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99-489: 1R74 , 2AZT 27232 14711 ENSG00000124713 ENSMUSG00000002769 Q14749 Q9QXF8 NM_018960 NM_001318865 NM_010321 NM_001364890 NP_001305794 NP_061833 NP_034451 NP_001351819 Glycine N -methyltransferase is an enzyme that in humans is encoded by the GNMT gene . The enzyme was first described by Blumenstein and Williams (1960) in guinea pig liver. However, this enzyme

198-487: 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

297-489: 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

396-753: A "C" shape, has a slight helical distortion due to repulsion between the closest pair of hydrogen atoms in the two extremal rings. This effect also causes distortion of picene. Adding another benzene ring to form dibenzo[c,g]phenanthrene creates steric hindrance between the two extreme hydrogen atoms. Adding two more rings on the same sense yields heptahelicene in which the two extreme rings overlap. These non-planar forms are chiral, and their enantiomers can be isolated. The benzenoid hydrocarbons have been defined as condensed polycyclic unsaturated fully-conjugated hydrocarbons whose molecules are essentially planar with all rings six-membered. Full conjugation means that all carbon atoms and carbon-carbon bonds must have

495-451: A PAH that was subsequently demonstrated to cause tumors . Cook, Hewett and Hieger then linked the specific spectroscopic fluorescent profile of benzo[ a ]pyrene to that of the carcinogenic component of coal tar, the first time that a specific compound from an environmental mixture (coal tar) was demonstrated to be carcinogenic. In the 1930s and later, epidemiologists from Japan, the UK, and

594-567: A PAH. Some sources, such as the US EPA and CDC , consider naphthalene to be the simplest PAH. Other authors consider PAHs to start with the tricyclic species phenanthrene and anthracene . Most authors exclude compounds that include heteroatoms in the rings, or carry substituents . A polyaromatic hydrocarbon may have rings of various sizes, including some that are not aromatic. Those that have only six-membered rings are said to be alternant . The following are examples of PAHs that vary in

693-482: A cyclic sequence, with two edge carbons shared between successive rings. All of them must be non-planar and have considerable higher bonding energy (computed to be at least 130 kcal/mol) than coronene; and, as of 2002, none of them had been synthesized. Other PAHs that might seem to be planar, considering only the carbon skeleton, may be distorted by repulsion or steric hindrance between the hydrogen atoms in their periphery. Benzo[c]phenanthrene, with four rings fused in

792-477: 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

891-828: A part of a detoxification process. Therefore, GNMT has been proposed to be a protein with diverse functionality. GNMT has been shown to detoxify some environmental carcinogens such as polyaromatic hydrocarbons and aflatoxin . There is mounting evidence that supports the involvement of GNMT deficiency in liver carcinogenesis. The glycoside natural product 1,2,3,4,6-penta-O-galloyl-β-d-glucopyranoside (PGG) isolated from Paeonia lactiflora , an Asian flower plant, induces GNMT mRNA and protein expression in Huh7 human hepatoma cells. 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

990-636: A primary human health risk of exposure to PAHs. Exposure to PAHs has also been linked with cardiovascular disease and poor fetal development. PAHs have been linked to skin , lung , bladder , liver , and stomach cancers in well-established animal model studies. Specific compounds classified by various agencies as possible or probable human carcinogens are identified in the section " Regulation and Oversight " below. Historically, PAHs contributed substantially to our understanding of adverse health effects from exposures to environmental contaminants , including chemical carcinogenesis . In 1775, Percivall Pott ,

1089-464: 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

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1188-439: 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

1287-461: A role in secretion. The properties of GNMT protein from rabbits, rats and humans, either purified from liver/pancreas, or expressed in Escherichia coli , have been well characterized. All GNMTs have very similar molecular and kinetic properties. Comparison of the cDNA and protein sequences of human, rabbit, pig and rat GNMTs shows similarities of over 84% at the nucleotide level and about 90% at

1386-451: 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

1485-449: 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

1584-1317: A substantial outdoor source of PAHs in particulate air pollution. Geographically, major roadways are thus sources of PAHs, which may distribute in the atmosphere or deposit nearby. Catalytic converters are estimated to reduce PAH emissions from gasoline-fired vehicles by 25-fold. People can also be occupationally exposed during work that involves fossil fuels or their derivatives, wood-burning, carbon electrodes , or exposure to diesel exhaust . Industrial activity that can produce and distribute PAHs includes aluminum , iron , and steel manufacturing; coal gasification , tar distillation, shale oil extraction ; production of coke , creosote , carbon black , and calcium carbide ; road paving and asphalt manufacturing; rubber tire production; manufacturing or use of metal working fluids; and activity of coal or natural gas power stations . PAHs typically disperse from urban and suburban non-point sources through road runoff , sewage , and atmospheric circulation and subsequent deposition of particulate air pollution. Soil and river sediment near industrial sites such as creosote manufacturing facilities can be highly contaminated with PAHs. Oil spills , creosote, coal mining dust, and other fossil fuel sources can also distribute PAHs in

