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<title>Enzyme inhibitor</title>
<authors>Wikipedia</authors>
<publisher>wikipedia.org</publisher>
<publishedplace>network</publishedplace>
<publishedyear>2010</publishedyear>
<edition></edition>
<category>Featured articles</category>
<section id="38339" fatherid="0" title="" lv="" priority="-1" level="1">
Enzyme inhibitors are molecules that bind to enzymes and decrease their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides. Not all molecules that bind to enzymes are inhibitors; enzyme activators bind to enzymes and increase their enzymatic activity.
The binding of an inhibitor can stop a substrate from entering the enzyme's active site and/or hinder the enzyme from catalysing its reaction.  Inhibitor binding is either reversible or irreversible. Irreversible inhibitors usually react with the enzyme and change it chemically. These inhibitors modify key amino acid residues needed for enzymatic activity. In contrast, reversible inhibitors bind non-covalently and different types of inhibition are produced depending on whether these inhibitors bind the enzyme, the enzyme-substrate complex, or both.
Many drug molecules are enzyme inhibitors, so their discovery and improvement is an active area of research in biochemistry and pharmacology. A medicinal enzyme inhibitor is often judged by its specificity (its lack of binding to other proteins) and its potency (its dissociation constant, which indicates the concentration needed to inhibit the enzyme). A high specificity and potency ensure that a drug will have few side effects and thus low toxicity.
Enzyme inhibitors also occur naturally and are involved in the regulation of metabolism. For example, enzymes in a metabolic pathway can be inhibited by downstream products. This type of negative feedback slows flux through a pathway when the products begin to build up and is an important way to maintain homeostasis in a cell. Other cellular enzyme inhibitors are proteins that specifically bind to and inhibit an enzyme target. This can help control enzymes that may be damaging to a cell, such as proteases or nucleases; a well-characterised example is the ribonuclease inhibitor, which binds to ribonucleases in one of the tightest known protein–protein interactions.Shapiro R, Vallee BL. Interaction of human placental ribonuclease with placental ribonuclease inhibitor. Biochemistry. 1991 Feb 26;30(8):2246–55. PMID 1998683 Natural enzyme inhibitors can also be poisons and are used as defenses against predators or as ways of killing prey.

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<section id="38340" fatherid="0" title="Reversible inhibitors" lv="" priority="2" level="1">
<section id="38341" fatherid="38340" title="Types of reversible inhibitor" lv="" priority="1" level="2">
Reversible inhibitors bind to enzymes with non-covalent interactions such as hydrogen bonds, hydrophobic interactions and ionic bonds. Multiple weak bonds between the inhibitor and the active site combine to produce strong and specific binding. In contrast to substrates and irreversible inhibitors, reversible inhibitors generally do not undergo chemical reactions when bound to the enzyme and can be easily removed by dilution or dialysis.
There are four kinds of reversible enzyme inhibitors. They are classified according to the effect of varying the concentration of the enzyme's substrate on the inhibitor.Berg J., Tymoczko J. and Stryer L. (2002) Biochemistry. W. H. Freeman and Company ISBN 0-7167-4955-6

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<section id="38342" fatherid="38340" title="Quantitative description of reversible inhibition" lv="" priority="2" level="2">
Reversible inhibition can be described quantitatively in terms of the inhibitor's binding to the enzyme and to the enzyme–substrate complex, and its effects on the kinetic constants of the enzyme. In the classic Michaelis–Menten scheme below, an enzyme (E) binds to its substrate (S) to form the enzyme–substrate complex ES. Upon catalysis, this complex breaks down to release product P and free enzyme. The inhibitor (I) can bind to either E or ES with the dissociation constants Ki or Ki', respectively.
When an enzyme has multiple substrates, inhibitors can show different types of inhibition depending on which substrate is considered. This results from the active site containing two different binding sites within the active site, one for each substrate. For example, an inhibitor might compete with substrate A for the first binding site, but be a non-competitive inhibitor with respect to substrate B in the second binding site.*Irwin H. Segel, Enzyme Kinetics : Behavior and Analysis of Rapid Equilibrium and Steady-State Enzyme Systems. Wiley–Interscience; New edition (1993), ISBN 0-471-30309-7

