur a t rat es sufficient for life. Sin ce enzymes are selective for their substrates and speed up only a few reac tions from among m any possibil ities, the set of enzymes made in a cell dete rmines which metabolic pathways occur in that cell. Like all ca talysts, enzymes work by lowering the activation energy ( Ea ‡ ) for a reaction, thus dramatically increasing the rate of the reaction. As a result, products are formed faster and reac tions reach t heir equilibriu m state more rapidly . Most enzyme reaction rates are millions of times faster than those ofcomparable un-catalyzed reactions. As with all catalysts, enzymes are not consumed by the reactions they catalyze, nor do they alterthe e quili brium of these rea ctions. However, enzymes do differfrom most other cata lysts in that they ar e high ly specific for theirsubstrates. Enzymes are known to catalyze about 4,000 biochemical reactions. [3] A few RNA molecules called ribozymes also catalyze re actions, with an important example being som e parts of the ribosome. [4][5] Syn thetic molecules called artificial enzymes also display enzyme-like catalysis. [6] Enzyme activity can be affected by other molecules. Inhibitors are molecules that decrease enzyme activity; act ivators are molecules that incre ase act ivity . Many drugs and pois ons are enzyme inhibi tors. Activity is also affecte d by temperature, chemical environm ent ( e.g., pH), and the concentration of substrate. Some enzymes are used commercially , for e xample, in the synthesis of a ntibio tics. In a ddition, som e household products use enzymes to speed up biochemical reactions (e.g., enzymes in biolog ical washing pow ders break down protein or fat stains on clothes; enzymes in meat tenderizers break down proteins into smaller mol ecules, making the meat easier to chew). Contents 1 Etymology and history 2 Structures and mec hanisms 2.1 Specificity 2.1.1 "Lock and key" model 2.2 Mechanisms 2.2.1 Transition State Stabilization 2.2.2 Dynamics and function 2.3 Allosteric modul ation 3 Cofactors and coenzymes 3.1 Cofactors 3.2 Coenzymes 4 Thermodynamics 5 Kinetics 6 Inhibition 7 Biological function 8 Control of activity 9 Involvement in disease 10 Naming conventions 11 Industrial a pplications 12 See also 13 References 1 of 18
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for the enzyme to catalyze its reaction are shown as purple spheres, and an enzyme inhibitor called
S -hexylglutathione is shown as a space-filling model,
filling the two active sites.
EnzymeFrom Wikipedia, the free encyclopedia
(Redirected from Enzymes)
Enzymes ( pronounced /ˈɛnzaɪmz/) are proteins that catalyze (i.e.,
increase the rates of) chemical reactions.[1][2] In enzymaticreactions, the molecules at the beginning of the process, calledsubstrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell needenzymes in order to occur at rates sufficient for life. Sinceenzymes are selective for their substrates and speed up only a fewreactions from among many possibilities, the set of enzymes madein a cell determines which metabolic pathways occur in that cell.
Like all catalysts, enzymes work by lowering the activation
energy ( E a‡) for a reaction, thus dramatically increasing the rate
of the reaction. As a result, products are formed faster andreactions reach their equilibrium state more rapidly. Most enzymereaction rates are millions of times faster than those of
comparable un-catalyzed reactions. As with all catalysts, enzymesare not consumed by the reactions they catalyze, nor do they alter the equilibrium of these reactions. However, enzymes do differ from most other catalysts in that they are highly specific for their substrates. Enzymes are known to catalyze about 4,000
biochemical reactions.[3] A few RNA molecules called ribozymes
also catalyze reactions, with an important example being some parts of the ribosome.[4][5] Synthetic molecules called
artificial enzymes also display enzyme-like catalysis.[6]
Enzyme activity can be affected by other molecules. Inhibitors are molecules that decrease enzyme activity;activators are molecules that increase activity. Many drugs and poisons are enzyme inhibitors. Activity is also affected by temperature, chemical environment (e.g., pH), and the concentration of substrate. Some enzymes are usedcommercially, for example, in the synthesis of antibiotics. In addition, some household products use enzymes to speed
up biochemical reactions (e.g., enzymes in biological washing powders break down protein or fat stains on clothes;enzymes in meat tenderizers break down proteins into smaller molecules, making the meat easier to chew).
Contents
1 Etymology and history2 Structures and mechanisms
2.1 Specificity2.1.1 "Lock and key" model
2.2 Mechanisms2.2.1 Transition State Stabilization
2.2.2 Dynamics and function
2.3 Allosteric modulation
3 Cofactors and coenzymes3.1 Cofactors3.2 Coenzymes
4 Thermodynamics5 Kinetics6 Inhibition7 Biological function8 Control of activity9 Involvement in disease10 Naming conventions
11 Industrial applications12 See also13 References
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As early as 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. However, the mechanism by which this occurred had not been identified.[8]
In the 19th century, when studying the fermentation of sugar to alcohol by yeast,Louis Pasteur came to the conclusion that this fermentation was catalyzed by a vitalforce contained within the yeast cells called "ferments", which were thought tofunction only within living organisms. He wrote that "alcoholic fermentation is an actcorrelated with the life and organization of the yeast cells, not with the death or
putrefaction of the cells."[9]
In 1877, German physiologist Wilhelm Kühne (1837–1900) first used the term
enzyme, which comes from Greek ενζυμον, "in leaven", to describe this process.[10]
The word enzyme was used later to refer to nonliving substances such as pepsin, andthe word ferment was used to refer to chemical activity produced by livingorganisms.
