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76-501: 2Z5Y , 2BXR , 2BXS , 2Z5X 4128 17161 ENSG00000189221 ENSMUSG00000025037 P21397 Q64133 NM_001270458 NM_000240 NM_173740 NP_000231 NP_001257387 NP_776101 Monoamine oxidase A , also known as MAO-A , is an enzyme ( E.C. 1.4.3.4) that in humans is encoded by the MAOA gene . This gene is one of two neighboring gene family members that encode mitochondrial enzymes which catalyze

152-487: A catalytic triad , stabilize charge build-up on the transition states using an oxyanion hole , complete hydrolysis using an oriented water substrate. 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 protein loop or unit of secondary structure , or even an entire protein domain . These motions give rise to

228-489: A conformational ensemble of slightly different structures that interconvert with one another at equilibrium . Different states within this ensemble may be associated with different aspects of an enzyme's function. For example, different conformations of the enzyme dihydrofolate reductase are associated with the substrate binding, catalysis, cofactor release, and product release steps of the catalytic cycle, consistent with catalytic resonance theory . Substrate presentation

304-511: A type of enzyme rather than being like an enzyme, but even in the decades since ribozymes' discovery in 1980–1982, the word enzyme alone often means the protein type specifically (as is used in this article). An enzyme's specificity comes from its unique three-dimensional structure . 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

380-657: A central domain that binds the amine substrate, and a C-terminal α-helix that is inserted in the outer mitochondrial membrane . MAO-A has a slightly larger substrate-binding cavity than MAO-B, which may be the cause of slight differences in catalytic activity between the two enzymes, as shown in quantitative structure-activity relationship experiments. Both enzymes are relatively large, about 60 kilodaltons in size, and are believed to function as dimers in living cells. Monoamine oxidase A catalyzes O 2 -dependent oxidation of primary arylalkyl amines , most importantly neurotransmitters such as dopamine and serotonin . This

456-430: A dimer enzyme, exhibits intragenic complementation . That is, when particular mutant versions of alkaline phosphatase were combined, the heterodimeric enzymes formed as a result exhibited a higher level of activity than would be expected based on the relative activities of the parental enzymes. These findings indicated that the dimer structure of the E. coli alkaline phosphatase allows cooperative interactions between

532-477: A first step and then checks that the product is correct in a second step. This two-step process results in average error rates of less than 1 error in 100 million reactions in high-fidelity mammalian polymerases. Similar proofreading mechanisms are also found in RNA polymerase , aminoacyl tRNA synthetases and ribosomes . Conversely, some enzymes display enzyme promiscuity , having broad specificity and acting on

608-444: A functional MAOA gene exhibited increased aggression towards intruder mice. Some types of aggression exhibited by these mice were territorial aggression, predatory aggression, and isolation-induced aggression. The MAO-A deficient mice that exhibited increased isolation-induced aggression reveals that an MAO-A deficiency may also contribute to a disruption in social interactions. There is research in both humans and mice to support that

684-551: A high provocation situation: Individuals with the low activity variant of the MAO-A gene were more likely (75% as opposed to 62%, out of a sample size of 70) to retaliate, and with greater force, as compared to those with a normal MAO-A variant if the perceived loss was large. The effects of MAOA genes on aggression have also been criticized for being heavily overstated. Indeed, the MAOA gene, even in conjunction with childhood adversity,

760-502: A large, multigenerational, and notoriously violent, Dutch kindred". A study of Finnish prisoners revealed that a MAOA-L (low-activity) genotype, which contributes to low dopamine turnover rate, was associated with extremely violent behavior. For the purpose of the study, "extremely violent behavior" was defined as at least ten committed homicides, attempted homicides or batteries. However, a large genome-wide association study has failed to find any large or statistically significant effects of

836-617: A non-covalent heterodimer is the enzyme reverse transcriptase , which is composed of two different amino acid chains. An exception is dimers that are linked by disulfide bridges such as the homodimeric protein NEMO . Some proteins contain specialized domains to ensure dimerization (dimerization domains) and specificity. The G protein-coupled cannabinoid receptors have the ability to form both homo- and heterodimers with several types of receptors such as mu-opioid , dopamine and adenosine A2 receptors. E. coli alkaline phosphatase ,

