Human glyoxalase I. Two zinc ions that are needed for the enzyme to catalyze its reaction are shown as purple spheres, and an enzyme inhibitor called S-hexylglutathione is shown as a space-filling model, filling the two active sites.

Enzymes are biomolecules that catalyze (i.e. increase the rates of) chemical reactions.^[1][2] Almost all enzymes are proteins. In enzymatic reactions, the molecules at the beginning of the process are called substrates, and the enzyme converts them into different molecules, the products. Almost all processes in a biological cell need enzymes in order to occur at significant rates. Since enzymes are extremely selective for their substrates and speed up only a few reactions from among many possibilities, the set of enzymes made in a cell determines which metabolic pathways occur in that cell. General Name, symbol, number zinc, Zn, 30 Chemical series transition metals Group, period, block 12, 4, d Appearance bluish pale gray Standard atomic weight 65. ... HIV protease in a complex with the protease inhibitor ritonavir. ... This is a calotte model of cyclohexane. ... A representation of the 3D structure of myoglobin, showing coloured alpha helices. ... Catalyst redirects here. ... Iron rusting - a chemical reaction with a slow reaction rate. ... For other uses, see Chemical reaction (disambiguation). ... A representation of the 3D structure of myoglobin showing coloured alpha helices. ... 3D (left and center) and 2D (right) representations of the terpenoid molecule atisane. ... For other uses, see Substrate. ... Drawing of the structure of cork as it appeared under the microscope to Robert Hooke from Micrographia which is the origin of the word cell being used to describe the smallest unit of a living organism Cells in culture, stained for keratin (red) and DNA (green) The cell is the... In biochemistry, a metabolic pathway is a series of chemical reactions occurring within a cell. ...

Like all catalysts, enzymes work by lowering the activation energy (E_a or ΔG^‡) for a reaction, thus dramatically increasing the rate of the reaction. Most enzyme reaction rates are millions of times faster than those of comparable uncatalyzed reactions. As with all catalysts, enzymes are not consumed by the reactions they catalyze, nor do they alter the equilibrium of these reactions. However, enzymes do differ from most other catalysts by being much more specific. Enzymes are known to catalyze about 4,000 biochemical reactions.^[3] A few RNA molecules called ribozymes catalyze reactions, with an important example being some parts of the ribosome.^[4][5] Synthetic molecules called artificial enzymes also display enzyme-like catalysis.^[6] The sparks generated by striking steel against a flint provide the activation energy to initiate combustion in this Bunsen burner. ... A burette, an apparatus for carrying out acid-base titration, is an important part of equilibrium chemistry. ... For other uses, see RNA (disambiguation). ... This article is about the chemical. ... Figure 1: Ribosome structure indicating small subunit (A) and large subunit (B). ... Schematic drawing of artificial phosphorylase An artificial enzyme is a synthetic, organic molecules prepared to recreate the active site of an enzyme. ...

Enzyme activity can be affected by other molecules. Inhibitors are molecules that decrease enzyme activity; activators are molecules that increase activity. Many drugs and poisons are enzyme inhibitors. Activity is also affected by temperature, chemical environment (e.g. pH), and the concentration of substrate. Some enzymes are used commercially, for example, in the synthesis of antibiotics. In addition, some household products use enzymes to speed up biochemical reactions (e.g., enzymes in biological washing powders break down protein or fat stains on clothes; enzymes in meat tenderizers break down proteins, making the meat easier to chew). HIV protease in a complex with the protease inhibitor ritonavir. ... Bacillus stearothermophilus phosphofructokinase. ... For other uses, see Drug (disambiguation). ... For other uses, see Poison (disambiguation). ... For other uses, see Temperature (disambiguation). ... For other uses, see PH (disambiguation). ... For other uses, see Concentration (disambiguation). ... Staphylococcus aureus - Antibiotics test plate. ... A display of Tide laundry detergent at a supermarket Laundry detergent is a substance which is a type of detergent that is added when one is washing laundry to help get the laundry cleaner. ... For other uses, see FAT. Fats consist of a wide group of compounds that are generally soluble in organic solvents and largely insoluble in water. ... A meat tenderizer on a wooden cutting board. ...

