115-409: 4U7T , 4QBR , 4U7P , 4QBS , 3A1B , 3LLR , 4QBQ , 3SVM , 3A1A , 2QRV 1788 13435 ENSG00000119772 ENSMUSG00000020661 Q9Y6K1 O88508 NM_001320893 NM_001375819 NM_001271753 NM_007872 NM_153743 NP_783329 NP_001362748 NP_001258682 NP_031898 NP_714965 DNA (cytosine-5)-methyltransferase 3A ( DNMT3A ) is an enzyme that catalyzes
230-487: 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
345-489: 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
460-684: A catalytic domain, occur as a heterotetramer (see Figure). These heterotetramers occur in the order: accessory protein-catalytic protein-catalytic protein-accessory protein. The particular complex shown in the Figure illustrates the heterotetramer formed by catalytic protein DNMT3A2 and accessory protein DNMT3B3. One accessory protein of the complex binds to an acidic patch on the nucleosome core (see top 3B3 in Figure). The connection of one accessory protein to
575-477: 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
690-532: A greater number of synaptic contacts in the NAcc shell than in the core. They are also larger and thicker, and contain more large dense core vesicles than their counterparts in the core. The nucleus accumbens, being one part of the reward system, plays an important role in processing rewarding stimuli, reinforcing stimuli (e.g., food and water), and those which are both rewarding and reinforcing (addictive drugs, sex, and exercise). The predominant response of neurons in
805-399: A large increase, even block most of the neural alterations seen in chronic drug abuse (i.e., the alterations mediated by ΔFosB). ΔFosB also plays an important role in regulating behavioral responses to natural rewards, such as palatable food, sex, and exercise. Natural rewards, like drugs of abuse, induce ΔFosB in the nucleus accumbens, and chronic acquisition of these rewards can result in
920-412: A paired environmental stimulus triggers a craving or desire to use the drug which they've become associated with ). In contrast to drugs, the release of dopamine in the NAcc shell by many types of rewarding non-drug stimuli typically undergoes habituation following repeated exposure (i.e., the amount of dopamine that is released from future exposure to a rewarding non-drug stimulus normally decreases as
1035-464: 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
1150-439: 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
1265-499: A result of repeated drug exposure); on the contrary, repeated exposure to drugs that induce dopamine release in the NAcc shell and core typically results in sensitization (i.e., the amount of dopamine that is released in the NAcc from future drug exposure increases as a result of repeated drug exposure). Sensitization of dopamine release in the NAcc shell following repeated drug exposure serves to strengthen stimulus-drug associations (i.e., classical conditioning that occurs when drug use
SECTION 10
#17327874167871380-493: A result of repeated exposure to that stimulus). In April 2007, two research teams reported on having inserted electrodes into the nucleus accumbens in order to use deep brain stimulation to treat severe depression . In 2010, experiments reported that deep brain stimulation of the nucleus accumbens was successful in decreasing depression symptoms in 50% of patients who did not respond to other treatments such as electroconvulsive therapy . Nucleus accumbens has also been used as
1495-474: A significant amount of basic residues (lysines and arginines), giving a positively charged surface that can bind to DNA. A separate region of the PWWP domain can bind to histone methyl-lysines through a hydrophobic pocket that includes the PWWP motif itself. The ADD domain of DNMT3A is composed of an N-terminal GATA-like zinc finger , a PHD finger and a C-terminal alpha helix , which, together, are arranged into
1610-400: A significant role in addiction . In addition, part of the nucleus accumbens core is centrally involved in the induction of slow-wave sleep . The nucleus accumbens plays a lesser role in processing fear (a form of aversion), impulsivity , and the placebo effect . It is involved in the encoding of new motor programs as well. The nucleus accumbens is an aggregate of neurons which
1725-452: A similar pathological addictive state through ΔFosB overexpression. Consequently, ΔFosB is the key transcription factor involved in addictions to natural rewards as well; in particular, ΔFosB in the nucleus accumbens is critical for the reinforcing effects of sexual reward. Research on the interaction between natural and drug rewards suggests that psychostimulants and sexual behavior act on similar biomolecular mechanisms to induce ΔFosB in