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<section id="38343" fatherid="38340" title="Measuring the dissociation constants of a reversible inhibitor" lv="" priority="3" level="2">
As noted above, an enzyme inhibitor is characterized by its two dissociation constants, Ki and Ki', to the enzyme and to the enzyme-substrate complex, respectively. The enzyme-inhibitor constant Ki can be measured directly by various methods; one extremely accurate method is isothermal titration calorimetry, in which the inhibitor is titrated into a solution of enzyme and the heat released or absorbed is measured.Holdgate GA. Making cool drugs hot: isothermal titration calorimetry as a tool to study binding energetics. Biotechniques. 2001 Jul;31(1):164–6 PMID 11464510 However, the other dissociation constant Ki' is difficult to measure directly, since the enzyme-substrate complex is short-lived and undergoing a chemical reaction to form the product. Hence, Ki' is usually measured indirectly, by observing the enzyme activity under various substrate and inhibitor concentrations, and fitting the dataLeatherbarrow RJ. Using linear and non-linear regression to fit biochemical data. Trends Biochem Sci. 1990 Dec;15(12):455–8. PMID 2077683 to a modified Michaelis–Menten equation
 
V = frac{V_{max}S}{alpha K_{m} + alpha^{prime}S} = frac{(1/alpha^{prime})V_{max}S}{(alpha/alpha^{prime}) K_{m} + S}

where the modifying factors α and α' are defined by the inhibitor concentration and its two dissociation constants

alpha = 1 + frac{I}{K_{i}}


alpha^{prime} = 1 + frac{I}{K_{i}^{prime}}.

Thus, in the presence of the inhibitor, the enzyme's effective Km and Vmax become (α/α')Km and (1/α')Vmax, respectively. However, the modified Michaelis-Menten equation assumes that binding of the inhibitor to the enzyme has reached equilibrium, which may be a very slow process for inhibitors with sub-nanomolar dissociation constants. In these cases, it is usually more practical to treat the tight-binding inhibitor as an irreversible inhibitor (see below); however, it can still be possible to estimate Ki' kinetically if Ki is measured independently.
The effects of different types of reversible enzyme inhibitors on enzymatic activity can be visualized using graphical representations of the Michaelis–Menten equation, such as Lineweaver–Burk and Eadie-Hofstee plots. For example, in the Lineweaver–Burk plots at the , the competitive inhibition lines intersect on the y-axis, illustrating that such inhibitors do not affect Vmax.  Similarly, the non-competitive inhibition lines intersect on the x-axis, showing these inhibitors do not affect Km. However, it can be difficult to estimate Ki and Ki' accurately from such plots,Tseng SJ, Hsu JP. A comparison of the parameter estimating procedures for the Michaelis–Menten model. J Theor Biol. 1990 Aug 23;145(4):457–64. PMID 2246896 so it is advisable to estimate these constants using more reliable nonlinear regression methods, as described above.

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<section id="38344" fatherid="38340" title="Special cases" lv="" priority="-4" level="2">
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<section id="38345" fatherid="38340" title="Examples of reversible inhibitors" lv="" priority="5" level="2">
As enzymes have evolved to bind their substrates tightly, and most reversible inhibitors bind in the active site of enzymes, it is unsurprising that some of these inhibitors are strikingly similar in structure to the substrates of their targets. An example of these substrate mimics are the protease inhibitors, a very successful class of antiretroviral drugs used to treat HIV.Hsu JT, Wang HC, Chen GW, Shih SR. Antiviral drug discovery targeting to viral proteases. Curr Pharm Des. 2006; 12(11):1301–14. PMID 16611117 The structure of ritonavir, a protease inhibitor based on a peptide and containing three peptide bonds, is shown on the . As this drug resembles the protein that is the substrate of the HIV protease, it competes with this substrate in the enzyme's active site.
Enzyme inhibitors are often designed to mimic the transition state or intermediate of an enzyme-catalysed reaction. This ensures that the inhibitor exploits the transition state stabilising effect of the enzyme, resulting in a better binding affinity (lower Ki) than substrate-based designs. An example of such a transition state inhibitor is the antiviral drug oseltamivir; this drug mimics the planar nature of the ring oxonium ion in the reaction of the viral enzyme neuraminidase.
However, not all inhibitors are based on the structures of substrates. For example, the structure of another HIV protease inhibitor tipranavir is shown on the . This molecule is not based on a peptide and has no obvious structural similarity to a protein substrate. These non-peptide inhibitors can be more stable than inhibitors containing peptide bonds, because they will not be substrates for peptidases and are less likely to be degraded.
In drug design it is important to consider the concentrations of substrates to which the target enzymes are exposed. For example, some protein kinase inhibitors have chemical structures that are similar to adenosine triphosphate, one of the substrates of these enzymes. However, drugs that are simple competitive inhibitors will have to compete with the high concentrations of ATP in the cell. Protein kinases can also be inhibited by competition at the binding sites where the kinases interact with their substrate proteins, and most proteins are present inside cells at concentrations much lower than the concentration of ATP. As a consequence, if two protein kinase inhibitors both bind in the active site with similar affinity, but only one has to compete with ATP, then the competitive inhibitor at the protein-binding site will inhibit the enzyme more effectively.Bogoyevitch MA, Barr RK, Ketterman AJ. Peptide inhibitors of protein kinases—discovery, characterisation and use. Biochim Biophys Acta. 2005 Dec 30;1754(1–2):79–99. PMID 16182621