[edit] Etymology and history

Eduard Buchner

As early as the late 1700s and early 1800s, the digestion of meat by stomach secretions^[7] and the conversion of starch to sugars by plant extracts and saliva were known. However, the mechanism by which this occurred had not been identified.^[8] 19th century (or early 20th century) photograph. ... 19th century (or early 20th century) photograph. ... Eduard Buchner (May 20, 1860 -- August 12, 1917) was a German chemist and zymologist, the winner of the 1907 Nobel Prize in Chemistry for his work on fermentation. ... For other uses, see Meat (disambiguation). ... Starch (CAS# 9005-25-8, chemical formula (C6H10O5)n,[1]) is a mixture of amylose and amylopectin (usually in 20:80 or 30:70 ratios). ... This article is about sugar as food and as an important and widely-traded commodity. ... For the band, see Saliva (band). ...

In the 19th century, when studying the fermentation of sugar to alcohol by yeast, Louis Pasteur came to the conclusion that this fermentation was catalyzed by a vital force contained within 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."^[9] For other uses, see Fermentation. ... This article does not cite any references or sources. ... Typical divisions Ascomycota (sac fungi) Saccharomycotina (true yeasts) Taphrinomycotina Schizosaccharomycetes (fission yeasts) Basidiomycota (club fungi) Urediniomycetes Sporidiales Yeasts are a growth form of eukaryotic micro organisms classified in the kingdom Fungi, with about 1,500 species described;[1] they dominate fungal diversity in the oceans. ... Louis Pasteur (December 27, 1822 – September 28, 1895) was a French chemist and microbiologist best known for his remarkable breakthroughs in the causes and prevention of disease. ... Vitalism is the doctrine that vital forces are active in living organisms, so that life cannot be explained solely by mechanism. ...

In 1878 German physiologist Wilhelm Kühne (1837–1900) first used the term enzyme, which comes from Greek ενζυμον "in leaven", to describe this process. The word enzyme was used later to refer to nonliving substances such as pepsin, and the word ferment used to refer to chemical activity produced by living organisms. Wilhelm Kühne (March 28, 1837 - June 10, 1900), German physiologist, was born at Hamburg. ... Pepsin is a digestive protease (EC 3. ...

In 1897 Eduard Buchner began to study the ability of yeast extracts that lacked any living yeast cells to ferment sugar. In a series of experiments at the University of Berlin, he found that the sugar was fermented even when there were no living yeast cells in the mixture.^[10] He named the enzyme that brought about the fermentation of sucrose "zymase".^[11] In 1907 he received the Nobel Prize in Chemistry "for his biochemical research and his discovery of cell-free fermentation". Following Buchner's example; enzymes are usually named according to the reaction they carry out. Typically the suffix -ase is added to the name of the substrate (e.g., lactase is the enzyme that cleaves lactose) or the type of reaction (e.g., DNA polymerase forms DNA polymers). Eduard Buchner (May 20, 1860 -- August 12, 1917) was a German chemist and zymologist, the winner of the 1907 Nobel Prize in Chemistry for his work on fermentation. ... Humboldt-Universität zu Berlin The Humboldt University of Berlin (German Humboldt-Universität zu Berlin) is Berlins oldest university, founded in 1810 as the University of Berlin (Universität zu Berlin) by the liberal Prussian educational reformer and linguist Wilhelm von Humboldt whose university model has strongly influenced... Zymase is a enzyme complex that catalyze glycolysis, the fermentation of sugar into ethanol and carbon dioxide. ... This is a list of Nobel Prize laureates in Chemistry from 1901 to 2006. ... For other uses, see Substrate. ... Lactase is a member of the β-galactosidase family of enzyme: enzymes that hydrolysis β 1,4 bonded attachments off of galactose. ... | IUPACName = | OtherNames = | Section1 = ! style=background: #F8EABA; text-align: center; colspan=2 | Identifiers |- | bgcolor = | CAS number | bgcolor = | [63-42-3] |- | PubChem | |- | MeSH | |- | Section2 = ! style=background: #F8EABA; text-align: center; colspan=2 | Properties |- | Molecular formula | C12H22O11 |- | Molar mass | 342. ... 3D structure of the DNA-binding helix-hairpin-helix motifs in human DNA polymerase beta A DNA polymerase is an enzyme that assists in DNA replication. ...