In 1897, Eduard Buchner submitted his first paper on the ability of yeast extracts that lacked any living yeast cells toferment sugar. In a series of experiments at the University of Berlin, he found that the sugar was fermented even
when there were no living yeast cells in the mixture.[11] He named the enzyme that brought about the fermentation of
sucrose "zymase".[12] In 1907, he received the Nobel Prize in Chemistry "for his biochemical research and hisdiscovery of cell-free fermentation". Following Buchner's example, enzymes are usually named according to thereaction they carry out. Typically, to generate the name of an enzyme, the suffix -ase is added to the name of itssubstrate (e.g., lactase is the enzyme that cleaves lactose) or the type of reaction (e.g., DNA polymerase forms DNA
polymers).[13]
Having shown that enzymes could function outside a living cell, the next step was to determine their biochemicalnature. Many early workers noted that enzymatic activity was associated with proteins, but several scientists (such as Nobel laureate Richard Willstätter) argued that proteins were merely carriers for the true enzymes and that proteins
er se were incapable of catalysis.[citation needed ] However, in 1926, James B. Sumner showed that the enzyme ureasewas a pure protein and crystallized it; Sumner did likewise for the enzyme catalase in 1937. The conclusion that pure proteins can be enzymes was definitively proved by Northrop and Stanley, who worked on the digestive enzymes
pepsin (1930), trypsin and chymotrypsin. These three scientists were awarded the 1946 Nobel Prize in Chemistry.[14]
This discovery that enzymes could be crystallized eventually allowed their structures to be solved by x-raycrystallography. 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.[15]
This high-resolution structure of lysozyme marked the beginning of the field of structural biology and the effort tounderstand how enzymes work at an atomic level of detail.
Structures and mechanisms
See also: Enzyme catalysis
Enzymes are generally globular proteins and range from just 62 amino acid residues in size, for the monomer of
4-oxalocrotonate tautomerase,[16] to over 2,500 residues in the animal fatty acid synthase.[17] A small number of RNA-based biological catalysts exist, with the most common being the ribosome; these are referred to as either
RNA-enzymes or ribozymes. The activities of enzymes are determined by their three-dimensional structure.[18]
However, although structure does determine function, predicting a novel enzyme's activity just from its structure is a
very difficult problem that has not yet been solved.[19]
Most enzymes are much larger than the substrates they act on, and only a small portion of the enzyme (around 2–4amino acids) is directly involved in catalysis.[20] The region that contains these catalytic residues, binds the substrate,and then carries out the reaction is known as the active site. Enzymes can also contain sites that bind cofactors, which
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II. The grey sphere is the zinc cofactor in the active
site. Diagram drawn from PDB 1MOO
(http://www.rcsb.org
/pdb/explore.do?structureId=1MOO) .
Diagrams to show the induced fit hypothesis of enzyme action
are needed for catalysis. Some enzymes also have binding sites for small molecules, which are often direct or indirect products or substrates of the reaction catalyzed. This binding can serve toincrease or decrease the enzyme's activity, providing a means for feedback regulation.
Like all proteins, enzymes are long, linear chains of amino acidsthat fold to produce a three-dimensional product. Each uniqueamino acid sequence produces a specific structure, which hasunique properties. Individual protein chains may sometimes grouptogether to form a protein complex. Most enzymes can bedenatured—that is, unfolded and inactivated—by heating or chemical denaturants, which disrupt the three-dimensionalstructure of the protein. Depending on the enzyme, denaturationmay be reversible or irreversible.
Structures of enzymes in complex with substrates or substrateanalogs during a reaction may be obtained using Time resolvedcrystallography methods.
Specificity
Enzymes are usually very specific as to which reactions they catalyze and the substrates that are involved in thesereactions. Complementary shape, charge and hydrophilic/hydrophobic characteristics of enzymes and substrates areresponsible for this specificity. Enzymes can also show impressive levels of stereospecificity, regioselectivity and
chemoselectivity.[21]
Some of the enzymes showing the highest specificity and accuracy are involved in the copying and expression of thegenome. 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.[22] This two-step process results in
average error rates of less than 1 error in 100 million reactions in high-fidelity mammalian polymerases.[23] Similar
proofreading mechanisms are also found in RNA polymerase,[24] aminoacyl tRNA synthetases[25] and ribosomes.[26]
Some enzymes that produce secondary metabolites are described as promiscuous, as they can act on a relatively broad range of different substrates. It has been suggested that this broad substrate specificity is important for the
evolution of new biosynthetic pathways.[27]
"Lock and key" model
Enzymes are very specific, and it was suggested by the Nobel laureate organic chemist Emil Fischer in 1894 that thiswas because both the enzyme and the substrate possess specific complementary geometric shapes that fit exactly into
one another.[28] This is often referred to as "the lock and key" model. However, while this model explains enzymespecificity, it fails to explain the stabilization of the transition state that enzymes achieve.
In 1958, Daniel Koshland suggested amodification to the lock and key model:
since enzymes are rather flexiblestructures, the active site is continuallyreshaped by interactions with the substrateas the substrate interacts with the
enzyme.[29] As a result, the substrate doesnot simply bind to a rigid active site; theamino acid side chains which make up theactive site are molded into the precise positions that enable the enzyme to perform its catalytic function. In some
cases, such as glycosidases, the substrate molecule also changes shape slightly as it enters the active site.[30] Theactive site continues to change until the substrate is completely bound, at which point the final shape and charge is
determined.[31]
Induced fit may enhance the fidelity of molecular recognition in the presence of competition andnoise via the conformational proofreading mechanism .[32]
Mechanisms
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Enzymes can act in several ways, all of which lower ΔG‡:[33]
Lowering the activation energy by creating an environment in which the transition state is stabilized (e.g.straining the shape of a substrate—by binding the transition-state conformation of the substrate/productmolecules, the enzyme distorts the bound substrate(s) into their transition state form, thereby reducing theamount of energy required to complete the transition).Lowering the energy of the transition state, but without distorting the substrate, by creating an environmentwith the opposite charge distribution to that of the transition state.Providing an alternative pathway. For example, temporarily reacting with the substrate to form anintermediate ES complex, which would be impossible in the absence of the enzyme.Reducing the reaction entropy change by bringing substrates together in the correct orientation to react.