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<section id="38346" fatherid="0" title="Irreversible inhibitors" lv="" priority="3" level="1">
<section id="38347" fatherid="38346" title="Types of irreversible inhibition" lv="" priority="1" level="2">
Irreversible inhibitors usually covalently modify an enzyme, and inhibition cannot therefore be reversed. Irreversible inhibitors often contain reactive functional groups such as nitrogen mustards, aldehydes, haloalkanes, alkenes, Michael acceptors, phenyl sulfonates, or fluorophosphonates. These electrophilic groups react with amino acid side chains to form covalent adducts. The residues modified are those with side chains containing nucleophiles such as hydroxyl or sulfhydryl groups; these include the amino acids serine (as in DFP, ), cysteine, threonine or tyrosine.Lundblad R. L. Chemical Reagents for Protein Modification CRC Press Inc (2004) ISBN 0-8493-1983-8
Irreversible inhibition is different from irreversible enzyme inactivation. Irreversible inhibitors are generally specific for one class of enzyme and do not inactivate all proteins; they do not function by destroying protein structure but by specifically altering the active site of their target. For example, extremes of pH or temperature usually cause denaturation of all protein structure, but this is a non-specific effect. Similarly, some non-specific chemical treatments destroy protein structure: for example, heating in concentrated hydrochloric acid will hydrolyse the peptide bonds holding proteins together, releasing free amino acids.N. Price, B. Hames, D. Rickwood (Ed.) Proteins LabFax Academic Press (1996) ISBN 0-12-564710-7
Irreversible inhibitors display time-dependent inhibition and their potency therefore cannot be characterized by an IC50 value. This is because the amount of active enzyme at a given concentration of irreversible inhibitor will be different depending on how long the inhibitor is pre-incubated with the enzyme. Instead, kobs/I values are used,Adam GC, Cravatt BF, Sorensen EJ. (2001) Profiling the specific reactivity of the proteome with non-directed activity-based probes. Chem. Biol. 8(1):81-95. wherekobs is the observed pseudo-first order rate of inactivation (obtained by plotting the log of % activity vs. time) and I is the concentration of inhibitor. The kobs/I parameter is valid as long as the inhibitor does not saturate binding with the enzyme (in which case kobs = kinact).

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<section id="38348" fatherid="38346" title="Analysis of irreversible inhibition" lv="" priority="2" level="2">
As shown in the figure to the , irreversible inhibitors form a reversible non-covalent complex with the enzyme (EI or ESI) and this then reacts to produce the covalently modified "dead-end complex" EI*. The rate at which EI* is formed is called the inactivation rate or kinact. Since formation of EI may compete with ES, binding of irreversible inhibitors can be prevented by competition either with substrate or with a second, reversible inhibitor. This protection effect is good evidence of a specific reaction of the irreversible inhibitor with the active site.
The binding and inactivation steps of this reaction are investigated by incubating the enzyme with inhibitor and assaying the amount of activity remaining over time. The activity will be decrease in a time-dependent manner, usually following exponential decay. Fitting these data to a rate equation gives the rate of inactivation at this concentration of inhibitor. This is done at several different concentrations of inhibitor. If a reversible EI complex is involved the inactivation rate will be saturable and fitting this curve will give kinact and Ki.Maurer T, Fung HL. Comparison of Methods for Analyzing Kinetic Data From Mechanism-Based Enzyme Inactivation: Application to Nitric Oxide Synthase. AAPS PharmSci. (2000) 2(1)E8. PMID 11741224
Another method that is widely used in these analyses is mass spectrometry. Here, accurate measurement of the mass of the unmodified native enzyme and the inactivated enzyme gives the increase in mass caused by reaction with the inhibitor and shows the stoichiometry of the reaction. This is usually done using a MALDI-TOF mass spectrometer. In a complementary technique, peptide mass fingerprinting involves digestion of the native and modified protein with a protease such as trypsin. This will produce a set of peptides that can be analysed using a mass spectrometer. The peptide that changes in mass after reaction with the inhibitor will be the one that contains the site of modification.

