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46-453: 1571 13106 ENSG00000130649 ENSMUSG00000025479 P05181 Q05421 NM_000773 NM_021282 NP_000764 NP_067257 Cytochrome P450 2E1 (abbreviated CYP2E1 , EC 1.14.13.n7 ) is a member of the cytochrome P450 mixed-function oxidase system, which is involved in the metabolism of xenobiotics in the body. This class of enzymes is divided up into a number of subcategories, including CYP1, CYP2, and CYP3, which as

92-564: A 16-fold increase in total catalytic capacity in rats who were both fasted and given large quantities of ethanol for 3 consecutive days. Starvation appears to upregulate CYP2E1 mRNA production in liver cells while alcohol seems to stabilize the enzyme itself post-translation and thus protect it from degradation by normal cellular proteolytic processes, giving the two an independent synergistic effect. Trees have been genetically engineered to overexpress rabbit CYP2E1 enzyme. These transgenic trees have been used to remove pollutants from groundwater,

138-515: A broad range of cell membrane and cell signaling properties, particularly in grey matter and retinal photoreceptor cell outer segments, which are rich in membranes. A systematic review found that DHA had no significant benefits in improving visual field in individuals with retinitis pigmentosa . Animal research shows effect of oral intake of deuterium-reinforced DHA (D-DHA) for prevention of macular degeneration . Omega−3 PUFAs such as DHA and eicosapentaenoic acid (EPA) are effective in

184-517: A broad range of activities. In various animal models and in vitro studies on animal and human tissues, they decrease hypertension and pain perception; suppress inflammation; inhibit angiogenesis , endothelial cell migration and endothelial cell proliferation; and inhibit the growth and metastasis of human breast and prostate cancer cell lines. It is suggested that the EDP and EEQ metabolites function in humans as they do in animal models and that, as products of

230-478: A component of neuronal membranes , the function of DHA is to support neuronal conduction and to allow the optimal functioning of neuronal membrane proteins (such as receptors and enzymes). Structurally, DHA is a carboxylic acid (- oic acid ) with a 22- carbon chain ( docosa- derives from the Ancient Greek for 22) and six ( hexa- ) cis double bonds ( -en- ); with the first double bond located at

276-420: A good direct source. Beef brain, for example, contains approximately 855 mg of DHA per 100 grams in a serving. While DHA may be the primary fatty acid found in certain specialized tissues, these tissues, aside from the brain, are typically small in size, such as the seminiferous tubules and the retina. As a result, animal-based foods, excluding the brain, generally offer minimal amounts of preformed DHA. In

322-461: A group are largely responsible for the breakdown of foreign compounds in mammals. While CYP2E1 itself carries out a relatively low number of these reactions (~4% of known P450-mediated drug oxidations), it and related enzymes CYP1A2 and CYP3A4 are responsible for the breakdown of many toxic environmental chemicals and carcinogens that enter the body, in addition to basic metabolic reactions such as fatty acid oxidations. CYP2E1 protein localizes to

368-443: A major contributor to forming the cited epoxides but could act locally in certain tissues to do so. Following is a table of selected substrates of CYP2E1. Where classes of agents are listed, there may be exceptions within the class. CYP2E1 exhibits structural motifs common to other human membrane-bound cytochrome P450 enzymes, and is composed of 12 major α-helices and 4 β-sheets with short intervening helices interspersed between

414-515: A monooxygenase to metabolize arachidonic acid to 19-hydroxyeicosatetraenoic acid (19-HETE) (see 20-Hydroxyeicosatetraenoic acid ). However, it also acts as an epoxygenase activity to metabolize docosahexaenoic acid to epoxides , primarily 19 R ,20 S -epoxyeicosapentaenoic acid and 19 S ,20 R -epoxyeicosapentaenoic acid isomers (termed 19,20-EDP) and eicosapentaenoic acid to epoxides, primarily 17 R ,18 S -eicosatetraenoic acid and 17 S ,18 R -eicosatetraenoic acid isomers (termed 17,18-EEQ). 19-HETE