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912-435: A nonsense point mutation in the eighth exon of the MAOA gene is responsible for impulsive aggressiveness due to a complete MAO-A deficiency. A number of transcription factors bind to the promoter region of MAO-A and upregulate its expression. These include: Sp1 transcription factor , GATA2 , TBP . Synthetic compounds that up-regulate the expression of MAO-A include Valproic acid (Depakote) Substances that inhibit

988-464: A quantitative theory of enzyme kinetics, which is referred to as Michaelis–Menten kinetics . The major contribution of Michaelis and Menten was to think of enzyme reactions in two stages. In the first, the substrate binds reversibly to the enzyme, forming the enzyme-substrate complex. This is sometimes called the Michaelis–Menten complex in their honor. The enzyme then catalyzes the chemical step in

1064-439: A range of different physiologically relevant substrates. Many enzymes possess small side activities which arose fortuitously (i.e. neutrally ), which may be the starting point for the evolutionary selection of a new function. To explain the observed specificity of enzymes, in 1894 Emil Fischer proposed that both the enzyme and the substrate possess specific complementary geometric shapes that fit exactly into one another. This

1140-409: A risk factor for violent delinquency, when present in association with stresses, i.e. family issues, low popularity or failing school. A connection between the MAO-A gene 3R version and several types of anti-social behaviour has been found: Maltreated children with genes causing high levels of MAO-A were less likely to develop antisocial behavior. Low MAO-A activity alleles which are overwhelmingly

1216-717: A second case, an individual was convicted of second-degree murder, rather than first-degree murder, based on a genetic test that revealed he had the low-activity MAOA variant. Judges in Germany are more likely to sentence offenders to involuntary psychiatric hospitalization on hearing an accused's MAOA-L genotype. Studies have linked methylation of the MAOA gene with nicotine and alcohol dependence in women. A second MAOA VNTR promoter, P2, influences epigenetic methylation and interacts with having experienced child abuse to influence antisocial personality disorder symptoms, only in women. A study of 34 non-smoking men found that methylation of

1292-451: 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 , to over 2,500 residues in

1368-449: A steady level inside the cell. For example, NADPH is regenerated through the pentose phosphate pathway and S -adenosylmethionine by methionine adenosyltransferase . This continuous regeneration means that small amounts of coenzymes can be used very intensively. For example, the human body turns over its own weight in ATP each day. As with all catalysts, enzymes do not alter the position of

1444-442: 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. Enzyme kinetics is the investigation of how enzymes bind substrates and turn them into products. The rate data used in kinetic analyses are commonly obtained from enzyme assays . In 1913 Leonor Michaelis and Maud Leonora Menten proposed

1520-457: Is k cat , also called the turnover number , 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 and incorporates the rate constants for all steps in the reaction up to and including the first irreversible step. Because the specificity constant reflects both affinity and catalytic ability, it

1596-838: Is orotidine 5'-phosphate decarboxylase , which allows a reaction that would otherwise take millions of years to occur in milliseconds. 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

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1672-421: 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

1748-439: Is an enzyme that in humans is encoded by the MAOA gene . The promoter of MAOA contains conserved binding sites for Sp1 , GATA2 , and TBP . This gene is adjacent to a related gene ( MAOB ) on the opposite strand of the X chromosome . In humans, there is a 30-base repeat sequence repeated several different numbers of times in the promoter region of MAO-A. There are 2R (two repeats), 3R, 3.5R, 4R, and 5R variants of

1824-454: Is called enzymology and the field of pseudoenzyme analysis recognizes that during evolution, some enzymes have lost the ability to carry out biological catalysis, which is often reflected in their amino acid sequences and unusual 'pseudocatalytic' properties. Enzymes are known to catalyze more than 5,000 biochemical reaction types. Other biocatalysts are catalytic RNA molecules , also called ribozymes . They are sometimes described as

