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98-488: 4GQS 1557 n/a ENSG00000165841 n/a P33261 n/a NM_000769 n/a NP_000760 n/a Cytochrome P450 2C19 (abbreviated CYP2C19 ) is an enzyme protein. It is a member of the CYP2C subfamily of the cytochrome P450 mixed-function oxidase system. This subfamily includes enzymes that catalyze metabolism of xenobiotics , including some proton pump inhibitors and antiepileptic drugs. In humans, it

196-487: 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

294-489: 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

392-526: A polygenist view, that human races had evolved separately from local varieties of Homo erectus . Dividing humans into five main races, and argued that each evolved in parallel but at different rates, so that some races had reached higher levels of evolution than others. He argued that the Caucasoid race had evolved 200,000 years prior to the "Congoid race", and hence represented a higher evolutionary stage. Coon argued that Caucasoid traits emerged prior to

490-487: A Caucasian physical stock existed. He divided this racial element into two main groups: a shorter and darker Mediterranean or Iberian race and a taller and lighter Nordic race. Wells asserted that Semitic and Hamitic populations were mainly of Mediterranean type, and Aryan populations were originally of Nordic type. He regarded the Basques as descendants of early Mediterranean peoples, who inhabited western Europe before

588-564: A change from the Supreme Court's earlier opinion in Ozawa v. United States , in which it had expressly approved of two lower court cases holding "high caste Hindus" to be "free white persons" within the meaning of the naturalization act. Government lawyers later recognized that the Supreme Court had "withdrawn" this approval in Thind . In 1946, the U.S. Congress passed a new law establishing

686-477: 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

784-470: A focus on skeletal anatomy, and especially cranial morphology, without regard to skin tone . Ancient and modern "Caucasoid" populations were thus not exclusively "white", but ranged in complexion from white-skinned to dark brown. Since the second half of the 20th century, physical anthropologists have switched from a typological understanding of human biological diversity towards a genomic and population-based perspective, and have tended to understand race as

882-408: A gene of reduced activity may seem somewhat paradoxical, but can be understood as follows. Clopidogrel is administered as a "prodrug", a drug that is inactive when taken, and then depends on the action of an enzyme in the body to be activated. In patients with a gene of reduced activity, clopidogrel may not be metabolized to its biologically active form and therefore not achieve pharmacological effect in

980-984: A lack of reference materials. In partnership with the clinical testing community, the Centers for Disease Control and Prevention established the Genetic Testing Reference Material Program to meet the need for publicly available characterized reference materials. Its goal is to improve the supply of publicly available and well-characterized genomic DNA used as reference materials for proficiency testing, quality control, test development/validation, and research studies. The allele frequencies of CYP2C19*2 and *3 are significantly higher in Chinese populations than in European or African populations, and are found at approximately 3–5% of European and 15–20% of Asian populations. Among Arab population,

1078-450: A member of the cytochrome P450 superfamily of enzymes. Enzymes in the CYP2C subfamily, including CYP2C19, account for approximately 20% of cytochrome P450 in the adult liver. These proteins are monooxygenases that catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This protein localizes to the endoplasmic reticulum and is known to metabolize many drugs. Polymorphism within this gene

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1176-665: A process that relies on the "star" nomenclature system maintained by the Pharmacogene Variation Consortium assigns labels to known polymorphisms that affect drug response. A label consists of a star (asterisk) character (*) followed by a number. The most common variant (also called wild type) has "CYP2C19*1" label. The variant genotypes of CYP2C19*2 (NM_000769.2:c.681GA; p.Pro227Pro; rs4244285), CYP2C19*3 (NM_000769.2:c.636G>A; p.Trp212Ter; rs4986893) and CYP2C19*17 (NM_000769.2:c.-806C>T; rs12248560) are major factors attributed to interindividual differences in

1274-464: 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

1372-439: 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

1470-406: A sharp nasal sill. Many anthropologists in the 20th century used the term "Caucasoid" in their literature, such as William Clouser Boyd , Reginald Ruggles Gates , Carleton S. Coon , Sonia Mary Cole , Alice Mossie Brues and Grover Krantz replacing the earlier term "Caucasian" as it had fallen out of usage. In the 19th century Meyers Konversations-Lexikon (1885–1890), Caucasoid was one of