460-463: A number of disease states. CYP2E1 expression levels have been correlated with a variety of dietary and physiological factors, such as ethanol consumption, diabetes, fasting, and obesity. It appears that cellular levels of the enzyme may be controlled by the molecular chaperone HSP90 , which upon association with CYP2E1 allows for transport to the proteasome and subsequent degradation. Ethanol and other substrates may disrupt this association, leading to

506-416: A post-translational mechanism for increased protein stability at low levels of ethanol and an additional transcriptional induction at high levels of ethanol. CYP2E1 is inhibited by a variety of small molecules, many of which act competitively . Two such inhibitors, indazole and 4-methylpyrazole , coordinate with the active site's iron atom and were crystallized with recombinant human CYP2E1 in 2008 to give

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552-505: A process known as phytoremediation . Enzyme Commission number The Enzyme Commission number ( EC number ) is a numerical classification scheme for enzymes , based on the chemical reactions they catalyze . As a system of enzyme nomenclature , every EC number is associated with a recommended name for the corresponding enzyme-catalyzed reaction. EC numbers do not specify enzymes but enzyme-catalyzed reactions. If different enzymes (for instance from different organisms) catalyze

598-701: A Δ4-desaturase, it is considered outdated. Marine bacteria and the microalgae Schizochytrium use an anerobic polyketide synthase pathway to synthesize DHA. DHA can be metabolized into DHA-derived specialized pro-resolving mediators (SPMs), DHA epoxides, electrophilic oxo-derivatives (EFOX) of DHA, neuroprostanes, ethanolamines, acylglycerols, docosahexaenoyl amides of amino acids or neurotransmitters, and branched DHA esters of hydroxy fatty acids, among others. The enzyme CYP2C9 metabolizes DHA to epoxydocosapentaenoic acids (EDPs; primarily 19,20-epoxy-eicosapentaenoic acid isomers [i.e. 10,11-EDPs]). Though mixed and plagued by methodological inconsistencies, there

644-548: Is a membrane protein expressed in high levels in the liver, where it composes nearly 50% of the total hepatic cytochrome P450 mRNA and 7% of the hepatic cytochrome P450 protein. The liver is therefore where most drugs undergo deactivation by CYP2E1, either directly or by facilitated excretion from the body. CYP2E1 enzyme metabolizes mostly small, polar molecules, including toxic laboratory chemicals such as dimethylformamide , aniline , and halogenated hydrocarbons (see table below) . While these oxidations are often of benefit to

690-499: Is a major reason for their observed hepatotoxicity in patients. CYP2E1 and other cytochrome P450 enzymes can inadvertently produce reactive oxygen species (ROS) in their active site when catalysis is not coordinated correctly, resulting in potential lipid peroxidation as well as protein and DNA oxidation. CYP2E1 is particularly susceptible to this phenomenon compared to other P450 enzymes, suggesting that its expression levels may be important for negative physiological effects observed in

736-485: Is an omega−3 fatty acid that is an important component of the human brain , cerebral cortex , skin , and retina . It is given the fatty acid notation 22:6( n −3) . It can be synthesized from alpha-linolenic acid or obtained directly from maternal milk (breast milk), fatty fish, fish oil, or algae oil. The consumption of DHA (e.g., from fatty fish such as salmon, herring, mackerel and sardines) contributes to numerous physiological benefits, including cognition. As

782-420: Is an inhibitor of 20-HETE, a broadly active signaling molecule, e.g. it constricts arterioles , elevates blood pressure, promotes inflammation responses, and stimulates the growth of various types of tumor cells; however the in vivo ability and significance of 19-HETE in inhibiting 20-HETE has not been demonstrated. The EDP ( epoxydocosapentaenoic acid ) and EEQ ( epoxyeicosatetraenoic acid ) metabolites have