Considering ΔH‡ alone overlooks this effect.Increases in temperatures speed up reactions. Thus, temperature increases help the enzyme function anddevelop the end product even faster. However, if heated too much, the enzyme’s shape deteriorates and theenzyme becomes denatured. Some enzymes like thermolabile enzymes work best at low temperatures.
Interestingly, this entropic effect involves destabilization of the ground state,[34] and its contribution to catalysis is
relatively small.[35]
Transition State Stabilization
The understanding of the origin of the reduction of ΔG‡ requires one to find out how the enzymes can stabilize itstransition state more than the transition state of the uncatalyzed reaction. Apparently, the most effective way for reaching large stabilization is the use of electrostatic effects, in particular, when having a relatively fixed polar
environment that is oriented toward the charge distribution of the transition state. [36] Such an environment does notexist in the uncatalyzed reaction in water.
Dynamics and function
See also: Protein dynamics
The internal dynamics of enzymes has been suggested to be linked with their mechanism of catalysis.[37][38][39]
Internal dynamics are the movement of parts of the enzyme's structure, such as individual amino acid residues, agroup of amino acids, or even an entire protein domain. These movements occur at various time-scales ranging fromfemtoseconds to seconds. Networks of protein residues throughout an enzyme's structure can contribute to catalysis
through dynamic motions.[40][41][42][43] This is simply seen in the kinetic scheme of the combined process, enzymaticactivity and dynamics; this scheme can have several independent Michaelis-Menten-like reaction pathways that are
connected through fluctuation rates. [44][45][46]
Protein motions are vital to many enzymes, but whether small and fast vibrations, or larger and slower conformationalmovements are more important depends on the type of reaction involved. However, although these movements areimportant in binding and releasing substrates and products, it is not clear if protein movements help to accelerate the
chemical steps in enzymatic reactions.[47] These new insights also have implications in understanding allostericeffects and developing new medicines.
Allosteric modulation
Main article: Allosteric regulation
Allosteric sites are sites on the enzyme that bind to molecules in thecellular environment. The sites form weak, noncovalent bonds with thesemolecules, causing a change in the conformation of the enzyme. Thischange in conformation translates to the active site, which then affects
the reaction rate of the enzyme.[48] Allosteric interactions can bothinhibit and activate enzymes and are a common way that enzymes are
controlled in the body.[49]
Cofactors and coenzymes Main articles: Cofactor (biochemistry) and Coenzyme
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The energies of the stages of a chemical reaction.
Substrates need a lot of energy to reach a transition
state, which then decays into products. The enzyme
stabilizes the transition state, reducing the energy
needed to form products.
Cofactors
Some enzymes do not need any additional components to show full activity. However, others require non-protein
molecules called cofactors to be bound for activity.[50] Cofactors can be either inorganic (e.g., metal ions andiron-sulfur clusters) or organic compounds (e.g., flavin and heme). Organic cofactors can be either prosthetic groups,which are tightly bound to an enzyme, or coenzymes, which are released from the enzyme's active site during thereaction. Coenzymes include NADH, NADPH and adenosine triphosphate. These molecules transfer chemical groups
between enzymes.[51]
An example of an enzyme that contains a cofactor is carbonic anhydrase, and is shown in the ribbon diagram above
with a zinc cofactor bound as part of its active site.[52] These tightly bound molecules are usually found in the activesite and are involved in catalysis. For example, flavin and heme cofactors are often involved in redox reactions.
Enzymes that require a cofactor but do not have one bound are called apoenzymes or apoproteins. An apoenzymetogether with its cofactor(s) is called a holoenzyme (this is the active form). Most cofactors are not covalentlyattached to an enzyme, but are very tightly bound. However, organic prosthetic groups can be covalently bound (e.g., biotin in the enzyme pyruvate carboxylase). The term "holoenzyme" can also be applied to enzymes that containmultiple protein subunits, such as the DNA polymerases; here the holoenzyme is the complete complex containing allthe subunits needed for activity.
Coenzymes
Coenzymes are small organic molecules that can be loosely or tightly bound to anenzyme. Tightly bound coenzymes can be called allosteric groups. Coenzymes transport
chemical groups from one enzyme to another.[53] Some of these chemicals such asriboflavin, thiamine and folic acid are vitamins (compounds which cannot be synthesized by the body and 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 adenosinetriphosphate, the acetyl group carried by coenzyme A, formyl, methenyl or methyl groupscarried by folic acid and the methyl group carried by S-adenosylmethionine.
Since coenzymes are chemically changed as a consequence of enzyme action, it is usefulto consider coenzymes to be a special class of substrates, or second substrates, which are
common to many different enzymes. For example, about 700 enzymes are known to usethe coenzyme NADH.[54]
Coenzymes are usually continuously regenerated and their concentrations maintained at a steady level inside the cell:for example, NADPH is regenerated through the pentose phosphate pathway and S -adenosylmethionine bymethionine adenosyltransferase. This continuous regeneration means that even small amounts of coenzymes are used
very intensively. For example, the human body turns over its own weight in ATP each day.[55]
Thermodynamics
Main articles: Activation energy, Thermodynamic
equilibrium, and Chemical equilibrium
As all catalysts, enzymes do not alter the position of the chemicalequilibrium of the reaction. Usually, in the presence of an enzyme,the reaction runs in the same direction as it would without theenzyme, just more quickly. However, in the absence of theenzyme, other possible uncatalyzed, "spontaneous" reactionsmight lead to different products, because in those conditions thisdifferent product is formed faster.