Having shown that enzymes could function outside a living cell, the next step was to determine their biochemical nature. Many early workers noted that enzymatic activity was associated with proteins, but several scientists (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. However, in 1926, James B. Sumner showed that the enzyme urease was a pure protein and crystallized it; Sumner did likewise for the enzyme catalase in 1937. The conclusion that pure proteins can be enzymes was definitively proved by Northrop and Stanley, who worked on the digestive enzymes pepsin (1930), trypsin and chymotrypsin. These three scientists were awarded the 1946 Nobel Prize in Chemistry.^[12] Richard Willstätter Richard Martin Willstätter (August 13, 1872 – August 3, 1942) was a German chemist whose study of the structure of chlorophyll and other plant pigments won him the 1915 Nobel Prize for Chemistry. ... James Batcheller Sumner (November 19, 1887 – August 12, 1955) was an American chemist. ... Helicobacter Pylori Urease drawn from PDB 1E9Z. Urease (EC 3. ... RNA expression pattern Orthologs Human Mouse Entrez Ensembl Uniprot Refseq Location Pubmed search Catalase is a common enzyme found in nearly all living organisms. ... John Howard Northrop (July 5, 1891 – May 27, 1987) was an American biochemist who won the Nobel Prize in Chemistry in 1946 (with James Batcheller Sumner and Wendell Meredith Stanley) for purifying and crystallizing certain enzymes. ... Wendell Meredith Stanley (August 16, 1904 – June 15, 1971) was an American biochemist, virologist and Nobel prize laureate. ...

This discovery that enzymes could be crystallized eventually allowed their structures to be solved by x-ray crystallography. This 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.^[13] 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. X-ray crystallography, also known as single-crystal X-ray diffraction, is the oldest and most common crystallographic method for determining the structure of molecules. ... Lysozyme single crystal. ... Albumen redirects here. ... Lord David Phillips is considered to be a founding father of the now expanding field of structural biology and was an influential figure in science and government. ... Structural biology is a branch of molecular biology concerned with the study of the architecture and shape of biological macromolecules--proteins and nucleic acids in particular—and what causes them to have the structures they have. ...

[edit] Structures and mechanisms

See also: Enzyme catalysis

Ribbon-diagram showing carbonic anhydrase II. The grey sphere is the zinc cofactor in the active site. Diagram drawn from PDB 1MOO.