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<section id="38349" fatherid="38346" title="Special cases" lv="" priority="3" level="2">
Not all irreversible inhibitors form covalent adducts with their enzyme targets. Some reversible inhibitors bind so tightly to their target enzyme that they are essentially irreversible. These tight-binding inhibitors may show kinetics similar to covalent irreversible inhibitors. In these cases, some of these inhibitors rapidly bind to the enzyme in a low-affinity EI complex and this then undergoes a slower rearrangement to a very tightly bound EI* complex (see figure above). This kinetic behaviour is called slow-binding.Szedlacsek, S.E. and Duggleby, R.G. Kinetics of slow and tight-binding inhibitors. Meth. Enzymol., (1995) 249: 144–180. PMID 7791610 This slow rearrangement after binding often involves a conformational change as the enzyme "clamps down" around the inhibitor molecule. Examples of slow-binding inhibitors include some important drugs, such methotrexate,Stone SR, Morrison JF. Mechanism of inhibition of dihydrofolate reductases from bacterial and vertebrate sources by various classes of folate analogues. Biochim Biophys Acta. 1986 Feb 14;869(3):275–85. PMID 3511964 allopurinol,Hille R, Massey V. Tight binding inhibitors of xanthine oxidase. Pharmacol Ther. 1981;14(2):249–63. PMID 4322209 and the activated form of acyclovir.Reardon JE. Herpes simplex virus type 1 and human DNA polymerase interactions with 2'-deoxyguanosine 5'-triphosphate analogues. Kinetics of incorporation into DNA and induction of inhibition. J Biol Chem. 1989 Nov 15;264(32):19039–44. PMID 2553730
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<section id="38350" fatherid="38346" title="Examples of irreversible inhibitors" lv="" priority="4" level="2">
Diisopropylfluorophosphate (DFP) is shown as an example of an irreversible protease inhibitor in the figure above . The enzyme hydrolyses the phosphorus–fluorine bond, but the phosphate residue remains bound to the serine in the active site, deactivating it.J. A. Cohen, R. A. Oosterbaan and F. Berends Organophosphorus compounds Meth. Enzymol. (1967) 11, 686 Similarly, DFP also reacts with the active site of acetylcholine esterase in the synapses of neurons, and consequently is a potent neurotoxin, with a lethal dose of less than 100 mg.Brenner, G. M. (2000): Pharmacology. Philadelphia, PA: W.B. Saunders Company. ISBN 0-7216-7757-6
Suicide inhibition is an unusual type of irreversible inhibition where the enzyme converts the inhibitor into a reactive form in its active site. An example is the inhibitor of polyamine biosynthesis, α-difluoromethylornithine or DFMO, which is an analogue of the amino acid ornithine, and is used to treat African trypanosomiasis (sleeping sickness). Ornithine decarboxylase can catalyse the decarboxylation of DFMO instead of ornithine, as shown above. However, this decarboxylation reaction is followed by the elimination of a fluorine atom, which converts this catalytic intermediate into a conjugated imine, a highly electrophilic species. This reactive form of DFMO then reacts with either a cysteine or lysine residue in the active site to irreversibly inactivate the enzyme.
Since irreversible inhibition often involves the initial formation of a non-covalent EI complex, it is sometimes possible for an inhibitor to bind to an enzyme in more than one way. For example, in the figure showing trypanothione reductase from the human protozoan parasite Trypanosoma cruzi, two molecules of an inhibitor called quinacrine mustard are bound in its active site. The top molecule is bound reversibly, but the lower one is bound covalently as it has reacted with an amino acid residue through its nitrogen mustard group.Saravanamuthu A, Vickers TJ, Bond CS, Peterson MR, Hunter WN, Fairlamb AH. Two interacting binding sites for quinacrine derivatives in the active site of trypanothione reductase: a template for drug design. J Biol Chem. 2004 Jul 9;279(28):29493–500. PMID 15102853