828-521: Is associated with cognitive decline. DHA levels are reduced in the brain tissue of severely depressed people. Aerobic eukaryotes, specifically microalgae, mosses , fungi , and some animals, perform biosynthesis of DHA as a series of desaturation and elongation reactions, catalyzed by the sequential action of desaturase and elongase enzymes . This pathway, originally identified in Thraustochytrium , applies to these groups: In humans, DHA

874-496: Is associated with its role in cardiovascular protection and lowering the risk of coronary artery disease. DHA supplementation has been shown to improve high-density lipoprotein (‘good cholesterol’), and lower total cholesterol as well as blood pressure levels. Foods high in omega−3 fatty acids may be recommended to women who want to become pregnant or when nursing. A working group from the International Society for

920-642: Is different from the 'FORMAT NUMBER' Oxidation /reduction reactions; transfer of H and O atoms or electrons from one substance to another Similarity between enzymatic reactions can be calculated by using bond changes, reaction centres or substructure metrics (formerly EC-BLAST], now the EMBL-EBI Enzyme Portal). Before the development of the EC number system, enzymes were named in an arbitrary fashion, and names like old yellow enzyme and malic enzyme that give little or no clue as to what reaction

966-488: Is either obtained from the diet or may be converted in small amounts from eicosapentaenoic acid (EPA, 20:5, ω-3). With the identification of FADS2 as a human Δ4-desaturase in 2015, it is now known that humans also follow the whole "aerobic eukaryote" pathway, involving Δ5-elongation to DPA and Δ4-desaturation to DHA. A "Sprecher's shunt" hypothesis, proposed in 1991, postulates that EPA is twice elongated to 24:5 ω-3, then desaturated to 24:6 ω-3 (via delta 6 desaturase ) in

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1012-463: Is important for the developing infant. Rates of DHA production in women are 15% higher than in men. DHA is a major fatty acid in brain phospholipids and the retina . Preliminary research has investigated its potential benefit in Alzheimer's disease , and cardiovascular disease , and other disorders. DHA is the most abundant omega−3 fatty acid in the brain and retina. DHA comprises 40% of

1058-485: Is little evidence of adverse health or cognitive effects due to DHA deficiency in adult vegetarians or vegans, breast milk levels remain a concern for supplying adequate DHA to the infant. Fish oil is widely sold in capsules containing a mixture of omega−3 fatty acids, including EPA and DHA. Oxidized fish oil in supplement capsules may contain lower levels of EPA and DHA. Light, oxygen exposure, and heat can all contribute to oxidation of fish oil supplements. Buying

1104-431: Is now convincing evidence from ecological, RCTs, meta-analyses and animal trials show a benefit for omega−3 dietary intake for cardiovascular health. Of the n −3 FAs, DHA has been argued to be the most beneficial due to its preferential uptake in the myocardium, its strongly anti-inflammatory activity and its metabolism toward neuroprotectins and resolvins, the latter of which directly contribute to cardiac function. DHA

1150-613: The CYP2E1 gene . The enzyme has been identified in fetal liver, where it is posited to be the predominant ethanol-metabolizing enzyme, and may be connected to ethanol-mediated teratogenesis . In rats, within one day of birth the hepatic CYP2E1 gene is activated transcriptionally. CYP2E1 expression is easily inducible, and can occur in the presence of a number of its substrates, including ethanol , isoniazid , tobacco , isopropanol , benzene , toluene , and acetone . For ethanol specifically, it seems that there exist two stages of induction,

1196-414: The omega-3 fatty acids , docosahexaenoic acid and eicosapentaenoic acid, the EDP and EEQ metabolites contribute to many of the beneficial effects attributed to dietary omega-3 fatty acids. EDP and EEQ metabolites are short-lived, being inactivated within seconds or minutes of formation by epoxide hydrolases , particularly soluble epoxide hydrolase , and therefore act locally. CYP2E1 is not regarded as being

1242-582: The polyunsaturated fatty acids (PUFAs) in the brain and 60% of the PUFAs in the retina. Fifty percent of a neuronal plasma membrane is composed of DHA. DHA modulates the carrier-mediated transport of choline, glycine, and taurine, the function of delayed rectifier potassium channels , and the response of rhodopsin contained in the synaptic vesicles . Phosphatidylserine (PS) – which contains high DHA content – has roles in neuronal signaling and neurotransmitter synthesis, and DHA deficiency