1568-533: A small immigration quota for Indians, which also permitted them to become citizens. Major changes to immigration law, however, only later came in 1965, when many earlier racial restrictions on immigration were lifted. This resulted in confusion about whether American Hispanics are included as "white", as the term Hispanic originally applied to Spanish heritage but has since expanded to include all people with origins in Spanish speaking countries . In other countries,

1666-533: A small mouth, facial angle of 100–90°, and orthognathism, exemplified by what Blumenbach saw in most ancient Greek crania and statues. Later anthropologists of the 19th and early 20th century such as James Cowles Prichard , Charles Pickering , Broca , Paul Topinard , Samuel George Morton , Oscar Peschel , Charles Gabriel Seligman , Robert Bennett Bean , William Zebina Ripley , Alfred Cort Haddon and Roland Dixon came to recognize other Caucasoid morphological features, such as prominent supraorbital ridges and

1764-485: A social classification of humans based on phenotype and ancestry as well as cultural factors, as the concept is also understood in the social sciences. In the United States , the root term Caucasian is still in use as a synonym for white or of European , Middle Eastern , or North African ancestry, a usage that has been criticized. In the eighteenth century, the prevalent view among European scholars

1862-451: 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

1960-449: 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

2058-442: 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

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2156-457: 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

2254-838: 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

2352-421: 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

2450-448: Is a table of selected substrates , inducers , and inhibitors of CYP2C19. Where classes of agents are listed, there may be exceptions within the class. Inhibitors of CYP2C19 can be classified by their potency , such as: 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

2548-493: Is associated with variable ability to metabolize drugs. The gene is located within a cluster of cytochrome P450 genes on chromosome no.10 arm q24. CYP2C19 also possesses epoxygenase activity: it is one of the principal enzymes responsible for attacking various long-chain polyunsaturated fatty acids at their double (i.e. alkene ) bonds to form epoxide products that act as signaling agents. It metabolizes: Along with CYP2C19, CYP2C8 , CYP2C9 , CYP2J2 , and possibly CYP2S1 are

2646-437: 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

2744-749: 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

2842-528: Is involved in processing or metabolizing at least 10% of commonly prescribed drugs. Variations to the enzyme can have a wide range of impacts to drug metabolism. In patients with an abnormal CYP2C19 variant certain benzodiazepines should be avoided, such as diazepam (Valium), lorazepam (Ativan), oxazepam (Serax), and temazepam (Restoril). Other categories of drugs impacted by modified CYP2C19 include proton pump inhibitors , anticonvulsants, hypnotics, sedatives, antimalarial drugs, and antiretroviral drugs. On

2940-399: Is involved. The Clinical Pharmacogenetics Implementation Consortium (CPIC) provides therapeutic guidelines that are widely utilized to suggest suitable treatment plans. These recommendations are particularly relevant for patients requiring antiplatelet medication and are based on the results of genotype testing. A key aspect of these CPIC guidelines is the translation of genotype to phenotype,

3038-511: Is modest, particularly compared to the impact of loss-of-function alleles (*2, *3), therefore, in case of these medications, the EM designation is sometimes applied instead of the UM one. For example, carriers of the *17 allele did not demonstrate different gastric pH comparing to *1 after taking the proton pump inhibitor omeprazole , a CYP2C19 substrate. Other studies concluded that the *17 allele seems to be

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3136-476: 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

3234-418: 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

3332-462: 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

3430-404: 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

3528-673: Is the CYP2C19 gene that encodes the CYP2C19 protein. CYP2C19 is a liver enzyme that acts on at least 10% of drugs in current clinical use, most notably the antiplatelet treatment clopidogrel (Plavix), drugs that treat pain associated with ulcers, such as omeprazole , antiseizure drugs such as mephenytoin , the antimalarial proguanil , and the anxiolytic diazepam . CYP2C19 has been annotated as (R)-limonene 6-monooxygenase and (S)-limonene 6-monooxygenase in UniProt . The gene encodes

3626-403: 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

3724-790: 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:

3822-614: 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

3920-626: The Dravidians and the Sinhalese were Caucasoid or a separate Dravida race, but by and in the 20th century, anthropologists predominantly declared Dravidians to be Caucasoid. Historically, the racial classification of the Turkic peoples was sometimes given as " Turanid ". Turanid racial type or "minor race", subtype of the Europid (Caucasian) race with Mongoloid admixtures, situated at