1683-504: A surgeon at St. Bartholomew's Hospital in London, observed that scrotal cancer was unusually common in chimney sweepers and proposed the cause as occupational exposure to soot . A century later, Richard von Volkmann reported increased skin cancers in workers of the coal tar industry of Germany, and by the early 1900s increased rates of cancer from exposure to soot and coal tar was widely accepted. In 1915, Yamigawa and Ichicawa were

1782-442: 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

1881-427: A variety of factors including proximity to municipal and industrial discharge points, wind direction and distance from major urban roadways, as well as tidal regime which controls the diluting effect of generally cleaner marine sediments relative to freshwater discharge. Consequently, the concentrations of pollutants in estuaries tends to decrease at the river mouth. Understanding of sediment hosted PAHs in estuaries

1980-457: 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

2079-838: 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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2178-450: Is a potent inhibitor of tRNA methyltransferases and a relatively weak inhibitor of GNMT. GNMT regulates the relative levels of SAM and SAH. Since SAM is the methyl donor for almost all cellular methylation reactions. GNMT is therefore likely to regulate cellular methylation capacity. An endogenous ligand of GNMT, 5-methyltetrahydropteroylpentaglutamate (5-CH3-H4PteGIu5) is a powerful inhibitor of this enzyme. Thus, GNMT has been proposed to link

2277-421: 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

2376-437: 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

2475-749: 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

2574-602: Is greater (each has a sextet in two of the three Clar structures) compared to the inner rings (each has a sextet in only one of the three). PAHs are nonpolar and lipophilic . Larger PAHs are generally insoluble in water, although some smaller PAHs are soluble. The larger members are also poorly soluble in organic solvents and in lipids . The larger members, e.g. perylene, are strongly colored. Polycyclic aromatic compounds characteristically yield radicals and anions upon treatment with alkali metals. The large PAH form dianions as well. The redox potential correlates with

2673-555: Is important for the protection of commercial fisheries (such as mussels ) and general environmental habitat conservation because PAHs can impact the health of suspension and sediment feeding organism. River-estuary surface sediments in the UK tend to have a lower PAH content than sediments buried 10–60 cm from the surface reflecting lower present day industrial activity combined with improvement in environmental legislation of PAH. Typical PAH concentrations in UK estuaries range from about 19 to 16,163 µg/kg (dry sediment weight) in

2772-720: Is low. Lower-temperature combustion, such as tobacco smoking or wood-burning , tends to generate low molecular weight PAHs, whereas high-temperature industrial processes typically generate PAHs with higher molecular weights. Incense is also a source. PAHs are typically found as complex mixtures. PAHs may result from the incomplete combustion of organic matter in natural wildfires . Substantially higher outdoor air, soil, and water concentrations of PAHs have been measured in Asia, Africa, and Latin America than in Europe, Australia,

2871-442: Is most abundant in the peri-portal region of the liver and exocrine tissue of the pancreas. The GNMT proteins located in tissues that are actively in secretion, such as the proximal kidney tubules, the submaxillary glands and the intestinal mucosa. GNMT is also expressed in various neurons presented in the cerebral cortex, hippocampus, substantia nigra and cerebellum. The presence of GNMT in these cells suggests that this enzyme may play

2970-476: 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

3069-418: 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

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3168-462: 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

3267-472: Is reversed as the lower molecular weight PAHs are attenuated by biotic decay and photodegradation . Evaluation of the PAH distributions using statistical methods such as principal component analyses (PCA) enabled the study to link the source (burnt moorland) to pathway (suspended stream sediment) to the depositional sink (reservoir bed). Concentrations of PAHs in river and estuarine sediments vary according to

3366-404: 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

3465-403: 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

3564-790: 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:

3663-507: The Cretaceous-Tertiary (K-T) boundary , more than 100 times the level in adjacent layers. The spike was attributed to massive fires that consumed about 20% of the terrestrial above-ground biomass in a very short time. PAHs are prevalent in the interstellar medium (ISM) of galaxies in both the nearby and distant Universe and make up a dominant emission mechanism in the mid-infrared wavelength range, containing as much as 10% of