1900-437: 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. The top-level classification is: These sections are subdivided by other features such as the substrate, products, and chemical mechanism . An enzyme

1976-749: Is fully specified by four numerical designations. For example, hexokinase (EC 2.7.1.1) is a transferase (EC 2) that adds a phosphate group (EC 2.7) to a hexose sugar, a molecule containing an alcohol group (EC 2.7.1). 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 . Non-homologous isofunctional enzymes . Unrelated enzymes that have

2052-488: Is known to have a very small effect. The vast majority of people with the associated alleles have not committed any violent acts. In a 2009 criminal trial in the United States, an argument based on a combination of "warrior gene" and history of child abuse was successfully used to avoid a conviction of first-degree murder and the death penalty; however, the convicted murderer was sentenced to 32 years in prison. In

2128-588: Is linked to apoptosis and cardiac damage during cardiac injury following ischemic- reperfusion . There is some association between low activity forms of the MAOA gene and autism . Mutations in the MAOA gene results in monoamine oxidase deficiency, or Brunner syndrome . Other disorders associated with MAO-A include Alzheimer's disease , aggression , panic disorder , bipolar disorder , major depressive disorder , and attention deficit hyperactivity disorder . Effects of parenting on self-regulation in adolescents appear to be moderated by 'plasticity alleles', of which

2204-476: 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 . Different enzymes that catalyze the same chemical reaction are called isozymes . The International Union of Biochemistry and Molecular Biology have developed a nomenclature for enzymes, the EC numbers (for "Enzyme Commission") . Each enzyme

2280-418: Is often referred to as "the lock and key" model. This early model explains enzyme specificity, but fails to explain the stabilization of the transition state that enzymes achieve. In 1958, Daniel Koshland suggested a modification to the lock and key model: since enzymes are rather flexible structures, the active site is continuously reshaped by interactions with the substrate as the substrate interacts with

2356-462: 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 Michaelis–Menten constant ( K m ), which is the substrate concentration required for an enzyme to reach one-half its maximum reaction rate; generally, each enzyme has a characteristic K M for a given substrate. Another useful constant

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2432-544: Is predicted from the known issues of candidate gene research, which can produce many substantial false positives. Low-activity variants of the VNTR promoter region of the MAO-A gene have been referred to as the warrior gene . When faced with social exclusion or ostracism, individuals with the low activity MAO-A variants showed higher levels of aggression than individuals with the high activity MAO-A gene. Low activity MAO-A could significantly predict aggressive behaviour in

2508-404: 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 ( 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. V max

2584-403: Is the ribosome which is a complex of protein and catalytic RNA components. Enzymes must bind their substrates before they can catalyse any chemical reaction. Enzymes are usually very specific as to what substrates they bind and then the chemical reaction catalysed. Specificity is achieved by binding pockets with complementary shape, charge and hydrophilic / hydrophobic characteristics to

2660-468: Is the initial step in the breakdown of these molecules. The products are the corresponding aldehyde , hydrogen peroxide , and ammonia : This reaction is believed to occur in three steps, using FAD as an electron-transferring cofactor. First, the amine is oxidized to the corresponding imine , with reduction of FAD to FADH 2 . Second, O 2 accepts two electrons and two protons from FADH 2 , forming H 2 O 2 and regenerating FAD. Third,

2736-790: 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 10 to 10 (M s ). At this point every collision of the enzyme with its substrate will result in catalysis, and the rate of product formation is not limited by the reaction rate but by the diffusion rate. Enzymes with this property are called catalytically perfect or kinetically perfect . Example of such enzymes are triose-phosphate isomerase , carbonic anhydrase , acetylcholinesterase , catalase , fumarase , β-lactamase , and superoxide dismutase . The turnover of such enzymes can reach several million reactions per second. But most enzymes are far from perfect:

2812-614: The DNA polymerases ; here the holoenzyme is the complete complex containing all the subunits needed for activity. Coenzymes are small organic molecules that can be loosely or tightly bound to an enzyme. Coenzymes transport chemical groups from one enzyme to another. Examples include NADH , NADPH and adenosine triphosphate (ATP). Some coenzymes, such as flavin mononucleotide (FMN), flavin adenine dinucleotide (FAD), thiamine pyrophosphate (TPP), and tetrahydrofolate (THF), are derived from vitamins . These coenzymes cannot be synthesized by

2888-547: The MAOA gene and major depressive disorder. In patients with major depressive disorder, those with MAOA G/T polymorphisms (rs6323) coding for the highest-activity form of the enzyme have a significantly lower magnitude of placebo response than those with other genotypes. In humans, an association between the 2R allele of the VNTR region of the gene and an increase in the likelihood of committing serious crime or violence has been found. The VNTR 2R allele of MAOA has been found to be

2964-511: 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. More recent, complex extensions of the model attempt to correct for these effects. Enzyme reaction rates can be decreased by various types of enzyme inhibitors. A competitive inhibitor and substrate cannot bind to

3040-458: The oxidative deamination of amines , such as dopamine , norepinephrine , and serotonin . A mutation of this gene results in Brunner syndrome . This gene has also been associated with a variety of other psychiatric disorders, including antisocial behavior. Alternatively spliced transcript variants encoding multiple isoforms have been observed. Monoamine oxidase A, also known as MAO-A,

3116-422: The 2R and 3R alleles of MAOA are two, with "the more plasticity alleles males (but not females) carried, the more and less self-regulation they manifested under, respectively, supportive and unsupportive parenting conditions." MAO-A levels in the brain as measured using positron emission tomography are elevated by an average of 34% in patients with major depressive disorder . Genetic association studies examining

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3192-463: The 3R allele in combination with abuse experienced during childhood resulted in an increased risk of aggressive behaviour as an adult, and men with the low activity MAOA allele were more genetically vulnerable even to punitive discipline as a predictor of antisocial behaviour. High testosterone, maternal tobacco smoking during pregnancy, poor material living standards, dropping out of school, and low IQ predicted violent behavior are associated with men with

3268-466: The MAOA gene on aggression. A separate GWAS on antisocial personality disorder likewise did not report a significant effect of MAOA. Another study, while finding effects from a candidate gene search, failed to find any evidence in a large GWAS. A separate analysis of human and rat genome wide association studies, Mandelian randomization studies, and causal pathway analyses likewise failed to reveal robust evidence of MAOA in aggression. This lack of replication

3344-437: The active site 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 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

3420-502: The active site. Organic cofactors can be either coenzymes , which are released from the enzyme's active site during the reaction, or prosthetic groups , which are tightly bound to an enzyme. Organic prosthetic groups can be covalently bound (e.g., biotin in enzymes such as pyruvate carboxylase ). An example of an enzyme that contains a cofactor is carbonic anhydrase , which uses a zinc cofactor bound as part of its active site. These tightly bound ions or molecules are usually found in

3496-407: The animal fatty acid synthase . Only a small portion of their structure (around 2–4 amino acids) is directly involved in catalysis: the catalytic site. 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

3572-578: The average values of k c a t / K m {\displaystyle k_{\rm {cat}}/K_{\rm {m}}} and k c a t {\displaystyle k_{\rm {cat}}} are about 10 5 s − 1 M − 1 {\displaystyle 10^{5}{\rm {s}}^{-1}{\rm {M}}^{-1}} and 10 s − 1 {\displaystyle 10{\rm {s}}^{-1}} , respectively. Michaelis–Menten kinetics relies on

3648-502: The body de novo and closely related compounds (vitamins) must be acquired from the diet. The chemical groups carried include: 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. Coenzymes are usually continuously regenerated and their concentrations maintained at

3724-471: 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. For example, carbonic anhydrase catalyzes its reaction in either direction depending on the concentration of its reactants: 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