1840-459: A single globular fold. This domain can act as a reader that specifically binds to histone H3 that is unmethylated at lysine 4 (H3K4me0). The ADD domain serves as an inhibitor of the methyltransferase domain until DNMT3A binds to the unmodified lysine 4 of histone 3 (H3K4me0) for its de novo methylating activity. DNMT3A thus seems to have an inbuilt control mechanism targeting DNA for methylation only at histones that are unmethylated at histone 3 with
1955-451: 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
2070-449: 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
2185-399: A target to treat small groups of patients with therapy-refractory obsessive-compulsive disorder. To treat addiction and in an attempt to treat mental illness radiofrequency ablation of the nucleus accumbens has been performed. The results are inconclusive and controversial. Activation of the NAcc has been shown to occur in the anticipation of effectiveness of a drug when a user is given
2300-442: 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
2415-457: 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
SECTION 20
#17327874167872530-838: 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
2645-421: 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
2760-493: Is described as having an outer shell and an inner core. Major glutamatergic inputs to the nucleus accumbens include the prefrontal cortex (particularly the prelimbic cortex and infralimbic cortex ), basolateral amygdala , ventral hippocampus , thalamic nuclei (specifically the midline thalamic nuclei and intralaminar nuclei of the thalamus ), and glutamatergic projections from the ventral tegmental area (VTA). The nucleus accumbens receives dopaminergic inputs from
2875-437: 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
2990-435: Is essential for genetic imprinting. Research on long-term memory storage in humans indicates that memory is maintained by DNA methylation , Rats in which a new, strong long-term memory is induced due to contextual fear conditioning have reduced expression of about 1,000 genes and increased expression of about 500 genes in the hippocampus region of the brain. These changes occur 24 hours after training. At this point, there
3105-749: 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
3220-560: Is modified expression of 9.17% of the rat hippocampal genome. Reduced expression of genes is associated with de novo methylations of the genes. In mice, this gene has shown reduced expression in ageing animals causes cognitive long-term memory decline. In Dnmt3a-/- mice, many genes associated with HSC self-renewal increase in expression and some fail to be appropriately repressed during differentiation. This suggests abrogation of differentiation in hematopoietic stem cells (HSCs) and an increase in self-renewal cell-division instead. Indeed, it
3335-481: Is necessary for the reinforcing effects of VTA stimulation. A 2018 study reported that D2 MSN activation enhanced motivation via inhibiting the ventral pallidum, thereby disinhibiting the VTA. An fMRI study conducted in 2005 found that when mother rats were in the presence of their pups the regions of the brain involved in reinforcement, including the nucleus accumbens, were highly active. Levels of dopamine increase in
3450-476: 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
3565-418: 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
DNA (cytosine-5)-methyltransferase 3A - Misplaced Pages Continue
3680-462: 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
3795-487: Is released into the nucleus accumbens following exposure to rewarding stimuli , including recreational drugs like substituted amphetamines , cocaine , nicotine and morphine . Phenethylamine and tyramine : Phenethylamine and tyramine are trace amines which are synthesized in neurons that express the aromatic amino acid hydroxylase (AADC) enzyme , which includes all dopaminergic neurons. Both compounds function as dopaminergic neuromodulators which regulate
3910-522: Is repeatedly paired with environmental stimuli) and these associations become less prone to extinction (i.e., "unlearning" these classically conditioned associations between drug use and environmental stimuli becomes more difficult). After repeated pairing, these classically conditioned environmental stimuli (e.g., contexts and objects that are frequently paired with drug use) often become drug cues which function as secondary reinforcers of drug use (i.e., once these associations are established, exposure to
4025-433: Is responsible for the pleasurable or "liking" component of some intrinsic rewards is also located in a small compartment within the medial NAcc shell. Addictive drugs have a larger effect on dopamine release in the shell than in the core. The nucleus accumbens core ( NAcc core ) is the inner substructure of the nucleus accumbens. Location: The nucleus accumbens core is part of the ventral striatum , located within