Furthermore, enzymes can couple two or more reactions, so that athermodynamically favorable reaction can be used to "drive" athermodynamically unfavorable one. For example, the hydrolysis
of ATP is often used to drive other chemical reactions.[56]
Enzymes catalyze the forward and backward reactions equally.They do not alter the equilibrium itself, but only the speed atwhich it is reached. For example, carbonic anhydrase catalyzes its
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Mechanism for a single substrate enzyme catalyzedreaction. The enzyme (E) binds a substrate (S) and
produces a product (P).
Saturation curve for an enzyme reaction showing the
relation between the substrate concentration (S) and
rate (v)
reaction in either direction depending on the concentration of its reactants.
(in tissues; high CO2 concentration)
(in lungs; low CO2 concentration)
Nevertheless, if the equilibrium is greatly displaced in one direction, that is, in a very exergonic reaction, the reactionis effectively irreversible. Under these conditions the enzyme will, in fact, only catalyze the reaction in the
thermodynamically allowed direction.
Kinetics
Main article: Enzyme kinetics
Enzyme kinetics is the investigation of how enzymes bindsubstrates and turn them into products. The rate data used inkinetic analyses are commonly obtained from enzyme assays,where since the 90s, the dynamics of many enzymes are studiedon the level of individual molecules.
In 1902 Victor Henri proposed a quantitative theory of enzyme
kinetics,[57] but his experimental data were not useful because thesignificance of the hydrogen ion concentration was not yetappreciated. After Peter Lauritz Sørensen had defined thelogarithmic pH-scale and introduced the concept of buffering in
1909[58] the German chemist Leonor Michaelis and his Canadian postdoc Maud Leonora Menten repeated Henri'sexperiments and confirmed his equation which is referred to as Henri-Michaelis-Menten kinetics (termed also
Michaelis-Menten kinetics).[59] Their work was further developed by G. E. Briggs and J. B. S. Haldane, who derived
kinetic equations that are still widely considered today a starting point in solving enzymatic activity.[60]
The major contribution of Henri was to think of enzyme reactions in two stages. In the first, the substrate bindsreversibly to the enzyme, forming the enzyme-substrate complex. This is sometimes called the Michaelis complex.The enzyme then catalyzes the chemical step in the reaction and releases the product. Note that the simple Michaelis
Menten mechanism for the enzymatic activity is considered today a basic idea, where many examples show that theenzymatic activity involves structural dynamics. This is incorporated in the enzymatic mechanism while introducing
several Michaelis Menten pathways that are connected with fluctuating rates [44][45][46]. Nevertheless, there is amathematical relation connecting the behavior obtained from the basic Michaelis Menten mechanism (that wasindeed proved correct in many experiments) with the generalized Michaelis Menten mechanisms involving dynamics
and activity; [61] this means that the measured activity of enzymes on the level of many enzymes may be explainedwith the simple Michaelis-Menten equation, yet, the actual activity of enzymes is richer and involves structuraldynamics.
Enzymes can catalyze up to several million reactions per second.For example, the uncatalyzed decarboxylation of orotidine5'-monophosphate has a half life of 78 million years. However,when the enzyme orotidine 5'-phosphate decarboxylase is added,
the same process takes just 25 milliseconds.[62] Enzyme ratesdepend on solution conditions and substrate concentration.Conditions that denature the protein abolish enzyme activity, suchas high temperatures, extremes of pH or high salt concentrations,while raising substrate concentration tends to increase activitywhen [S] is low. To find the maximum speed of an enzymaticreaction, the substrate concentration is increased until a constantrate of product formation is seen. This is shown in the saturationcurve on the right. Saturation happens because, as substrateconcentration increases, more and more of the free enzyme isconverted into the substrate-bound ES form. At the maximumreaction rate (V max) 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. However, V max is only
one kinetic constant of enzymes. The amount of substrate needed to achieve a given rate of reaction is also important.This is given by the Michaelis-Menten constant ( K m), which is the substrate concentration required for an enzyme toreach one-half its maximum reaction rate. Each enzyme has a characteristic K m for a given substrate, and this can
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Competitive inhibitors bind reversibly to the enzyme, preventing the
binding of substrate. On the other hand, binding of substrate prevents
binding of the inhibitor. Substrate and inhibitor compete for the
enzyme.
show how tight the binding of the substrate is to the enzyme. Another useful constant is k cat, which is the number of substrate molecules handled by one active site per second.
The efficiency of an enzyme can be expressed in terms of k cat/ K m. This is also called the specificity constant andincorporates the rate constants for all steps in the reaction. Because the specificity constant reflects both affinity andcatalytic ability, it is useful for comparing different enzymes against each other, or the same enzyme with different
substrates. The theoretical maximum for the specificity constant is called the diffusion limit and is about 108 to 109
(M
−1
s
−1
). At this point every collision of the enzyme with its substrate will result in cata lysis, and the ra te of productformation is not limited by the reaction rate but by the diffusion rate. Enzymes with this property are calledcatalytically perfect or kinetically perfect . Example of such enzymes are triose-phosphate isomerase, carbonicanhydrase, acetylcholinesterase, catalase, fumarase, β-lactamase, and superoxide dismutase.