3800-425: The conversion of starch to sugars by plant extracts and saliva were known but the mechanisms by which these occurred had not been identified. French chemist Anselme Payen was the first to discover an enzyme, diastase , in 1833. A few decades later, when studying the fermentation of sugar to alcohol by yeast , Louis Pasteur concluded that this fermentation was caused by a vital force contained within

3876-433: 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. Enzymes can couple two or more reactions, so that a thermodynamically favorable reaction can be used to "drive"

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3952-564: The enzymatic activity of MAO-A include: Enzyme Enzymes ( / ˈ ɛ n z aɪ m z / ) are proteins that act as biological catalysts by accelerating chemical reactions . The molecules upon which enzymes may act are called substrates , and the enzyme converts the substrates into different molecules known as products . Almost all metabolic processes in the cell need enzyme catalysis in order to occur at rates fast enough to sustain life. Metabolic pathways depend upon enzymes to catalyze individual steps. The study of enzymes

4028-592: 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. The discovery that enzymes could be crystallized eventually allowed their structures to be solved by x-ray crystallography . This

4104-483: The enzyme at the same time. Often competitive inhibitors strongly resemble the real substrate of the enzyme. For example, the drug methotrexate is a competitive inhibitor of the enzyme dihydrofolate reductase , which catalyzes the reduction of dihydrofolate to tetrahydrofolate. The similarity between the structures of dihydrofolate and this drug are shown in the accompanying figure. This type of inhibition can be overcome with high substrate concentration. In some cases,

4180-403: The enzyme. As a result, the substrate does not simply bind to a rigid active site; the amino acid side-chains that make up the active 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. The active site continues to change until

4256-427: 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 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

4332-405: The gene may alter its expression in the brain. A dysfunctional MAOA gene has been correlated with increased aggression levels in mice, and has been correlated with heightened levels of aggression in humans. In mice, a dysfunctional MAOA gene is created through insertional mutagenesis (called 'Tg8'). Tg8 is a transgenic mouse strain that lacks functional MAO-A enzymatic activity. Mice that lacked

4408-432: The imine is hydrolyzed by water, forming ammonia and the aldehyde. Compared to MAO-B, MAO-A has a higher specificity for serotonin and norepinephrine , while the two enzymes have similar affinity for dopamine and tyramine . MAO-A is a key regulator for normal brain function. In the brain, the highest levels of transcription occur in the brain stem , hypothalamus , amygdala , habenula , and nucleus accumbens , and

4484-409: The inhibitor can bind to a site other than the binding-site of the usual substrate and exert an allosteric effect to change the shape of the usual binding-site. Dimeric protein A protein homodimer is formed by two identical proteins while a protein heterodimer is formed by two different proteins. Most protein dimers in biochemistry are not connected by covalent bonds . An example of

4560-431: The low-activity alleles. According to a large meta-analysis in 2014, the 3R allele had a small, nonsignificant effect on aggression and antisocial behavior, in the absence of other interaction factors. Owing to methodological concerns, the authors do not view this as evidence in favor of an effect. The MAO-A gene was the first candidate gene for antisocial behavior and was identified during a "molecular genetic analysis of

4636-691: The lowest in the thalamus , spinal cord , pituitary gland , and cerebellum . Its expression is regulated by the transcription factors SP1, GATA2, and TBP via cAMP -dependent regulation. MAO-A is also expressed in cardiomyocytes , where it is induced in response to stress such as ischemia and inflammation . MAO-A produces an amine oxidase, which is a class of enzyme known to affect carcinogenesis. Clorgyline , an MAO-A enzyme inhibitor, prevents apoptosis in melanoma cells, in vitro. Cholangiocarcinoma suppresses MAO-A expression, and those patients with higher MAO-A expression had less adjacent organ invasion and better prognosis and survival. MAOA activity

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4712-474: The mixture. He named the enzyme that brought about the fermentation of sucrose " zymase ". In 1907, he received the Nobel Prize in Chemistry for "his discovery of cell-free fermentation". Following Buchner's example, enzymes are usually named according to the reaction they carry out: the suffix -ase is combined with the name of the substrate (e.g., lactase is the enzyme that cleaves lactose ) or to