4018-745: The Mesolithic and Neolithic (e.g. Afalou , Hvellinge, Fjelkinge). Coon's theories on race were much disputed in his lifetime, and are considered pseudoscientific in modern anthropology. After discussing various criteria used in biology to define subspecies or races, Alan R. Templeton concludes in 2016: "[T]he answer to the question whether races exist in humans is clear and unambiguous: no." Drawing from Petrus Camper 's theory of facial angle , Blumenbach and Cuvier classified races, through their skull collections based on their cranial features and anthropometric measurements. Caucasoid traits were recognised as: thin nasal aperture ("nose narrow"),

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4116-511: 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

4214-494: The "Mediterranean type" which he considered to be distinct from Caucasians, rather than a subtype of it as others had done. While Blumenbach had erroneously thought that light skin color was ancestral to all humans and the dark skin of southern populations was due to sun, Coon thought that Caucasians had lost their original pigmentation as they moved North. Coon used the term "Caucasoid" and "White race" synonymously. In 1962, Coon published The Origin of Races , wherein he proposed

4312-600: The 1780s by members of the Göttingen school of history – notably Christoph Meiners in 1785 and Johann Friedrich Blumenbach in 1795 —it had originally referred in a narrow sense to the native inhabitants of the Caucasus region. In his The Outline of History of Mankind (1785), the German philosopher Christoph Meiners first used the concept of a "Caucasian" ( Kaukasisch ) race in its wider racial sense. Meiners' term

4410-760: The Cro-Magnons, and were present in the Skhul and Qafzeh hominids . However, these fossils and the Predmost specimen were held to be Neanderthaloid derivatives because they possessed short cervical vertebrae , lower and narrower pelves, and had some Neanderthal skull traits. Coon further asserted that the Caucasoid race was of dual origin, consisting of early dolichocephalic (e.g. Galley Hill , Combe-Capelle , Téviec ) and Neolithic Mediterranean Homo sapiens (e.g. Muge , Long Barrow , Corded ), as well as Neanderthal-influenced brachycephalic Homo sapiens dating to

4508-400: 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

4606-437: 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

4704-502: 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

4802-407: 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

4900-518: The anthropologist Georges Cuvier , Blumenbach classified the Caucasian race by cranial measurements and bone morphology in addition to skin pigmentation. Following Meiners, Blumenbach described the Caucasian race as consisting of the native inhabitants of Europe, West Asia, the Indian peninsula, and North Africa. This usage later grew into the widely used color terminology for race , contrasting with

4998-551: The arrival of Aryan Celts from the direction of central Europe. The "Northcaucasian race" is a sub-race proposed by Carleton S. Coon (1930). It comprises the native populations of the North Caucasus , the Balkars , Karachays and Vainakh ( Chechens and Ingushs ). An introduction to anthropology, published in 1953, gives a more complex classification scheme: Besides its use in anthropology and related fields,

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5096-660: The author, including but not limited to Mediterranean , Atlantid , Nordic , East Baltic , Alpine , Dinaric , Turanid , Armenoid , Iranid , Indid , Arabid , and Hamitic . Some authors also proposed a Pamirid race (or Pamir-Fergana race ) in Central Asia, named after the Pamir range and the Fergana valley . H.G. Wells argued that across Europe, North Africa, the Horn of Africa, West Asia, Central Asia and South Asia,

5194-578: 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

5292-440: The basis of their ability to metabolize (S)-mephenytoin or other CYP2C19 substrates, individuals can be classified as ultrarapid metabolizers (UM), extensive metabolizers (EM) or poor metabolizers (PM). In the case of proton pump inhibitors, PMs exhibit a drug exposure that is 3 to 13 times higher than that of EMs. Loss-of-function alleles, CYP2C19*2 and CYP2C19*3 (and others, which are the subject of ongoing research) predict PMs, and

5390-502: 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

5488-622: The body. The relative risk of major cardiac events among patients treated with clopidogrel is 1.53 to 3.69 times higher for carriers of CYP2C19*2 and CYP2C19*3 compared with non-carriers. A 2020 systematic review and meta-analysis also confirmed that the CYP2C19*2 variant has a strong association with clopidogrel resistance. In 2021 a higher risk of stroke at 90 days was found with clopidogrel than ticagrelor , which does not require metabolic conversion, among Han Chinese CYP2C19 loss-of-function carriers with minor ischemic stroke or TIA. The following