4140-404: 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
4255-403: 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
4370-790: 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:
4485-509: Is widely expressed among mammals. There are two main protein isoforms, DNMT3A1 and DNMT3A2 with molecular weights of about 130 kDa and 100 kDa, respectively. The DNMT3A2 protein, which lacks the N-terminal region of DNMT3A1, is encoded by a transcript initiated from a downstream promoter. These isoforms exist in different cell types. When originally established, DNMT3A2 was found to be highly expressed in testis, ovary, spleen, and thymus. It
4600-614: 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
4715-404: The globus pallidus , known as the ventral pallidum (VP). The VP, in turn, projects to the medial dorsal nucleus of the dorsal thalamus , which projects to the prefrontal cortex as well as back to the ventral and to dorsal striatum . Other efferents from the nucleus accumbens include connections with the tail of the ventral tegmental area , substantia nigra , and the reticular formation of
DNA (cytosine-5)-methyltransferase 3A - Misplaced Pages Continue
4830-511: 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
4945-427: The mesocorticolimbic projection . The most important transcription factors that produce these alterations are ΔFosB , cyclic adenosine monophosphate ( cAMP ) response element binding protein ( CREB ), and nuclear factor kappa B ( NFκB ). ΔFosB is the most significant gene transcription factor in addiction since its viral or genetic overexpression in the nucleus accumbens is necessary and sufficient for many of
5060-805: The pons . The nucleus accumbens shell ( NAcc shell ) is a substructure of the nucleus accumbens. The shell and core together form the entire nucleus accumbens. Location: The shell is the outer region of the nucleus accumbens, and – unlike the core – is considered to be part of the extended amygdala , located at its rostral pole. Cell types: Neurons in the nucleus accumbens are mostly medium spiny neurons (MSNs) containing mainly D1-type (i.e., DRD1 and DRD5 ) or D2-type (i.e., DRD2 , DRD3 , and DRD4 ) dopamine receptors . A subpopulation of MSNs contain both D1-type and D2-type receptors, with approximately 40% of striatal MSNs expressing both DRD1 and DRD2 mRNA. These mixed-type NAcc MSNs with both D1-type and D2-type receptors are mostly confined to
5175-580: The preoptic area of the hypothalamus . The nucleus accumbens and the olfactory tubercle collectively form the ventral striatum . The ventral striatum and dorsal striatum collectively form the striatum , which is the main component of the basal ganglia . The dopaminergic neurons of the mesolimbic pathway project onto the GABAergic medium spiny neurons of the nucleus accumbens and olfactory tubercle. Each cerebral hemisphere has its own nucleus accumbens, which can be divided into two structures:
5290-525: The CA1 and ventral subiculum of the hippocampus to the dorsomedial area of the nucleus accumbens. Slight depolarizations of cells in the nucleus accumbens correlates with positivity of the neurons of the hippocampus, making them more excitable. The correlated cells of these excited states of the medium spiny neurons in the nucleus accumbens are shared equally between the subiculum and CA1. The subiculum neurons are found to hyperpolarize (increase negativity) while
5405-406: The CA1 neurons "ripple" (fire > 50 Hz) in order to accomplish this priming. The nucleus accumbens is one of the few regions that receives a high density of histaminergic projections from the tuberomammillary nucleus (the sole source of histamine neurons in the brain). The output neurons of the nucleus accumbens send axonal projections to the basal ganglia and the ventral analog of
5520-466: The NAcc are GABAergic medium spiny neurons (MSNs) which primarily express either D1-type or D2-type receptors; about 1–2% of the remaining neuronal types are large aspiny cholinergic interneurons and another 1–2% are GABAergic interneurons. Compared to the GABAergic MSNs in the shell, those in the core have an increased density of dendritic spines, branch segments, and terminal segments. From
5635-535: The NAcc shell have inhibitory control on turning behavior influenced by dopamine, and GABA B receptors have inhibitory control over turning behavior mediated by acetylcholine . Glutamate : Studies have shown that local blockade of glutamatergic NMDA receptors in the NAcc core impaired spatial learning. Another study demonstrated that both NMDA and AMPA (both glutamate receptors ) play important roles in regulating instrumental learning. Serotonin (5-HT): Overall, 5-HT synapses are more abundant and have