1288-727: The International Congress of Biochemistry in Brussels set up the Commission on Enzymes under the chairmanship of Malcolm Dixon in 1955. The first version was published in 1961, and the Enzyme Commission was dissolved at that time, though its name lives on in the term EC Number . The current sixth edition, published by the International Union of Biochemistry and Molecular Biology in 1992 as

1334-502: The Study of Fatty Acids and Lipids recommended 300 mg/day of DHA for pregnant and lactating women, whereas the average consumption was between 45 mg and 115 mg per day of the women in the study, similar to a Canadian study. A major structural component of the mammalian central nervous system, DHA is the most abundant omega−3 fatty acid in the brain and retina. Brain and retinal function rely on dietary intake of DHA to support

1380-439: The body, certain carcinogens and toxins are bioactivated by CYP2E1, implicating the enzyme in the onset of hepatotoxicity caused by certain classes of drugs (see disease relevance section below). CYP2E1 also plays a role in several important metabolic reactions, including the conversion of ethanol to acetaldehyde and to acetate in humans, where it works alongside alcohol dehydrogenase and aldehyde dehydrogenase . In

1426-453: The conversion sequence of acetyl-CoA to glucose, CYP2E1 transforms acetone via hydroxyacetone (acetol) into propylene glycol and methylglyoxal , the precursors of pyruvate , acetate and lactate . CYP2E1 also carries out the metabolism of endogenous fatty acids such as the ω-1 hydroxylation of fatty acids such as arachidonic acid , involving it in important signaling pathways that may link it to diabetes and obesity. Thus, it acts as

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1472-405: The early 1980s, NASA sponsored scientific research on a plant-based food source that could generate oxygen and nutrition on long-duration space flights . Certain species of marine algae produced rich nutrients, leading to the development of an algae-based, vegetable-like oil that contains two polyunsaturated fatty acids, DHA and arachidonic acid . DHA is widely used as a food supplement . It

1518-483: The endoplasmic reticulum and is induced by ethanol, the diabetic state, and starvation. The enzyme metabolizes both endogenous substrates, such as ethanol, acetone, and acetal, as well as exogenous substrates including benzene, carbon tetrachloride, ethylene glycol, and nitrosamines which are premutagens found in cigarette smoke. Due to its many substrates, this enzyme may be involved in such varied processes as gluconeogenesis, hepatic cirrhosis, diabetes, and cancer. CYP2E1

1564-575: The first true crystal structures of the enzyme. Other inhibitors include diethyldithiocarbamate (in cancer ), and disulfiram (in alcoholism ). CYP2E1 is expressed in high levels in the liver, where it works to clear toxins from the body. In doing so, CYP2E1 bioactivates a variety of common anesthetics, including paracetamol (acetaminophen) , halothane , enflurane , and isoflurane. The oxidation of these molecules by CYP2E1 can produce harmful substances such as trifluoroacetic acid chloride from halothane or NAPQI from paracetamol (acetaminophen) and

1610-409: The heme center, restricting active site volume compared to related enzymes that have less bulky residues at this position. T, which also protrudes into the active site, is particularly important for substrate positioning above the reactive iron center and is hence highly conserved by many cytochrome P450 enzymes. Its hydroxyl group is well-positioned to donate a hydrogen bond to potential acceptors on

1656-426: The higher expression levels observed in their presence. The increased expression of CYP2E1 accompanying these health conditions may therefore contribute to their pathogenesis by increasing the rate of production of ROS in the body. According to a 1995 publication by Y Hu et al., a study in rats revealed a 8- to 9-fold elevation of CYP2E1 with fasting alone, compared to a 20-fold increase in enzyme level accompanied by