3762-614: 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

3861-520: The River Clyde and 626 to 3,766 µg/kg in the River Mersey . In general estuarine sediments with a higher natural total organic carbon content (TOC) tend to accumulate PAHs due to high sorption capacity of organic matter. A similar correspondence between PAHs and TOC has also been observed in the sediments of tropical mangroves located on the coast of southern China. Cancer is

3960-511: 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

4059-472: The ocean can be a substantial sink for PAHs. Algae and some invertebrates such as protozoans , mollusks , and many polychaetes have limited ability to metabolize PAHs and bioaccumulate disproportionate concentrations of PAHs in their tissues; however, PAH metabolism can vary substantially across invertebrate species. Most vertebrates metabolize and excrete PAHs relatively rapidly. Tissue concentrations of PAHs do not increase ( biomagnify ) from

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4158-658: The DNA sequence is altered in genes that regulate cell replication , cancer can result. Mutagenic PAHs, such as benzo[ a ]pyrene, usually have four or more aromatic rings as well as a "bay region", a structural pocket that increases reactivity of the molecule to the metabolizing enzymes. Mutagenic metabolites of PAHs include diol epoxides, quinones , and radical PAH cations . These metabolites can bind to DNA at specific sites, forming bulky complexes called DNA adducts that can be stable or unstable. Stable adducts may lead to DNA replication errors, while unstable adducts react with

4257-459: The DNA strand, removing a purine base (either adenine or guanine ). Such mutations, if they are not repaired, can transform genes encoding for normal cell signaling proteins into cancer-causing oncogenes . Quinones can also repeatedly generate reactive oxygen species that may independently damage DNA. Enzymes in the cytochrome family ( CYP1A1 , CYP1A2 , CYP1B1 ) metabolize PAHs to diol epoxides. PAH exposure can increase production of

4356-510: The U.S., and Canada. Polycyclic aromatic hydrocarbons are primarily found in natural sources such as bitumen . PAHs can also be produced geologically when organic sediments are chemically transformed into fossil fuels such as oil and coal . The rare minerals idrialite , curtisite , and carpathite consist almost entirely of PAHs that originated from such sediments, that were extracted, processed, separated, and deposited by very hot fluids. High levels of such PAHs have been detected in

4455-709: The US, including Richard Doll and various others, reported greater rates of death from lung cancer following occupational exposure to PAH-rich environments among workers in coke ovens and coal carbonization and gasification processes. The structure of a PAH influences whether and how the individual compound is carcinogenic. Some carcinogenic PAHs are genotoxic and induce mutations that initiate cancer; others are not genotoxic and instead affect cancer promotion or progression. PAHs that affect cancer initiation are typically first chemically modified by enzymes into metabolites that react with DNA, leading to mutations. When

4554-573: The United States. A year-long sampling campaign in Athens, Greece found a third (31%) of PAH urban air pollution to be caused by wood-burning, like diesel and oil (33%) and gasoline (29%). It also found that wood-burning is responsible for nearly half (43%) of annual PAH cancer-risk ( carcinogenic potential) compared to the other sources and that wintertime PAH levels were 7 times higher than in other seasons, especially if atmospheric dispersion

4653-400: 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

4752-437: 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

4851-502: 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

4950-419: The amino acid level. All GNMTs are 130 kDa tetramers consisting of four identical subunits, each having a Mr of 32 kDa. The structure of recombinant rat, mouse and human GNMTs have been solved. The four nearly spherical subunits are arranged to form a flat and square tetramer with a large hole in the center. The active sites are located in the near center of each subunit. Glycine N -methyltransferase catalyzes

5049-407: 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

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5148-633: The atmosphere and the top layers of surface waters can produce nitrogenated, halogenated, hydroxylated, and oxygenated PAHs; some of these compounds can be more toxic, water-soluble, and mobile than their parent PAHs. The British Geological Survey reported the amount and distribution of PAH compounds including parent and alkylated forms in urban soils at 76 locations in Greater London . The study showed that parent (16 PAH) content ranged from 4 to 67 mg/kg (dry soil weight) and an average PAH concentration of 18 mg/kg (dry soil weight) whereas

5247-455: The atmosphere predominantly in gaseous form, although the physical state of four-ring PAHs can depend on temperature. In contrast, compounds with five or more rings have low solubility in water and low volatility; they are therefore predominantly in solid state , bound to particulate air pollution , soils , or sediments . In solid state, these compounds are less accessible for biological uptake or degradation, increasing their persistence in