Michaelis-Menten kinetics relies on the law of mass action, which is derived from the assumptions of free diffusionand thermodynamically driven random collision. However, many biochemical or cellular processes deviatesignificantly from these conditions, because of macromolecular crowding, phase-separation of the enzyme/substrate
/product, or one or two-dimensional molecular movement.[63] In these situations, a fractal Michaelis-Menten kinetics
may be applied.[64][65][66][67]
Some enzymes operate with kinetics which are faster than diffusion rates, which would seem to be impossible. Severalmechanisms have been invoked to explain this phenomenon. Some proteins are believed to accelerate catalysis by
drawing their substrate in and pre-orienting them by using dipolar electric fields. Other models invoke a quantum-mechanical tunneling explanation, whereby a proton or an electron can tunnel through activation barriers, although
for proton tunneling this model remains somewhat controversial.[68][69] Quantum tunneling for protons has been
observed in tryptamine.[70] This suggests that enzyme catalysis may be more accurately characterized as "through the barrier" rather than the traditional model, which requires substrates to go "over" a lowered energy barrier.
Inhibition
Main article: Enzyme inhibitor
Enzyme reaction rates can be decreased byvarious types of enzyme inhibitors.
Competitive inhibition
In competitive inhibition, the inhibitor andsubstrate compete for the enzyme (i.e., they can
not bind at the same time).[72] Often competitiveinhibitors strongly resemble the real substrate of the enzyme. For example, methotrexate is acompetitive inhibitor of the enzyme dihydrofolatereductase, which catalyzes the reduction of dihydrofolate to tetrahydrofolate. The similarity between the structures of folic acid and this drugare shown in the figure to the right bottom. Insome cases, the inhibitor can bind to a site other than the binding-site of the usual substrate andexert an allosteric effect to change the shape of the usual binding-site. For example, strychnineacts as an allosteric inhibitor of the glycine receptor in the mammalian spinal cord and brain stem. Glycine is a major post-synaptic inhibitory neurotransmitter with a specific receptor site. Strychnine binds to an alternate site thatreduces the affinity of the glycine receptor for glycine, resulting in convulsions due to lessened inhibition by the
glycine.[73] In competitive inhibition the maximal rate of the reaction is not changed, but higher substrateconcentrations are required to reach a given maximum rate, increasing the apparent K m.
Uncompetitive inhibition
In uncompetitive inhibition the inhibitor can not bind to the free enzyme, but only to the ES-complex. TheEIS-complex thus formed is enzymatically inactive. This type of inhibition is rare, but may occur in multimericenzymes.
Non-competitive inhibition
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Types of inhibition. This classification was introduced by W.W.
Cleland.[71]
The coenzyme folic acid (left) and the anti-cancer drug methotrexate
(right) are very similar in structure. As a result, methotrexate is a
competitive inhibitor of many enzymes that use folates.
Non-competitive inhibitors can bind to theenzyme at the binding site at the same time as thesubstrate,but not to the active site. Both the EIand EIS complexes are enzymatically inactive.Because the inhibitor can not be driven from theenzyme by higher substrate concentration (incontrast to competitive inhibition), the apparentV
maxchanges. But because the substrate can still
bind to the enzyme, the K m stays the same.
Mixed inhibition
This type of inhibition resembles thenon-competitive, except that the EIS-complex hasresidual enzymatic activity.This type of inhibitor does not follow Michaelis-Menten equation.
In many organisms inhibitors may act as part of afeedback mechanism. If an enzyme produces toomuch of one substance in the organism, thatsubstance may act as an inhibitor for the enzyme
at the beginning of the pathway that produces it,causing production of the substance to slow downor stop when there is sufficient amount. This is aform of negative feedback. Enzymes which aresubject to this form of regulation are oftenmultimeric and have allosteric binding sites for regulatory substances. Their substrate/velocity plots are not hyperbolar, but sigmoidal (S-shaped).
Irreversible inhibitors react with the enzyme andform a covalent adduct with the protein. Theinactivation is irreversible. These compoundsinclude eflornithine a drug used to treat the
parasitic disease sleeping sickness.[74] Penicillinand Aspirin also act in this manner. With thesedrugs, the compound is bound in the active siteand the enzyme then converts the inhibitor into anactivated form that reacts irreversibly with one or more amino acid residues.
Uses of inhibitors
Since inhibitors modulate the function of enzymes they are often used as drugs. A common example of an inhibitor that is used as a drug is aspirin, which inhibits the COX-1 and COX-2 enzymes that produce the inflammationmessenger prostaglandin, thus suppressing pain and inflammation. However, other enzyme inhibitors are poisons. For example, the poison cyanide is an irreversible enzyme inhibitor that combines with the copper and iron in the active
site of the enzyme cytochrome c oxidase and blocks cellular respiration.[75]
Biological function
Enzymes serve a wide variety of functions inside living organisms. They are indispensable for signal transduction and
cell regulation, often via kinases and phosphatases.[76] They also generate movement, with myosin hydrolyzing ATP
to generate muscle contraction and also moving cargo around the cell as part of the cytoskeleton.[77] Other ATPasesin the cell membrane are ion pumps involved in active transport. Enzymes are also involved in more exotic functions,
such as luciferase generating light in fireflies.[78] Viruses can also contain enzymes for infecting cells, such as the HIVintegrase and reverse transcriptase, or for viral release from cells, like the influenza virus neuraminidase.