Enzymes are generally globular proteins and range from just 62 amino acid residues in size, for the monomer of 4-oxalocrotonate tautomerase,^[14] to over 2,500 residues in the animal fatty acid synthase.^[15] A small number of RNA-based biological catalysts exist, with the most common being the ribosome, these are either referred to as RNA-enzymes, or ribozymes. The activities of enzymes are determined by their three-dimensional structure.^[16] Most enzymes are much larger than the substrates they act on, and only a small portion of the enzyme (around 3–4 amino acids) is directly involved in catalysis.^[17] The region that contains these catalytic residues, binds the substrate, and then carries out the reaction is known as the active site. Enzymes can also contain sites that bind cofactors, which are needed for catalysis. Some enzymes also have binding sites for small molecules, which are often direct or indirect products or substrates of the reaction catalyzed. This binding can serve to increase or decrease the enzyme's activity, providing a means for feedback regulation. Enzyme catalysis is the catalysis of chemical reactions by enzyme molecules. ... Image File history File links Carbonic_anhydrase. ... Image File history File links Carbonic_anhydrase. ... Carbonic anhydrase (carbonate dehydratase) is a family of metalloenzymes (enzymes that contain one or more metal atoms as a functional component of the enzyme) that catalyze the rapid interconversion of carbon dioxide and water into carbonic acid, protons, and bicarbonate ions. ... General Name, symbol, number zinc, Zn, 30 Chemical series transition metals Group, period, block 12, 4, d Appearance bluish pale gray Standard atomic weight 65. ... A monomer (from Greek mono one and meros part) is a small molecule that may become chemically bonded to other monomers to form a polymer [1]. // Examples of monomers are hydrocarbons such as the alkene and arene homologous series. ... 4-Oxalocrotonate tautomerase (EC 5. ... Fatty acids are aliphatic acids fundamental to energy production and storage, cellular structure and as intermediates in the biosynthesis of hormones and other biologically important molecules. ... Figure 1: Ribosome structure indicating small subunit (A) and large subunit (B). ... This article is about the chemical. ... In biochemistry, many proteins are actually assemblies of more than one protein (polypeptide) molecule, which in the context of the larger assemblage are known as protein subunits. ... This article is about the class of chemicals. ... The active site of an enzyme contains the catalytic and binding sites. ... A cofactor is any substance that needs to be present in addition to an enzyme to catalyze a certain reaction. ... For other uses, see Feedback (disambiguation). ...

Like all proteins, enzymes are made as long, linear chains of amino acids that fold to produce a three-dimensional product. Each unique amino acid sequence produces a specific structure, which has unique properties. Individual protein chains may sometimes group together to form a protein complex. Most enzymes can be denatured—that is, unfolded and inactivated—by heating or chemical denaturants, which disrupt the three-dimensional structure of the protein. Depending on the enzyme, denaturation may be reversible or irreversible. Protein before and after folding. ... In biochemistry and chemistry, the tertiary structure of a protein or any other macromolecule is its three-dimensional structure, as defined by the atomic coordinates. ... A protein complex is a group of two or more associated proteins formed by protein-protein interaction that is stable over time. ... Irreversible egg protein denaturation and loss of solubility, caused by the high temperature (while cooking it) Denaturation is the alteration of a protein or nucleic acids shape through some form of external stress (for example, by applying heat, acid or alkali), in such a way that it will no... In biochemistry and chemistry, the tertiary structure of a protein or any other macromolecule is its three-dimensional structure, as defined by the atomic coordinates. ...

[edit] Specificity

Enzymes are usually very specific as to which reactions they catalyze and the substrates that are involved in these reactions. Complementary shape, charge and hydrophilic/hydrophobic characteristics of enzymes and substrates are responsible for this specificity. Enzymes can also show impressive levels of stereospecificity, regioselectivity and chemoselectivity.^[18] For other uses, see Substrate. ... The adjective hydrophilic describes something that likes water (from Greek hydros = water; philos = friend). ... In chemistry, hydrophobic or lipophilic species, or hydrophobes, tend to be electrically neutral and nonpolar, and thus prefer other neutral and nonpolar solvents or molecular environments. ... In chemistry, stereospecificity is the property of a chemical reaction that yields different stereoisomeric reaction products from two stereoisomeric reactants depending on the reaction conditions. ... In chemistry, regioselectivity is the preference of one direction of chemical bond making or breaking over all other possible directions. ... Chemical reactions are defined usually in small contexts (only up to a small number of neighbouring atoms), such generalizations are a matter of utility. ...