5750-399: The NAcc shell. The neurons in the shell, as compared to the core, have a lower density of dendritic spines , less terminal segments, and less branch segments than those in the core. The shell neurons project to the subcommissural part of the ventral pallidum as well as the ventral tegmental area and to extensive areas in the hypothalamus and extended amygdala. Function: The shell of
5865-400: 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 a type of enzyme rather than being like an enzyme, but even in
SECTION 50
#17327874167875980-544: The activation of D2-type MSNs in the nucleus accumbens promotes aversion . In late 2017, studies on rodents which utilized optogenetic and chemogenetic methods found that the indirect pathway (i.e., D2-type) medium spiny neurons in the nucleus accumbens core which co-express adenosine A 2A receptors and project to the ventral pallidum are involved in the regulation of slow-wave sleep . In particular, optogenetic activation of these indirect pathway NAcc core neurons induces slow-wave sleep and chemogenetic activation of
6095-437: 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
6210-502: 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
6325-407: 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
6440-578: 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
6555-523: The basal ganglia. Cell types: The core of the NAcc is made up mainly of medium spiny neurons containing mainly D1-type or D2-type dopamine receptors. The D1-type medium spiny neurons mediate reward-related cognitive processes, whereas the D2-type medium spiny neurons mediate aversion-related cognition. The neurons in the core, as compared to the neurons in the shell, have an increased density of dendritic spines, branch segments, and terminal segments. From
6670-502: 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
6785-471: 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
6900-425: 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
7015-471: The core encodes new motor programs which facilitate the acquisition of a given reward in the future. The indirect pathway (i.e., D2-type) neurons in the NAcc core which co-express adenosine A 2A receptors activation-dependently promote slow-wave sleep. The NAcc core has also been shown to mediate general Pavlovian-instrumental transfer , a phenomenon in which a classically conditioned stimulus modifies operant behavior. Approximately 95% of neurons in
SECTION 60
#17327874167877130-409: The core of the NAcc impair performance after devaluation and inhibit the effect of general PIT. On the other hand, lesions to the shell only impair the effect of specific PIT. This distinction is thought to reflect consummatory and appetitive conditioned responses in the NAcc shell and the NAcc core, respectively. In the dorsal striatum, a dichotomy has been observed between D1-MSNs and D2-MSNs, with
7245-407: The core, the neurons project to other sub-cortical areas such as the globus pallidus and the substantia nigra. GABA is one of the main neurotransmitters in the NAcc, and GABA receptors are also abundant. Function: The nucleus accumbens core is involved in the cognitive processing of motor function related to reward and reinforcement and the regulation of slow-wave sleep . Specifically,
7360-449: The core, the neurons project to other sub-cortical areas such as the globus pallidus and the substantia nigra. GABA is one of the main neurotransmitters in the NAcc, and GABA receptors are also abundant. These neurons are also the main projection or output neurons of the nucleus accumbens. Some of the neurotransmitters, neuromodulators, and hormones that signal through receptors within the nucleus accumbens include: Dopamine : Dopamine
7475-626: The de novo DNMT proteins. In addition, whether the DNA methyltransferase (DNMT3A1, DNMT3A2 or DNMT3B) acts on an available CpG site depends on the sequence flanking the CpG site within the linker DNA. DNMT1 is responsible for maintenance DNA methylation while DNMT3A and DNMT3B carry out both maintenance – correcting the errors of DNMT1 – and de novo DNA methylation. After DNMT1 knockout in human cancer cells, these cells were found to retain their inherited methylation pattern, which suggests maintenance activity by
7590-444: 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
7705-433: 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"
7820-592: 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
7935-483: 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,
8050-422: 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 is called enzymology and the field of pseudoenzyme analysis recognizes that during evolution, some enzymes have lost
8165-403: 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
8280-427: 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