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<section id="38351" fatherid="0" title="Discovery and design of inhibitors" lv="" priority="4" level="1">
New drugs are the products of a long drug development process, the first step of which is often the discovery of a new enzyme inhibitor. In the past the only way to discover these new inhibitors was by trial and error: screening huge libraries of compounds against a target enzyme and hoping that some useful leads would emerge. This brute force approach is still successful and has even been extended by combinatorial chemistry approaches that quickly produce large numbers of novel compounds and high-throughput screening technology to rapidly screen these huge chemical libraries for useful inhibitors.
More recently, an alternative approach has been applied: rational drug design uses the three-dimensional structure of an enzyme's active site to predict which molecules might be inhibitors. These predictions are then tested and one of these tested compounds may be a novel inhibitor. This new inhibitor is then used to try to obtain a structure of the enzyme in an inhibitor/enzyme complex to show how the molecule is binding to the active site, allowing changes to be made to the inhibitor to try to optimise binding. This test and improve cycle is then repeated until a sufficiently potent inhibitor is produced. Computer-based methods of predicting the affinity of an inhibitor for an enzyme are also being developed, such as molecular docking and molecular mechanics.

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<section id="38352" fatherid="0" title="Uses of inhibitors" lv="" priority="5" level="1">
<section id="38353" fatherid="38352" title="" lv="" priority="-1" level="2">
Enzyme inhibitors are found in nature and are also designed and produced as part of pharmacology and biochemistry. Natural poisons are often enzyme inhibitors that have evolved to defend a plant or animal against predators. These natural toxins include some of the most poisonous compounds known. Artificial inhibitors are often used as drugs, but can also be insecticides such as malathion, herbicides such as glyphosate, or disinfectants such as triclosan.
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<section id="38354" fatherid="38352" title="Chemotherapy" lv="" priority="2" level="2">
The most common uses for enzyme inhibitors are as drugs to treat disease. Many of these inhibitors target a human enzyme and aim to correct a pathological condition. However, not all drugs are enzyme inhibitors. Some, such as anti-epileptic drugs, alter enzyme activity by causing more or less of the enzyme to be produced. These effects are called enzyme induction and inhibition and are alterations in gene expression, which is unrelated to the type of enzyme inhibition discussed here. Other drugs interact with cellular targets that are not enzymes, such as ion channels or membrane receptors.
An example of a medicinal enzyme inhibitor is sildenafil (Viagra), a common treatment for male erectile dysfunction. This compound is a potent inhibitor of cGMP specific phosphodiesterase type 5, the enzyme that degrades the signalling molecule cyclic guanosine monophosphate.Maggi M, Filippi S, Ledda F, Magini A, Forti G. Erectile dysfunction: from biochemical pharmacology to advances in medical therapy. Eur J Endocrinol. 2000 Aug;143(2):143–54 PMID 10913932 This signalling molecule triggers smooth muscle relaxation and allows blood flow into the corpus cavernosum, which causes an erection. Since the drug decreases the activity of the enzyme that halts the signal, it makes this signal last for a longer period of time.
Another example of the structural similarity of some inhibitors to the substrates of the enzymes they target is seen in the figure comparing the drug methotrexate to folic acid. Folic acid is a substrate of dihydrofolate reductase, an enzyme involved in making nucleotides that is potently inhibited by methotrexate. Methotrexate blocks the action of dihydrofolate reductase and thereby halts the production of nucleotides. This block of nucleotide biosynthesis is more toxic to rapidly growing cells than non-dividing cells, since a rapidly-growing cell has to carry out DNA replication, therefore methotrexate is often used in cancer chemotherapy.McGuire JJ. Anticancer antifolates: current status and future directions. Curr Pharm Des. 2003;9(31):2593–613. PMID 14529544
Drugs also are used to inhibit enzymes needed for the survival of pathogens. For example, bacteria are surrounded by a thick cell wall made of a net-like polymer called peptidoglycan. Many antibiotics such as penicillin and vancomycin inhibit the enzymes that produce and then cross-link the strands of this polymer together.Katz AH, Caufield CE. Structure-based design approaches to cell wall biosynthesis inhibitors. Curr Pharm Des. 2003;9(11):857–66. PMID 12678870 This causes the cell wall to lose strength and the bacteria to burst. In the figure, a molecule of penicillin (shown in a ball-and stick form) is shown bound to its target, the transpeptidase from the bacteria Streptomyces R61 (the protein is shown as a ribbon-diagram).
Drug design is facilitated when an enzyme that is essential to the pathogen's survival is absent or very different in humans. In the example above, humans do not make peptidoglycan, therefore inhibitors of this process are selectively toxic to bacteria. Selective toxicity is also produced in antibiotics by exploiting differences in the structure of the ribosomes in bacteria, or how they make fatty acids.