Some of the enzymes showing the highest specificity and accuracy are involved in the copying and expression of the genome. These enzymes have "proof-reading" mechanisms. Here, an enzyme such as DNA polymerase catalyzes a reaction in a first step and then checks that the product is correct in a second step.^[19] This two-step process results in average error rates of less than 1 error in 100 million reactions in high-fidelity mammalian polymerases.^[20] Similar proofreading mechanisms are also found in RNA polymerase,^[21] aminoacyl tRNA synthetases^[22] and ribosomes.^[23] In biology the genome of an organism is the whole hereditary information of an organism that is encoded in the DNA (or, for some viruses, RNA). ... 3D structure of the DNA-binding helix-hairpin-helix motifs in human DNA polymerase beta A DNA polymerase is an enzyme that assists in DNA replication. ... Subclasses & Infraclasses Subclass †Allotheria* Subclass Prototheria Subclass Theria Infraclass †Trituberculata Infraclass Metatheria Infraclass Eutheria For the folk-rock band see The Mammals. ... This article does not cite any references or sources. ... An aminoacyl tRNA synthetase (abbreviated aaRs) is an enzyme that catalyzes the binding of a specific amino acid to a tRNA to form an aminoacyl-tRNA. The synthetase hydrolyzes ATP to bind the appropriate amino acid to the 3 hydroxyl of the tRNA molecule. ... Figure 1: Ribosome structure indicating small subunit (A) and large subunit (B). ...

Some enzymes that produce secondary metabolites are described as promiscuous, as they can act on a relatively broad range of different substrates. It has been suggested that this broad substrate specificity is important for the evolution of new biosynthetic pathways.^[24] It has been suggested that this article or section be merged into natural product. ...

[edit] "Lock and key" model

Enzymes are very specific, and it was suggested by Emil Fischer in 1894 that this was because both the enzyme and the substrate possess specific complementary geometric shapes that fit exactly into one another.^[25] This is often referred to as "the lock and key" model. However, while this model explains enzyme specificity, it fails to explain the stabilization of the transition state that enzymes achieve. The "lock and key" model has proven inaccurate and the induced fit model is the most currently accepted enzyme-substrate-coenzyme figure. Hermann Emil Fischer (October 9, 1852 - July 15, 1919) was a German chemist and recipient of the Nobel Prize for Chemistry in 1902. ...

[edit] Induced fit model

Diagrams to show the induced fit hypothesis of enzyme action.

In 1958 Daniel Koshland suggested a modification to the lock and key model: since enzymes are rather flexible structures, the active site is continually reshaped by interactions with the substrate as the substrate interacts with the enzyme.^[26] As a result, the substrate does not simply bind to a rigid active site, the amino acid side chains which make up the active site are moulded 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.^[27] The active site continues to change until the substrate is completely bound, at which point the final shape and charge is determined.^[28] Image File history File links Induced_fit_diagram. ... Image File history File links Induced_fit_diagram. ... Daniel E. Koshland, Jr. ... The term Side chain can have different meanings depending on the context: In chemistry and biochemistry a side chain is a part of a molecule attached to a core structure. ...

[edit] Mechanisms

Enzymes can act in several ways, all of which lower ΔG^‡:^[29]

• Lowering the activation energy by creating an environment in which the transition state is stabilized (e.g. straining the shape of a substrate - by binding the transition-state conformation of the substrate/product molecules, the enzyme distorts the bound substrate(s) into their transition state form, thereby reducing the amount of energy required to complete the transition).
• Lowering the energy of the transition state, but without distorting the substrate, by creating an environment with the opposite charge distribution to that of the transition state.
• Providing an alternative pathway. For example, temporarily reacting with the substrate to form an intermediate ES complex, which would be impossible in the absence of the enzyme.
• Reducing the reaction entropy change by bringing substrates together in the correct orientation to react. Considering ΔH^‡ alone overlooks this effect.