5346-578: 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

5445-502: 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

5544-441: The central ring is less aromatic and therefore more reactive. In contrast, in anthracene the resonance structures have one sextet each, which can be at any of the three rings, and the aromaticity spreads out more evenly across the whole molecule. This difference in number of sextets is reflected in the differing ultraviolet–visible spectra of these two isomers, as higher Clar pi-sextets are associated with larger HOMO-LUMO gaps;

5643-471: 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

5742-425: 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

5841-486: The de novo synthesis of methyl groups to the ratio of SAM to SAH, which in turn serves as a bridge between methionine and one-carbon metabolism. In addition to the methyltransferase activity, the 4S polycyclic aromatic hydrocarbon (PAH)-binding protein and GNMT are one and the same protein. The catalytic site resembles a molecular basket, unlike most other SAM-dependent methyltransferases, which therefore suggests that GNMT may be capable of capturing unidentified chemicals as

5940-444: 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

6039-508: The distant universe. In June 2013, PAHs were detected in the upper atmosphere of Titan , the largest moon of the planet Saturn . Volcanic eruptions may emit PAHs. Certain PAHs such as perylene can also be generated in anaerobic sediments from existing organic material, although it remains undetermined whether abiotic or microbial processes drive their production. Most PAHs are insoluble in water, which limits their mobility in

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6138-433: 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"

6237-408: The environment, although PAHs sorb to fine-grained organic-rich sediments . Aqueous solubility of PAHs decreases approximately logarithmically as molecular mass increases. Two-ringed PAHs, and to a lesser extent three-ringed PAHs, dissolve in water, making them more available for biological uptake and degradation . Further, two- to four-ringed PAHs volatilize sufficiently to appear in

6336-656: The environment. Human exposure varies across the globe and depends on factors such as smoking rates, fuel types in cooking, and pollution controls on power plants, industrial processes, and vehicles. Developed countries with stricter air and water pollution controls, cleaner sources of cooking (i.e., gas and electricity vs. coal or biofuels), and prohibitions of public smoking tend to have lower levels of PAH exposure, while developing and undeveloped countries tend to have higher levels. Surgical smoke plumes have been proven to contain PAHs in several independent research studies. Burning solid fuels such as coal and biofuels in

6435-436: The environment. Two- and three-ringed PAHs can disperse widely while dissolved in water or as gases in the atmosphere, while PAHs with higher molecular weights can disperse locally or regionally adhered to particulate matter that is suspended in air or water until the particles land or settle out of the water column . PAHs have a strong affinity for organic carbon , and thus highly organic sediments in rivers , lakes , and

6534-592: 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

6633-483: 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,

6732-422: 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

6831-403: 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

6930-427: 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

7029-410: The first to experimentally produce cancers, specifically of the skin, by topically applying coal tar to rabbit ears. In 1922, Ernest Kennaway determined that the carcinogenic component of coal tar mixtures was an organic compound consisting of only carbon and hydrogen. This component was later linked to a characteristic fluorescent pattern that was similar but not identical to benz[ a ]anthracene ,

7128-407: The highest-wavelength absorbance of phenanthrene is at 293 nm, while anthracene is at 374 nm. Three Clar structures with two sextets each are present in the four-ring chrysene structure: one having sextets in the first and third rings, one in the second and fourth rings, and one in the first and fourth rings. Superposition of these structures reveals that the aromaticity in the outer rings

7227-482: The home for cooking and heating is a dominant global source of PAH emissions that in developing countries leads to high levels of exposure to indoor particulate air pollution containing PAHs, particularly for women and children who spend more time in the home or cooking. In industrial countries, people who smoke tobacco products, or who are exposed to second-hand smoke , are among the most highly exposed groups; tobacco smoke contributes to 90% of indoor PAH levels in

7326-516: The homes of smokers. For the general population in developed countries, the diet is otherwise the dominant source of PAH exposure, particularly from smoking or grilling meat or consuming PAHs deposited on plant foods, especially broad-leafed vegetables, during growth. Exposure also occurs through drinking alcohol aged in charred barrels, flavored with peat smoke, or made with roasted grains. PAHs are typically at low concentrations in drinking water. Emissions from vehicles such as cars and trucks can be

7425-620: 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. Polyaromatic hydrocarbon Polycyclic aromatic hydrocarbons are discussed as possible starting materials for abiotic syntheses of materials required by the earliest forms of life . The terms polyaromatic hydrocarbon , or polynuclear aromatic hydrocarbon (abbreviated as PNA) are also used for this concept. By definition, polycyclic aromatic hydrocarbons have multiple aromatic rings, precluding benzene from being considered