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<section id="38355" fatherid="38352" title="Metabolic control" lv="" priority="3" level="2">
Enzyme inhibitors are also important in metabolic control. Many metabolic pathways in the cell are inhibited by metabolites that control enzyme activity through allosteric regulation or substrate inhibition. A good example is the allosteric regulation of the glycolytic pathway. This catabolic pathway consumes glucose and produces ATP, NADH and pyruvate. A key step for the regulation of glycolysis is an early reaction in the pathway catalysed by phosphofructokinase-1 (PFK1). When ATP levels rise, ATP binds an allosteric site in PFK1 to decrease the rate of the enzyme reaction; glycolysis is inhibited and ATP production falls. This negative feedback control helps maintain a steady concentration of ATP in the cell. However, metabolic pathways are not just regulated through inhibition since enzyme activation is equally important. With respect to PFK1, fructose 2,6-bisphosphate and ADP are examples of metabolites that are allosteric activators.Okar DA, Lange AJ. Fructose-2,6-bisphosphate and control of carbohydrate metabolism in eukaryotes. Biofactors. 1999;10(1):1–14.
Physiological enzyme inhibition can also be produced by specific protein inhibitors. This mechanism occurs in the pancreas, which synthesises many digestive precursor enzymes known as zymogens. Many of these are activated by the trypsin protease, so it is important to inhibit the activity of trypsin in the pancreas to prevent the organ from digesting itself. One way in which the activity of trypsin is controlled is the production of a specific and potent trypsin inhibitor protein in the pancreas. This inhibitor binds tightly to trypsin, preventing the trypsin activity that would otherwise be detrimental to the organ.Nicholas Price, Lewis Stevens, Fundamentals of Enzymology, Oxford University Press, (1999) ISBN 0-19-850229-X Although the trypsin inhibitor is a protein, it avoids being hydrolysed as a substrate by the protease by excluding water from trypsin's active site and destabilising the transition state.Smyth TP. Substrate variants versus transition state analogues as noncovalent reversible enzyme inhibitors. Bioorg Med Chem. 2004 Aug 1;12(15):4081–8. PMID 15246086 Other examples of physiological enzyme inhibitor proteins include the barstar inhibitor of the bacterial ribonuclease barnaseHartley RW. Barnase and barstar: two small proteins to fold and fit together. Trends Biochem Sci. 1989 Nov;14(11):450–4. PMID 2696173 and the inhibitors of protein phosphatases.Oliver CJ, Shenolikar S. Physiologic importance of protein phosphatase inhibitors. Front Biosci. 1998 Sep 1;3:D961–72. PMID 9727084

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<section id="38356" fatherid="38352" title="Pesticides and herbicides" lv="" priority="4" level="2">
Many herbicides and pesticides are enzyme inhibitors. Acetylcholinesterase (AChE) is an enzyme found in animals from insects to humans.  It is essential to nerve cell function through its mechanism of breaking down the neurotransmitter acetylcholine into its constituents, acetate and choline.  This is somewhat unique among neurotransmitters as most, including serotonin, dopamine, and norepinephrine, are absorbed from the synaptic c rather than cleaved.  A large number of AChE inhibitors are used in both medicine and agriculture.  Reversible competitive inhibitors, such as edrophonium, physostigmine, and neostigmine, are used in the treatment of myasthenia gravis and in anaesthesia.  The carbamate pesticides are also examples of reversible AChE inhibitors.  The organophosphate insecticides such as malathion, parathion, and chlorpyrifos irreversibly inhibit acetylcholinesterase.
The herbicide glyphosate is an inhibitor of 3-phosphoshikimate 1-carboxyvinyltransferase, other herbicides, such as the sulfonylureas inhibit the enzyme acetolactate synthase. Both these enzymes are needed for plants to make branched-chain amino acids. Many other enzymess are inhibited by herbicides, including enzymes needed for the biosynthesis of lipids and carotenoids and the processes of photosynthesis and oxidative phosphorylation.