1702-664: The last version published as a printed book, contains 3196 different enzymes. Supplements 1-4 were published 1993–1999. Subsequent supplements have been published electronically, at the website of the Nomenclature Committee of the International Union of Biochemistry and Molecular Biology. In August 2018, the IUBMB modified the system by adding the top-level EC 7 category containing translocases. Docosahexaenoic acid Docosahexaenoic acid ( DHA )

1748-417: The letters "EC" followed by four numbers separated by periods. Those numbers represent a progressively finer classification of the enzyme. Preliminary EC numbers exist and have an 'n' as part of the fourth (serial) digit (e.g. EC 3.5.1.n3). For example, the tripeptide aminopeptidases have the code "EC 3.4.11.4", whose components indicate the following groups of enzymes: NB:The enzyme classification number

1794-456: The mitochondria, then shortened to DHA (22:6 ω-3) via beta oxidation in the peroxisome . The hypothesis became accepted for a while because scientists have (until 2015) long tried and failed to find a Δ4-desaturase in mammals. However, the shunt model does not match clinical data, specifically as patients with beta oxidation defects do not display issues in DHA synthesis. With the identification of

1840-441: The prevention and treatment of asthma and allergic diseases. Ordinary types of cooked salmon contain 500–1500 mg DHA and 300–1000 mg EPA per 100 grams. Additional rich seafood sources of DHA include caviar (3400 mg per 100 grams), anchovies (1292 mg per 100 grams), mackerel (1195 mg per 100 grams), and cooked herring (1105 mg per 100 grams). Brains from mammals taken as food are also

1886-419: The same reaction, then they receive the same EC number. Furthermore, through convergent evolution , completely different protein folds can catalyze an identical reaction (these are sometimes called non-homologous isofunctional enzymes ) and therefore would be assigned the same EC number. By contrast, UniProt identifiers uniquely specify a protein by its amino acid sequence. Every enzyme code consists of

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1932-464: The substrate, and its methyl group has also been implicated in the positioning of fatty acids within the active site. A number of residues proximal to the active site including L help make up a constricted, hydrophobic access channel which may also be important for determining the enzyme's specificity towards small molecules and ω-1 hydroxylation of fatty acids. In humans, the CYP2E1 enzyme is encoded by

1978-683: The third carbon from the omega end. Its trivial name is cervonic acid (from the Latin word cerebrum for "brain"), its systematic name is all-cis-docosa-4,7,10,13,16,19-hexa-enoic acid . In organisms that do not eat algae containing DHA nor animal products containing DHA, DHA is instead produced internally from α-linolenic acid , a shorter omega−3 fatty acid manufactured by plants (and also occurring in animal products as obtained from plants). Limited amounts of eicosapentaenoic and docosapentaenoic acids are possible products of α-linolenic acid metabolism in young women and men. DHA in breast milk

2024-442: The two. Like other enzymes of this class, the active site of CYP2E1 contains an iron atom bound by a heme center which mediates the electron transfer steps necessary to carry out oxidation of its substrates. The active site of CYP2E1 is the smallest observed in human P450 enzymes, with its small capacity attributed in part to the introduction of an isoleucine at position 115. The side-chain of this residue protrudes out above

2070-457: Was catalyzed were in common use. Most of these names have fallen into disuse, though a few, especially proteolyic enzymes with very low specificity, such as pepsin and papain , are still used, as rational classification on the basis of specificity has been very difficult. By the 1950s the chaos was becoming intolerable, and after Hoffman-Ostenhof and Dixon and Webb had proposed somewhat similar schemes for classifying enzyme-catalyzed reactions,

2116-640: Was first used primarily in infant formulas. In 2019, the US Food and Drug Administration published qualified health claims for DHA. Some manufactured DHA is a vegetarian product extracted from algae, and it competes on the market with fish oil that contains DHA and other omega−3s such as EPA . Both fish oil and DHA are odorless and tasteless after processing as a food additive. Vegetarian diets typically contain limited amounts of DHA, and vegan diets typically contain no DHA. In preliminary research, algae-based supplements increased DHA levels. While there

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