8395-581: The expressed DNMT3s. DNMT3s show equal affinity for unmethylated and hemimethylated DNA substrates while DNMT1 has a 10-40 fold preference for hemimethylated DNA. The DNMT3s can bind to both forms and hence potentially do both maintenance and de novo modifications. De novo methylation is the main recognized activity of DNMT3A, which is essential for processes such as those mentioned in the introductory paragraphs. Genetic imprinting prevents parthenogenesis in mammals, and hence forces sexual reproduction and its multiple consequences on genetics and phylogenesis. DNMT3A
8510-468: The expression of appetitive or consummatory behaviors. The motivational effects of AMPA antagonists, and to a lesser extent GABA agonists, is anatomically flexible. Stressful conditions can expand the fear inducing regions, while a familiar environment can reduce the size of the fear inducing region. Furthermore, cortical input from the orbitofrontal cortex (OFC) biases the response towards that of appetitive behavior, and infralimbic input, equivalent to
8625-435: The former being reinforcing and enhancing locomotion , and the latter being aversive and reducing locomotion . Such a distinction has been traditionally assumed to apply to the nucleus accumbens as well, but evidence from pharmacological and optogenetics studies is conflicting. Furthermore, a subset of NAcc MSNs express both D1 and D2 MSNs, and pharmacological activation of D1 versus D2 receptors need not necessarily activate
8740-434: The gene most commonly found mutated in clonal hematopoiesis , a common aging-related phenomenon in which hematopoietic stem cells (HSCs) or other early blood cell progenitors contribute to the formation of a genetically distinct subpopulation of blood cells . DNMT3A is a 130 kDa protein encoded by 23 exons found on chromosome 2p23 in humans. There exists a 98% homology between human and murine homologues. DNMT3A
8855-494: The hormonal control over dopaminergic projections with regard to glucocorticoid receptors could lead to new treatments for psychotic symptoms. A recent study demonstrated that suppression of the glucocorticoid receptors led to a decrease in the release of dopamine, which may lead to future research involving anti-glucocorticoid drugs to potentially relieve psychotic symptoms. GABA: A recent study on rats that used GABA agonists and antagonists indicated that GABA A receptors in
8970-448: The human subgenual cingulate cortex, suppresses the response regardless of valence. The nucleus accumbens is neither necessary nor sufficient for instrumental learning, although manipulations can affect performance on instrumental learning tasks. One task where the effect of NAcc lesions is evident is Pavlovian-instrumental transfer (PIT), where a cue paired with a specific or general reward can enhance instrumental responding. Lesions to
9085-422: 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. Nucleus accumbens The nucleus accumbens ( NAc or NAcc ; also known as the accumbens nucleus , or formerly as the nucleus accumbens septi , Latin for ' nucleus adjacent to the septum ') is a region in the basal forebrain rostral to
9200-611: The lysine at the 4th position from the amino end being un-methylated. The catalytic domain (the methyltransferase domain) is highly conserved, even among prokaryotes . The three DNA methyltransferases (DNMT3A1, DNMT3A2 and DNMT3B) catalyze reactions placing a methyl group onto a cytosine, usually at a CpG site in DNA. The accompanying Figure shows a methyltransferase complex containing DNMT3A2. These enzymes, to be effective, must act in conjunction with an accessory protein (e.g. DNMT3B3, DNMT3L, or others). Two accessory proteins (which have no catalytic activity), complexed to two DNMTs with
9315-425: The medial shell. A rostro-caudal gradient exists for the enhancement of appetitive versus fearful responses, the latter of which is traditionally thought to require only D1 receptor function, and the former of which requires both D1 and D2 function. One interpretation of this finding, the disinhibition hypothesis, posits that inhibition of accumbens MSNs (which are GABAergic) disinhibits downstream structures, enabling
9430-474: 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
9545-459: The neural adaptations and behavioral effects (e.g., expression-dependent increases in self-administration and reward sensitization ) seen in drug addiction. ΔFosB overexpression has been implicated in addictions to alcohol (ethanol) , cannabinoids , cocaine , methylphenidate , nicotine , opioids , phencyclidine , propofol , and substituted amphetamines , among others. Increases in nucleus accumbens ΔJunD expression can reduce or, with
9660-467: The neural populations exactly. While most studies show no effect of selective optogenetic stimulation of D1 or D2 MSNs on locomotor activity, one study has reported a decrease in basal locomotion with D2-MSN stimulation. While two studies have reported reduced reinforcing effects of cocaine with D2-MSN activation, one study has reported no effect. NAcc D2-MSN activation has also been reported to enhance motivation, as assessed by PIT, and D2 receptor activity