An important function of enzymes is in the digestive systems of animals. Enzymes such as amylases and proteases
break down large molecules (starch or proteins, respectively) into smaller ones, so they can be absorbed by theintestines. Starch molecules, for example, are too large to be absorbed from the intestine, but enzymes hydrolyze thestarch chains into smaller molecules such as maltose and eventually glucose, which can then be absorbed. Differentenzymes digest different food substances. In ruminants which have herbivorous diets, microorganisms in the gut
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Glycolytic enzymes and their functions in the metabolic pathway of glycolysis
produce another enzyme, cellulase to break down the cellulose cell walls of plant fiber.[79]
Several enzymes can work together ina specific order, creating metabolic pathways. In a metabolic pathway,one enzyme takes the product of another enzyme as a substrate. After the catalytic reaction, the product isthen passed on to another enzyme.Sometimes more than one enzymecan catalyze the same reaction in parallel, this can allow more complexregulation: with for example a lowconstant activity being provided byone enzyme but an inducible highactivity from a second enzyme.
Enzymes determine what steps occur in these pathways. Without enzymes, metabolism would neither progressthrough the same steps, nor be fast enough to serve the needs of the cell. Indeed, a metabolic pathway such asglycolysis could not exist independently of enzymes. Glucose, for example, can react directly with ATP to become phosphorylated at one or more of its carbons. In the absence of enzymes, this occurs so slowly as to be insignificant.However, if hexokinase is added, these slow reactions continue to take place except that phosphorylation at carbon 6occurs so rapidly that if the mixture is tested a short time later, glucose-6-phosphate is found to be the only significant product. Consequently, the network of metabolic pathways within each cell depends on the set of functional enzymesthat are present.
Control of activity
There are five main ways that enzyme activity is controlled in the cell.
Enzyme production (transcription and translation of enzyme genes) can be enhanced or diminished by a cell inresponse to changes in the cell's environment. This form of gene regulation is called enzyme induction andinhibition (see enzyme induction). For example, bacteria may become resistant to antibiotics such as penicillin
because enzymes called beta-lactamases are induced that hydrolyze the crucial beta-lactam ring within the penicillin molecule. Another example are enzymes in the liver called cytochrome P450 oxidases, which areimportant in drug metabolism. Induction or inhibition of these enzymes can cause drug interactions.
1.
Enzymes can be compartmentalized, with different metabolic pathways occurring in different cellular compartments. For example, fatty acids are synthesized by one set of enzymes in the cytosol, endoplasmicreticulum and the Golgi apparatus and used by a different set of enzymes as a source of energy in the
mitochondrion, through β-oxidation.[80]
2.
Enzymes can be regulated by inhibitors and activators. 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 regulatorymechanism is called a negative feedback mechanism, because the amount of the end product produced isregulated by its own concentration. Negative feedback mechanism can effectively adjust the rate of synthesis ointermediate metabolites according to the demands of the cells. This helps allocate materials and energy
economically, and prevents the manufacture of excess end products. The control of enzymatic action helps tomaintain a stable internal environment in living organisms.
3.
Enzymes can be regulated through post-translational modification. This can include phosphorylation,myristoylation and glycosylation. For example, in the response to insulin, the phosphorylation of multipleenzymes, including glycogen synthase, helps control the synthesis or degradation of glycogen and allows the
cell to respond to changes in blood sugar.[81] Another example of post-translational modification is the cleavageof the polypeptide chain. Chymotrypsin, a digestive protease, is produced in inactive form as chymotrypsinogenin the pancreas and transported in this form to the stomach where it is activated. This stops the enzyme fromdigesting the pancreas or other tissues before it enters the gut. This type of inactive precursor to an enzyme isknown as a zymogen.
4.
Some enzymes may become activated when localized to a different environment (e.g. from a reducing(cytoplasm) to an oxidizing (periplasm) environment, high pH to low pH etc.). For example, hemagglutinin inthe influenza virus is activated by a conformational change caused by the acidic conditions, these occur when it
is taken up inside its host cell and enters the lysosome.[82]
5.
Involvement in disease
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Since the tight control of enzyme activity is essential for homeostasis, anymalfunction (mutation, overproduction, underproduction or deletion) of a singlecritical enzyme can lead to a genetic disease. The importance of enzymes isshown by the fact that a lethal illness can be caused by the malfunction of justone type of enzyme out of the thousands of types present in our bodies.
One example is the most common type of phenylketonuria. A mutation of a singleamino acid in the enzyme phenylalanine hydroxylase, which catalyzes the firststep in the degradation of phenylalanine, results in build-up of phenylalanine andrelated products. This can lead to mental retardation if the disease is
untreated.[83]
Another example is when germline mutations in genes coding for DNA repair enzymes cause hereditary cancer syndromes such as xeroderma pigmentosum.Defects in these enzymes cause cancer since the body is less able to repair mutations in the genome. This causes a slow accumulation of mutations andresults in the development of many types of cancer in the sufferer.
Oral administration of enzymes can be used to treat several diseases (e.g. pancreatic insufficiency and lactoseintolerance). Since enzymes are proteins themselves they are potentially subject to inactivation and digestion in thegastrointestinal environment. Therefore a non-invasive imaging assay was developed to monitor gastrointestinal
activity of exogenous enzymes (prolyl endopeptidase as potential adjuvant therapy for celiac disease) in vivo.[84]
Naming conventions
An enzyme's name is often derived from its substrate or the chemical reaction it catalyzes, with the word ending in-ase. Examples are lactase, alcohol dehydrogenase and DNA polymerase. This may result in different enzymes, calledisozymes, with the same function having the same basic name. Isoenzymes have a different amino acid sequence andmight be distinguished by their optimal pH, kinetic properties or immunologically. Isoenzyme and isozyme arehomologous proteins. Furthermore, the normal physiological reaction an enzyme catalyzes may not be the same asunder artificial conditions. This can result in the same enzyme being identified with two different names. For example,glucose isomerase, which is used industrially to convert glucose into the sweetener fructose, is a xylose isomerase in
vivo.