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<section id="38357" fatherid="38352" title="Natural poisons" lv="" priority="5" level="2">
Animals and plants have evolved to synthesize a vast array of poisonous products including secondary metabolites, peptides and proteins that can act as inhibitors. Natural toxins are usually small organic molecules and are so diverse that there are probably natural inhibitors for most metabolic processes.Tan G, Gyllenhaal C, Soejarto DD. Biodiversity as a source of anticancer drugs. Curr Drug Targets. 2006 Mar;7(3):265-77. PMID 16515527 The metabolic processes targeted by natural poisons encompass more than enzymes in metabolic pathways and can also include the inhibition of receptor, channel and structural protein functions in a cell. For example, paclitaxel (taxol), an organic molecule found in the Pacific yew tree, binds tightly to tubulin dimers and inhibits their assembly into microtubules in the cytoskeleton.Abal M, Andreu JM, Barasoain I. Taxanes: microtubule and centrosome targets, and cell cycle dependent mechanisms of action. Curr Cancer Drug Targets. 2003 Jun;3(3):193–203. PMID 12769688
Many natural poisons act as neurotoxins that can cause paralysis leading to death and have functions for defence against predators or in hunting and capturing prey. Some of these natural inhibitors, despite their toxic attributes, are valuable for therapeutic uses at lower doses.Hostettmann K, Borloz A, Urbain A, Marston A, Natural Product Inhibitors of Acetylcholinesterase Current Organic Chemistry, 2006 May;10(8):825–47 An example of a neurotoxin are the glycoalkaloids, from the plant species in the Solanaceae family (includes potato, tomato and eggplant), that are acetylcholinesterase inhibitors. Inhibition of this enzyme causes an uncontrolled increase in the acetylcholine neurotransmitter, muscular paralysis and then death. Neurotoxicity can also result from the inhibition of receptors; for example, atropine from deadly nightshade (Atropa belladonna) that functions as a competitive antagonist of the muscarinic acetylcholine receptors.DeFrates LJ, Hoehns JD, Sakornbut EL, Glascock DG, Tew AR. Antimuscarinic intoxication resulting from the ingestion of moonflower seeds. Ann Pharmacother. 2005 Jan;39(1):173-6. PMID 15572604
Although many natural toxins are secondary metabolites, these poisons also include peptides and proteins. An example of a toxic peptide is alpha-amanitin, which is found in relatives of the death cap mushroom. This is a potent enzyme inhibitor, in this case preventing the RNA polymerase II enzyme from transcribing DNA.Vetter J. Toxins of Amanita phalloides. Toxicon. 1998 Jan;36(1):13–24. PMID 9604278 The algal toxin microcystin is also a peptide and is an inhibitor of protein phosphatases.Holmes CF, Maynes JT, Perreault KR, Dawson JF, James MN. Molecular enzymology underlying regulation of protein phosphatase-1 by natural toxins. Curr Med Chem. 2002 Nov;9(22):1981–9. PMID 12369866 This toxin can contaminate water supplies after algal blooms and is a known carcinogen that can also cause acute liver hemorrhage and death at higher doses.Bischoff K. The toxicology of microcystin-LR: occurrence, toxicokinetics, toxicodynamics, diagnosis and treatment. Vet Hum Toxicol. 2001 Oct;43(5):294-7. PMID 11577938
Proteins can also be natural poisons or antinutrients, such as the trypsin inhibitors (discussed above) that are found in some legumes, as shown in the figure above. A less common class of toxins are toxic enzymes: these act as irreversible inhibitors of their target enzymes and work by chemically modifying their substrate enzymes. An example is ricin, an extremely potent protein toxin found in castor oil beans. This enzyme is a glycosidase that inactivates ribosomes. Since ricin is a catalytic irreversible inhibitor, this allows just a single molecule of ricin to kill a cell.Hartley MR, Lord JM. Cytotoxic ribosome-inactivating lectins from plants. Biochim Biophys Acta. 2004 Sep 1;1701(1–2):1–14. PMID 15450171

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<section id="38359" fatherid="0" title="References" lv="" priority="-7" level="1">
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<section id="38360" fatherid="0" title="External links" lv="" priority="-8" level="1">
Category:Medicinal chemistry
Category:Enzymes
Category:Metabolism
Category:Enzyme inhibitors

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