4788-528: The precise orientation and dynamics of the active site. In some enzymes, no amino acids are directly involved in catalysis; instead, the enzyme contains sites to bind and orient catalytic cofactors . Enzyme structures may also contain allosteric sites where the binding of a small molecule causes a conformational change that increases or decreases activity. A small number of RNA -based biological catalysts called ribozymes exist, which again can act alone or in complex with proteins. The most common of these

4864-406: The reaction and releases the product. This work was further developed by G. E. Briggs and J. B. S. Haldane , who derived kinetic equations that are still widely used today. 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

4940-733: The reaction rate of the enzyme. 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. Some enzymes do not need additional components to show full activity. Others require non-protein molecules called cofactors to be bound for activity. Cofactors can be either inorganic (e.g., metal ions and iron–sulfur clusters ) or organic compounds (e.g., flavin and heme ). These cofactors serve many purposes; for instance, metal ions can help in stabilizing nucleophilic species within

5016-408: The relationship between high-activity MAOA variants and depression have produced mixed results, with some studies linking the high-activity variants to major depression in females, depressed suicide in males, major depression and sleep disturbance in males and major depressive disorder in both males and females. Other studies failed to find a significant relationship between high-activity variants of

5092-745: The repeat sequence, with the 3R and 4R variants most common in all populations. The variants of the promoter have been found to appear at different frequencies in different ethnic groups in an American sample cohort. The epigenetic modification of MAOA gene expression through methylation likely plays an important role in women. A study from 2010 found epigenetic methylation of MAOA in men to be very low and with little variability compared to women, while having higher heritability in men than women. MAO-A shares 70% amino acid sequence identity with its homologue MAO-B. Accordingly, both proteins have similar structures. Both MAO-A and MAO-B exhibit an N-terminal domain that binds flavin adenine dinucleotide (FAD),

5168-410: The same enzymatic activity have been called non-homologous isofunctional enzymes . 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. Enzymes are generally globular proteins , acting alone or in larger complexes . The sequence of the amino acids specifies

5244-412: The structure which in turn determines the catalytic activity of the enzyme. Although structure determines function, a novel enzymatic activity cannot yet be predicted from structure alone. Enzyme structures unfold ( denature ) when heated or exposed to chemical denaturants and this disruption to the structure typically causes a loss of activity. Enzyme denaturation is normally linked to temperatures above

5320-519: The substrate is completely bound, at which point the final shape and charge distribution is determined. Induced fit may enhance the fidelity of molecular recognition in the presence of competition and noise via the conformational proofreading mechanism. Enzymes can accelerate reactions in several ways, all of which lower the activation energy (ΔG , Gibbs free energy ) Enzymes may use several of these mechanisms simultaneously. For example, proteases such as trypsin perform covalent catalysis using

5396-405: The substrates. Enzymes can therefore distinguish between very similar substrate molecules to be chemoselective , regioselective and stereospecific . 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

5472-399: 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. By the late 17th and early 18th centuries, the digestion of meat by stomach secretions and

5548-438: The type of reaction (e.g., DNA polymerase forms DNA polymers). 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. In 1926, James B. Sumner showed that

5624-486: The yeast cells called "ferments", which were thought to function only within living organisms. He wrote that "alcoholic fermentation is an act correlated with the life and organization of the yeast cells, not with the death or putrefaction of the cells." In 1877, German physiologist Wilhelm Kühne (1837–1900) first used the term enzyme , which comes from Ancient Greek ἔνζυμον (énzymon)  ' leavened , in yeast', to describe this process. The word enzyme

5700-581: 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. 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. 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

5776-457: Was used later to refer to nonliving substances such as pepsin , and the word ferment was used to refer to chemical activity produced by living organisms. Eduard Buchner submitted his first paper on the study of yeast extracts in 1897. In a series of experiments at the University of Berlin , he found that sugar was fermented by yeast extracts even when there were no living yeast cells in

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