5586-498: The boundary of the distribution of the Mongoloid and Europid "great races". There was no universal consensus of the validity of the "Caucasoid" grouping within those who attempted to categorize human variation. Thomas Henry Huxley in 1870 wrote that the "absurd denomination of 'Caucasian ' " was in fact a conflation of his Xanthochroi (Nordic) and Melanochroi (Mediterranean) types. The postulated subraces vary depending on

5684-471: 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

5782-425: 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

5880-444: 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

5978-520: The differences in other genes that affect drug response have to be excluded. The prevalence of the CYP2C19*17 variant is less than 5% in Asian populations and is approximately four times higher in European and African populations. The alleles CYP2C19*2 and *3 may reduce the efficacy of clopidogrel (Plavix), an antiplatelet medication. The basis for this reduced effect of clopidogrel in patients who have

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6076-433: 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"

6174-592: 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

6272-483: 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,

6370-422: 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

6468-403: 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

6566-427: 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

6664-414: The factor responsible for lower response to some drugs, even at higher doses, for example, to escitalopram for symptom remission in major depressive disorder patients. CYP2C19*17 carrier status is significantly associated with enhanced response to clopidogrel and an increased risk of bleeding; the highest risk was observed for CYP2C19*17 homozygous patients. A study found that escitalopram serum concentration

6762-405: The following CYP2C19 alleles: *4.001 (*4A), *4.002 (*4B), *5, *6, *7, *8, *9, *10, and *35, all of them associated with diminished enzyme activity. Although these tier 2 alleles are included in many platforms, they were not included in the tier 1 recommendations because of low minor allele frequency (which can increase false-positive occurrences), less well-characterized impact on CYP2C19 function, or

6860-619: The frequency of CYP2C19 genotypes including *1/*17, *1/*2, *2/*2, *3/*3, and *1/*3 were 20.2%, 16.7%, 6.1%, 5.45%, 0.7%, and 0.35%, respectively. In a study of 2.29 million direct-to-consumer genetics research participants, the overall frequencies of *2, *3, and *17 were 15.2%, 0.3%, and 20.4%, respectively, but varied by ethnicity. The most common variant diplotypes were *1/*17 at 26% and *1/*2 at 19.4%. The less common *2/*17, *17/*17 and *2/*2 genotypes occurred at 6.0%, 4.4%, and 2.5%, respectively. Overall, 58.3% of participants had at least one increased-function or no-function CYP2C19 allele. CYP2C19

6958-520: The gain-of-function CYP2C19*17 allele predicts UMs. Although the amount of CYP2C19 enzyme produced by the *17 allele is greater than of the *1 allele, whether the carriers of the *17 allele experience any significant difference in response to drugs compared to the wild-type, is a topic of ongoing research, studies show varying results. Some studies have found that the *17 variant's effect on the metabolism of omeprazole , pantoprazole , escitalopram , sertraline , voriconazole , tamoxifen and clopidogrel

7056-536: 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. Caucasian race Introduced in the 1780s by members of the Göttingen school of history , the term denoted one of three purported major races of humankind (those three being Caucasoid, Mongoloid , and Negroid ). In biological anthropology , Caucasoid has been used as an umbrella term for phenotypically similar groups from these different regions, with

7154-419: The main producers of EETs and, very likely EEQs, EDPs, and the epoxides of linoleic acid. Pharmacogenomics is a study that analyzes how an individual's genetic makeup affects the response to drugs of this individual. There are many common genetic variations that affect the expression of the CYP2C19 gene , which in turn influences the enzyme activity in the metabolic pathways of those drugs in which this enzyme

7252-474: 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

7350-584: The pharmacokinetics and response to CYP2C19 substrates. CYP2C19*2 and *3 ( loss-of-function alleles ) are associated with diminished enzyme activity, whereas CYP2C19*17 ( gain-of-function allele ) results in increased activity. The Working Group of the Association for Molecular Pathology Clinical Practice Committee recommended these three variant alleles to be included in the minimal clinical pharmacogenomic testing panel, called tier 1 . The extended panel of variant alleles, called tier 2 , additionally includes

7448-550: The populations of the Middle East, North Africa, the Horn of Africa, Central Asia and South Asia. He counted as "white" only European peoples and their descendants, as well as a few populations in areas adjacent to or opposite southern Europe, in parts of Anatolia and parts of the Rif and Atlas mountains. In 1939, Coon argued that the Caucasian race had originated through admixture between Homo neanderthalensis and Homo sapiens of