The International Union of Biochemistry and Molecular Biology have developed a nomenclature for enzymes, the EC
numbers; each enzyme is described by a sequence of four numbers preceded by "EC". The first number broadlyclassifies the enzyme based on its mechanism.
The top-level classification is[85]
EC 1 Oxidoreductases: catalyze oxidation/reduction reactionsEC 2 Transferases: transfer a functional group (e.g. a methyl or phosphate group)EC 3 Hydrolases: catalyze the hydrolysis of various bondsEC 4 Lyases: cleave various bonds by means other than hydrolysis and oxidationEC 5 Isomerases: cata lyze isomerization changes within a single moleculeEC 6 Ligases: join two molecules with covalent bonds.
According to the naming conventions, enzymes are generally classified into six main family classes and many
sub-family classes. Some web-servers, e.g., EzyPred (http://www.csbio.sjtu.edu.cn/bioinf/EzyPred/) [86] and
bioinformatics tools have been developed to predict which main family class [87] and sub-family class [88] [89] anenzyme molecule belongs to according to its sequence information alone via the pseudo amino acid composition.
Industrial applications
Enzymes are used in the chemical industry and other industrial applications when extremely specific catalysts arerequired. However, enzymes in general are limited in the number of reactions they have evolved to catalyze and also by their lack of stability in organic solvents and at high temperatures. Consequently, protein engineering is an activearea of research and involves attempts to create new enzymes with novel properties, either through rational design or
in vitro evolution.[90][91]
These efforts have begun to be successful, and a few enzymes have now been desiged "fromscratch" to catalyze reactions that do not occur in nature. [92]
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Production of sugars from starch,such as in making high-fructose corn
syrup.[93] In baking, catalyze breakdown of starch in the flour tosugar. Yeast fermentation of sugar
produces the carbon dioxide thatraises the dough.
ProteasesBiscuit manufacturers use them tolower the protein level of flour.
Baby foods Trypsin To predigest baby foods
Brewing industry
Germinating barley used for
malt
Enzymes from barley are releasedduring the mashing stage of beer production.
They degrade starch and proteins to produce simple sugar, amino acidsand peptides that are used by yeastfor fermentation.
Industrially produced barley enzymesWidely used in the brewing processto substitute for the natural enzymes
found in barley.Amylase, glucanases, proteases
Split polysaccharides and proteins inthe malt.
Betaglucanases and arabinoxylanasesImprove the wort and beer filtrationcharacteristics.
Amyloglucosidase and pullulanasesLow-calorie beer and adjustment of fermentability.
ProteasesRemove cloudiness produced duringstorage of beers.
Acetolactatedecarboxylase (ALDC)Increases fermentation efficiency by
reducing diacetyl formation.[94]
Fruit juices Cellulases, pectinases Clarify fruit juices.
Dairy industry
Roquefort cheese
Rennin, derived from the stomachs of young ruminant animals (like calvesand lambs)
Manufacture of cheese, used tohydrolyze protein
Microbially produced enzyme Now finding increasing use in thedairy industry
Lipases
Is implemented during the production of Roquefort cheese toenhance the ripening of the blue-mold cheese.
LactasesBreak down lactose to glucose andgalactose.
Meat tenderizers Papain To soften meat for cooking
Starch industry
Glucose Fructose
Amylases, amyloglucosideases andglucoamylases
Converts starch into glucose andvarious syrups.
Glucose isomerase
Converts glucose into fructose in production of high-fructose syrupsfrom starchy materials. These syrupshave enhanced sweetening properties and lower calorific valuesthan sucrose for the same level of sweetness.
Rubber industry CatalaseTo generate oxygen from peroxideto convert latex into foam rubber
Photographic industry Protease (ficin)Dissolve gelatin off scrap film,allowing recovery of its silver content.
Molecular biology
Part of the DNA double helix
Restriction enzymes, DNA ligase and polymerases
Used to manipulate DNA in geneticengineering, important in pharmacology, agriculture andmedicine. Essential for restrictiondigestion and the polymerase chain
reaction. Molecular biology is alsoimportant in forensic science.
See also
List of enzymesEnzyme productEnzyme substrateEnzyme catalysisEnzyme assayProtein dynamics
The Proteolysis MapRNA BiocatalysisSUMO enzymesK i Database
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Recommendations of the Nomenclature Committee of the International Union of Biochemistry and Molecular Biology onthe Nomenclature and Classification of Enzymes by the Reactions they Catalyse. Nomenclature Committee of theInternational Union of Biochemistry and Molecular Biology (NC-IUBMB)^ Shen, HB; Chou, KC (2007). "EzyPred: A top-down approach for predicting enzyme functional classes and subclasses". Biochemical and b iophysical research communications 364 (1): 53–9. doi:10.1016/j.bbrc.2007.09.098 (http://dx.doi.org/10.1016%2Fj.bbrc.2007.09.098) . PMID 17931599 (http://www.ncbi.nlm.nih.gov/pubmed/17931599) .