7524-404: The lowest to highest levels of food chains. PAHs transform slowly to a wide range of degradation products. Biological degradation by microbes is a dominant form of PAH transformation in the environment. Soil-consuming invertebrates such as earthworms speed PAH degradation, either through direct metabolism or by improving the conditions for microbial transformations. Abiotic degradation in

7623-474: 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

7722-402: The most important for the characterization of the properties of that PAH. For example, phenanthrene has two Clar structures: one with just one aromatic sextet (the middle ring), and the other with two (the first and third rings). The latter case is therefore the more characteristic electronic nature of the two. Therefore, in this molecule the outer rings have greater aromatic character whereas

7821-457: The non-planarity may be forced by the topology of the molecule and the stiffness (in length and angle) of the carbon-carbon bonds. For example, unlike coronene , corannulene adopts a bowl shape in order to reduce the bond stress. The two possible configurations, concave and convex, are separated by a relatively low energy barrier (about 11 kcal / mol ). In theory, there are 51 structural isomers of coronene that have six fused benzene rings in

7920-425: The number and arrangement of their rings: Most PAHs, like naphthalene, anthracene, and coronene, are planar. This geometry is a consequence of the fact that the σ-bonds that result from the merger of sp hybrid orbitals of adjacent carbons lie on the same plane as the carbon atom. Those compounds are achiral , since the plane of the molecule is a symmetry plane. In rare cases, PAHs are not planar. In some cases,

8019-551: The overall distribution also suggested that the PAHs in London soils had undergone weathering and been modified by a variety of pre-and post-depositional processes such as volatilization and microbial biodegradation . Managed burning of moorland vegetation in the UK has been shown to generate PAHs which become incorporated into the peat surface. Burning of moorland vegetation such as heather initially generates high amounts of two- and three-ringed PAHs relative to four- to six-ringed PAHs in surface sediments, however, this pattern

8118-528: 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

8217-406: 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

8316-733: 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

8415-410: 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

8514-530: The size of the PAH. The dominant sources of PAHs in the environment are from human activity: wood-burning and combustion of other biofuels such as dung or crop residues contribute more than half of annual global PAH emissions, particularly due to biofuel use in India and China. As of 2004, industrial processes and the extraction and use of fossil fuels made up slightly more than one quarter of global PAH emissions, dominating outputs in industrial countries such as

8613-462: The sp structure of benzene. This class is largely a subset of the alternant PAHs, but is considered to include unstable or hypothetical compounds like triangulene or heptacene . As of 2012, over 300 benzenoid hydrocarbons had been isolated and characterized. The aromaticity varies for PAHs. According to Clar's rule , the resonance structure of a PAH that has the largest number of disjoint aromatic pi sextets —i.e. benzene -like moieties—is

8712-412: 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

8811-519: 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

8910-405: 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

9009-412: The synthesis of N -methylglycine ( sarcosine ) from glycine using S -adenosylmethionine (SAM) (AdoMet) as the methyl donor. GNMT acts as an enzyme to regulate the ratio of S -adenosylmethionine (SAM) to S -adenosylhomocysteine (SAH) (AdoHcy) and participates in the detoxification pathway in liver cells. GNMT competes with tRNA methyltransferases for SAM and the product, S -adenosylhomocysteine (SAH),

9108-399: 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

9207-569: The total PAH content (33 PAH) ranged from 6 to 88 mg/kg and fluoranthene and pyrene were generally the most abundant PAHs. Benzo[ a ]pyrene (B a P), the most toxic of the parent PAHs, is widely considered a key marker PAH for environmental assessments; the normal background concentration of B a P in the London urban sites was 6.9 mg/kg (dry soil weight). London soils contained more stable four- to six-ringed PAHs which were indicative of combustion and pyrolytic sources, such as coal and oil burning and traffic-sourced particulates. However,

9306-466: The total integrated infrared luminosity of galaxies. PAHs generally trace regions of cold molecular gas, which are optimum environments for the formation of stars. NASA's Spitzer Space Telescope and James Webb Space Telescope include instruments for obtaining both images and spectra of light emitted by PAHs associated with star formation . These images can trace the surface of star-forming clouds in our own galaxy or identify star forming galaxies in

9405-438: 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

9504-486: 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

9603-581: 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

9702-455: Was not purified until 1972 in the rabbit liver by Kerr. In 1984, Cook and Wagner demonstrated that a liver cytosolic folate binding protein is identical to GNMT. The human GMNT gene was cloned in 2000 by Chen and coworkers. GNMT is an abundant enzyme in liver cytosol and consists of 0.9% to 3% of the soluble protein present in liver. In addition to liver, GNMT activity has been found in a number of other tissues including pancreas and kidney. GNMT

9801-457: 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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