9775-588: The nucleosome core. As shown by Manzo et al., there are both specific individual binding sites for the three catalytic DNMTs (3A1, 3A2 and 3B3) as well as overlapping binding sites of these enzymes. There are 28 million CpG sites in the human genome. Many of these CpGs are located within CpG islands (regions of DNA) of relatively high density of CpG sites. Of these regions, there are 3,970 regions exclusively enriched for DNMT3A1, 3,838 regions for DNMT3A2 and 3,432 regions for DNMT3B, and there are sites that are shared between
9890-400: The nucleosome orients the heterotetramer. The orientation places the first catalytic DNMT (closest to the accessory protein connected to the nucleosome) in an intermediate position (not close to the linker DNA). The second catalytic DNMT (lower 3A2 in Figure) is placed at the linker DNA. Methylations can take place within this linker DNA (as shown in the Figure) but not on any DNA wrapped around
10005-413: The nucleus accumbens and possess cross-sensitization effects that are mediated through ΔFosB. Similar to drug rewards, non-drug rewards also increase the level of extracellular dopamine in the NAcc shell. Drug-induced dopamine release in the NAcc shell and NAcc core is usually not prone to habituation (i.e., the development of drug tolerance : a decrease in dopamine release from future drug exposure as
10120-597: The nucleus accumbens core and the nucleus accumbens shell. These substructures have different morphology and functions. Different NAcc subregions (core vs shell) and neuron subpopulations within each region ( D1-type vs D2-type medium spiny neurons) are responsible for different cognitive functions . As a whole, the nucleus accumbens has a significant role in the cognitive processing of motivation , aversion , reward (i.e., incentive salience , pleasure , and positive reinforcement ), and reinforcement learning (e.g., Pavlovian-instrumental transfer ); hence, it has
10235-407: The nucleus accumbens during maternal behavior, while lesions in this area upset maternal behavior. When women are presented pictures of unrelated infants, fMRIs show increased brain activity in the nucleus accumbens and adjacent caudate nucleus, proportionate to the degree to which the women find these infants "cute". Activation of D1-type MSNs in the nucleus accumbens is involved in reward, whereas
10350-443: The nucleus accumbens has been described by Gordon Mogensen as the interface between the limbic and motor system. The nucleus accumbens is causally related to the experience of pleasure. Microinjections of μ-opioid agonists, δ-opioid agonists or κ-opioid agonists in the rostrodorsal quadrant of the medial shell enhance "liking", while more caudal injections can inhibit disgust reactions, liking reactions, or both. The regions of
10465-434: The nucleus accumbens is involved in the cognitive processing of reward , including subjective "liking" reactions to certain pleasurable stimuli , motivational salience , and positive reinforcement . That NAcc shell has also been shown to mediate specific Pavlovian-instrumental transfer , a phenomenon in which a classically conditioned stimulus modifies operant behavior . A "hedonic hotspot" or pleasure center which
10580-444: The nucleus accumbens is selectively increased during the perception of pleasant, emotionally arousing pictures and during mental imagery of pleasant, emotional scenes. However, as BOLD is thought to be an indirect measure of regional net excitation to inhibition, the extent to which BOLD measures valence dependent processing is unknown. Because of the abundance of NAcc inputs from limbic regions and strong NAcc outputs to motor regions,
10695-404: The nucleus accumbens that can be ascribed a causal role in the production of pleasure are limited both anatomically and chemically, as besides opioid agonists only endocannabinoids can enhance liking. In the nucleus accumbens as a whole, dopamine, GABA receptor agonist or AMPA antagonists solely modify motivation, while the same is true for opioid and endocannabinoids outside of the hotspot in
10810-423: The nucleus accumbens to the reward sucrose is inhibition; the opposite is true in response to the administration of aversive quinine . Substantial evidence from pharmacological manipulation also suggests that reducing the excitability of neurons in the nucleus accumbens is rewarding, as, for example, would be true in the case of μ-opioid receptor stimulation. The blood oxygen level dependent signal (BOLD) in
10925-528: 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