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Further reading
Etymology and history
" New Beer in an Old Bottle: Eduard Buchner
and the Growth of Biochemical Knowledge,edited by Athel Cornish-Bowden and published by Universitat de València (1997): ISBN84-370-3328-4" (http://web.archive.org/web/20080207101706/http://bip.cnrs-mrs.fr /bip10/buchner.htm) . Archived from theoriginal (http://bip.cnrs-mrs.fr/bip10/buchner.htm) on 2008-02-07.http://web.archive.org/web/20080207101706
/http://bip.cnrs-mrs.fr/bip10/buchner.htm., Ahistory of early enzymology.Williams, Henry Smith, 1863–1943. A History of
Science: in Five Volumes. Volume IV: Modern
Development of the Chemical and Biological
Sciences (http://etext.lib.virginia.edu/toc/modeng/public/Wil4Sci.html) , A textbook from the 19th century.Kleyn J, Hough J (1971). "The microbiology of brewing". Annu. Rev. Microbiol. 25: 583–608.doi:10.1146/annurev.mi.25.100171.003055(http://dx.doi.org/10.1146%2Fannurev.mi.25.100171.003055) .PMID 4949040 (http://www.ncbi.nlm.nih.gov
/pubmed/4949040) .
Enzyme structure and mechanism
Kinetics and inhibition
Cornish-Bowden, Athel. Fundamentals of
Enzyme Kinetics. (3rd edition), Portland Press,2004. ISBN 1-85578-158-1.Segel Irwin H. Enzyme Kinetics: Behavior and
Analysis of Rapid Equilibrium and Steady-State
Enzyme Systems. (New Ed edition), Wiley-Interscience, 1993. ISBN 0-471-30309-7.Baynes, John W. Medical Biochemistry. (2ndedition), Elsevier-Mosby, 2005. ISBN0-7234-3341-0, p. 57.
Function and control of enzymes in the cell
Price, N. and Stevens, L. Fundamentals of
Enzymology: Cell and Molecular Biology of Catalytic Proteins. Oxford University Press,1999. ISBN 0-19-850229-X."Nutritional and Metabolic Diseases"(http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=gnd.chapter.86) . Chapter of theon-line textbook Introduction to Genes and
Disease from the NCBI.
Enzyme-naming conventions
Enzyme Nomenclature(http://www.chem.qmul.ac.uk/iubmb/enzyme/) ,Recommendations for enzyme names from the
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in protein science: a guide to enzyme catalysisand protein folding . San Francisco: W.H.Freeman. ISBN 0-7167-3268-8.Walsh C (1979). Enzymatic reaction
mechanisms. San Francisco: W. H. Freeman.ISBN 0-7167-0070-0.
Page, M. I., and Williams, A. (Eds.). Enzyme Mechanisms. Royal Society of Chemistry, 1987.ISBN 0-85186-947-5.Bugg, T. Introduction to Enzyme and CoenzymeChemistry. (2nd edition), Blackwell PublishingLimited, 2004. ISBN 1-4051-1452-5.Warshel, A. Computer Modeling of Chemical
Reactions in enzymes and Solutions. John Wiley& Sons Inc., 1991. ISBN 0-471-18440-3.
Thermodynamics
"Reactions and Enzymes"
(http://www.emc.maricopa.edu/faculty/farabee/BIOBK/BioBookEnzym.html) Chapter 10 of on-line biology book at Estrella MountainCommunity College.
Nomenclature Committee of the InternationalUnion of Biochemistry and Molecular Biology.Koshland, D. The Enzymes, v. I, ch. 7. Acad.Press, New York, 1959.
Industrial applications
"History of industrial enzymes"
(http://www.mapsenzymes.com/History_of_Enzymes.asp) , Article about thehistory of industrial enzymes from the late 1900sto the present times.
External links
Structure/Function of Enzymes (http://mcdb-webarchive.mcdb.ucsb.edu/sears/biochemistry/) , Web tutorialon enzyme structure and function.Enzymes in diagnosis (http://www.science2day.info/2008/02/enzyme-test-or-cpk-test-what-is-it.html) Roleof enzymes in diagnosis of diseases.Enzyme spotlight (http://www.ebi.ac.uk/intenz/spotlight.jsp) Monthly feature at the EuropeanBioinformatics Institute on a selected enzyme.AMFEP (http://www.amfep.org/) , Association of Manufacturers and Formulators of Enzyme ProductsBRENDA (http://www.brenda-enzymes.org/) database, a comprehensive compilation of information andliterature references about all known enzymes; requires payment by commercial users.Enzyme Structures Database (http://www.ebi.ac.uk/thornton-srv/databases/enzymes/) links to the known3-D structure data of enzymes in the Protein Data Bank.ExPASy enzyme (http://us.expasy.org/enzyme/) database, links to Swiss-Prot sequence data, entries in other databases and to related literature searches.KEGG: Kyoto Encyclopedia of Genes and Genomes (http://www.genome.jp/kegg/) Graphical andhypertext-based information on biochemical pathways and enzymes.[1] (http://www.enzyme-database.org/) enzyme databaseMACiE (http://www.ebi.ac.uk/thornton-srv/databases/MACiE/) database of enzyme reaction mechanisms.MetaCyc database of enzymes and metabolic pathwaysFace-to-Face Interview with Sir John Cornforth who was awarded a Nobel Prize for work on
stereochemistry of enzyme-catalyzed reactions (http://www.vega.org.uk/video/programme/19) Freeviewvideo by the Vega Science TrustSigma Aldrich Enzyme Assays by Enzyme Name (http://www.sigmaaldrich.com/life-science/metabolomics/enzyme-explorer.html) —Hundreds of assays sorted by enzyme name.Bugg TD (2001). "The development of mechanistic enzymology in the 20th century". Nat Prod Rep 18 (5):465–93. doi:10.1039/b009205n (http://dx.doi.org/10.1039%2Fb009205n) . PMID 11699881(http://www.ncbi.nlm.nih.gov/pubmed/11699881) .
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