7546-528: 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

7644-492: The racial categorizations of color established by Meiners' and Blumenbach's works, along with many other early steps of anthropology, well into the late 19th and mid-to-late 20th centuries, increasingly used to justify political policies, such as segregation and immigration restrictions, and other opinions based in prejudice. For example, Thomas Henry Huxley (1870) classified all populations of Asian nations as Mongoloid. Lothrop Stoddard (1920) in turn classified as "brown" most of

7742-406: 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

7840-733: 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

7938-410: 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

8036-636: The stereotypical " Circassian beauties " and the Georgian people ; both Georgia and Circassia are in the Caucasus region. The "Circassian beauty" stereotype had its roots in the Middle Ages, while the reputation for the attractiveness of the Georgian people was developed by early modern travellers to the region such as Jean Chardin . The term Caucasian as a racial category was introduced in

8134-412: 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

8232-519: 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

8330-405: 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

8428-399: 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

8526-1004: The term "Caucasian" has often been used in the United States in a different, social context to describe a group commonly called " white people ". "White" also appears as a self-reporting entry in the U.S. Census. Naturalization as a United States citizen was restricted to "free white persons" by the Naturalization Act of 1790 , and later extended to other resident populations by the Naturalization Act of 1870 , Indian Citizenship Act of 1924 and Immigration and Nationality Act of 1952 . The Supreme Court in United States v. Bhagat Singh Thind (1923) decided that Asian Indians were ineligible for citizenship because, though deemed "Caucasian" anthropologically, they were not white like European descendants since most laypeople did not consider them to be "white" people. This represented

8624-466: The terms Negroid , Mongoloid , and Australoid . There was never consensus among the proponents of the "Caucasoid race" concept regarding how it would be delineated from other groups such as the proposed Mongoloid race. Carleton S. Coon (1939) included the populations native to all of Central and Northern Asia, including the Ainu people , under the Caucasoid label. However, many scientists maintained

8722-441: The three great races of humankind, alongside Mongoloid and Negroid . The taxon was taken to consist of a number of subtypes. The Caucasoid peoples were usually divided into three groups on ethnolinguistic grounds, termed Aryan ( Indo-European ), Semitic ( Semitic languages ), and Hamitic (Hamitic languages i.e. Berber - Cushitic - Egyptian ). 19th century classifications of the peoples of India were initially uncertain if

8820-438: 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

8918-486: 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

9016-487: Was 42% lower in patients homozygous for CYP2C19*17. An important limitation of all these studies is the single-gene analysis, since most drugs that are metabolized by CYP2C19 are also metabolized by CYP2D6 and CYP3A4 enzymes. Besides that, other genes are involved in drug response, for example, escitalopram is transported by P-glycoprotein , encoded by the ABCB1 gene. In order for the studies on CYP2C19*17 to be conclusive,

9114-452: Was Johann Friedrich Blumenbach, a colleague of Meiners', who later came to be considered one of the founders of the discipline of anthropology , who gave the term a wider audience, by grounding it in the new methods of craniometry and Linnean taxonomy . Blumenbach did not credit Meiners with his taxonomy, although his justification clearly points to Meiners' aesthetic viewpoint of Caucasus origins. In contrast to Meiners, however, Blumenbach

9212-407: Was a monogenist—he considered all humans to have a shared origin and to be a single species. Blumenbach, like Meiners, did rank his Caucasian grouping higher than other groups in terms of mental faculties or potential for achievement despite pointing out that the transition from one race to another is so gradual that the distinctions between the races presented by him are "very arbitrary". Alongside

9310-581: 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

9408-528: Was given wider circulation in the 1790s by many people. Meiners imagined that the Caucasian race encompassed all of the ancient and most of the modern native populations of Europe, the aboriginal inhabitants of West Asia (including the Phoenicians, Hebrews and Arabs), the autochthones of Northern Africa (Berbers, Egyptians, Abyssinians and neighboring groups), the Indians, and the ancient Guanches . It

9506-608: Was that the human species had its origin in the region of the Caucasus Mountains . This view was based upon the Caucasus being the location for the purported landing point of Noah's Ark – from whom the Bible states that humanity is descended – and the location for the suffering of Prometheus , who in Hesiod 's myth had crafted humankind from clay. In addition, the most beautiful humans were reputed by Europeans to be

9604-457: 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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