11040-401: The protagonists DNMT1 , DNMT3A and DNMT3B . While de novo DNA methylation modifies the information passed on by the parent to the progeny, it enables key epigenetic modifications essential for processes such as cellular differentiation and embryonic development , transcriptional regulation , heterochromatin formation, X-inactivation , imprinting and genome stability. DNMT3a is
11155-794: The protein and this mutation may cause loss of function. DNMT3A mutations are associated with poor overall survival, suggesting that they have an important common effect on the potential of AML cells to cause lethal disease. It has also been found that DNMT3A -mutated cell lines exhibit transcriptome instability , in that they have much more erroneous RNA splicing as compared to their isogenic wildtype counterparts. Mutations in this gene are also associated with Tatton-Brown–Rahman syndrome , an overgrowth disorder. DNMT3A has been shown to interact with: 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
11270-406: 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
11385-733: 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
11500-500: The reuptake and release of dopamine into the Nacc via interactions with VMAT2 and TAAR1 in the axon terminal of mesolimbic dopamine neurons. Glucocorticoids and dopamine: Glucocorticoid receptors are the only corticosteroid receptors in the nucleus accumbens shell. L-DOPA , steroids , and specifically glucocorticoids are currently known to be the only known endogenous compounds that can induce psychotic problems, so understanding
11615-410: 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
11730-401: The same neurons increases the number and duration of slow-wave sleep episodes. Chemogenetic inhibition of these NAcc core neurons suppresses sleep. In contrast, the D2-type medium spiny neurons in the NAcc shell which express adenosine A 2A receptors have no role in regulating slow-wave sleep. Current models of addiction from chronic drug use involve alterations in gene expression in
11845-456: The structure of DNMT3B1 and also with the two accessory proteins DNMT3B3 and DNMT3L (see Figure of simplified domains of DNMT3A isoforms). The two accessory proteins stimulate de novo methylation by each of their interactions with the three isoforms that have a functional catalytic domain. In general, all DNMTs require accessory proteins for their biological function. The PWWP motif is within an about 100 amino acid domain that has one area with
11960-412: 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
12075-519: 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
12190-405: 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
12305-399: 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
12420-503: The transfer of methyl groups to specific CpG structures in DNA, a process called DNA methylation . The enzyme is encoded in humans by the DNMT3A gene . This enzyme is responsible for de novo DNA methylation. Such function is to be distinguished from maintenance DNA methylation which ensures the fidelity of replication of inherited epigenetic patterns. DNMT3A forms part of the family of DNA methyltransferase enzymes, which consists of
12535-438: 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
12650-526: The ventral tegmental area, which connect via the mesolimbic pathway . The nucleus accumbens is often described as one part of a cortico-basal ganglia-thalamo-cortical loop . Dopaminergic inputs from the VTA modulate the activity of GABAergic neurons within the nucleus accumbens. These neurons are activated directly or indirectly by euphoriant drugs (e.g., amphetamine , opiates , etc.) and by participating in rewarding experiences (e.g., sex, music, exercise, etc.). Another major source of input comes from
12765-486: 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
12880-581: 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
12995-588: Was found that differentiation was partially rescued if Dnmt3a-/- HSCs experienced an additional Ctnb1 knockdown – Ctnb1 codes for β-catenin, which participates in self-renewal cell division. This gene is frequently mutated in cancer, being one of 127 frequently mutated genes identified in the Cancer Genome Atlas project DNMT3A mutations were most commonly seen in acute myeloid leukaemia (AML) where they occurred in just over 25% of cases sequenced. These mutations most often occur at position R882 in
13110-571: Was more recently shown to be inducibly expressed in brain hippocampus and needed in the hippocampus when establishing memory. DNMT3A2 is also upregulated in the nucleus accumbens shell in response to cocaine . DNMT3A consists of three major protein domains: the Pro-Trp-Trp-Pro (PWWP) domain, the ATRX-DNMT3-DNMT3L (ADD) domain and the catalytic methyltransferase domain. The structures of DNMT3A1 and DNMT3A2 have analogies with
13225-457: 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
#786213