Interestingly, this entropic effect involves destabilization of the ground state,^[30] and its contribution to catalysis is relatively small.^[31] The sparks generated by striking steel against a flint provide the activation energy to initiate combustion in this Bunsen burner. ...

[edit] Transition State Stabilization

The understanding of the origin of the reduction of ΔG^‡ requires one to find out how the enzymes can stabilize its transition state more than the transition state of the uncatalyzed reaction. Apparently, the most effective way for reaching large stabilization is the use of electrostatic effects, in particular, by having a relatively fixed polar environment that is oriented toward the charge distribution of the transition state.^[32] Such an environment does not exist in the uncatalyzed reaction in water.

[edit] Dynamics and function

Recent investigations have provided new insights into the connection between internal dynamics of enzymes and their mechanism of catalysis.^[33][34][35] An enzyme's internal dynamics are the movement of its internal parts (e.g. amino acids, a group of amino acids, a loop region, an alpha helix, neighboring beta-sheets or even an entire domain) of these proteins. These movements occur at various time-scales ranging from femtoseconds to seconds. Networks of protein residues throughout an enzyme's structure can contribute to catalysis through dynamic motions.^{[36][37][38][39]} Protein motions are vital to many enzymes, but whether small and fast vibrations, or larger and slower conformational movements are more important depends on the type of reaction involved. However, although these movements are important in binding and releasing substrates and products, it is not clear if protein movements help to accelerate the chemical steps in enzymatic reactions.^[40] These new insights also have implications in understanding allosteric effects and developing new drugs. A femtosecond is the SI unit of time equal to 10-15 of a second. ...

[edit] Allosteric modulation

Allosteric enzymes change their structure in response to binding of effectors. Modulation can be direct, where the effector binds directly to binding sites in the enzyme, or indirect, where the effector binds to other proteins or protein subunits that interact with the allosteric enzyme and thus influence catalytic activity. In biochemistry, an enzyme or other protein is allosteric if its activity or efficiency changes in response to the binding of an effector molecule at a so-called allosteric site. ... An effector is a small molecule that binds to a protein and thereby alters the activity of that protein. ... A binding site is a region on a protein to which specific ligands bind. ... In structural biology, a protein subunit or subunit protein is a double protein molecule that assembles (or coassembles) with other protein molecules to form a multimeric or oligomeric protein. ...

[edit] Cofactors and coenzymes

Main articles: Cofactor (biochemistry) and Coenzyme

A cofactor is any substance that needs to be present in addition to an enzyme to catalyze a certain reaction. ... Coenzyme A Coenzymes are small organic non-protein molecules that carry chemical groups between enzymes. ...

[edit] Cofactors

Some enzymes do not need any additional components to show full activity. However, others require non-protein molecules called cofactors to be bound for activity.^[41] Cofactors can be either inorganic (e.g., metal ions and iron-sulfur clusters) or organic compounds, (e.g., flavin and heme). Organic cofactors can be either prosthetic groups, which are tightly bound to an enzyme, or coenzymes, which are released from the enzyme's active site during the reaction. Coenzymes include NADH, NADPH and adenosine triphosphate. These molecules act to transfer chemical groups between enzymes.^[42] Inorganic chemistry is the branch of chemistry concerned with the properties and reactions of inorganic compounds. ... An iron-sulfur cluster is a structural motif found in certain metalloproteins, such as the ferredoxins, as well as NADH dehydrogenase and Coenzyme Q - cytochrome c reductase of the electron transfer system. ... An organic compound is any member of a large class of chemical compounds whose molecules contain carbon, with exception of carbides, carbonates, carbon oxides and gases containing carbon. ... Riboflavin Flavin is a vaginal ring whose biochemical smell is pungent. ... Structure of Heme b A heme or haem is a prosthetic group that consists of an iron atom contained in the center of a large heterocyclic organic ring called a porphyrin. ... A coenzyme is an organic non-protein molecule that is a functional part of an enzyme. ... Coenzyme A Coenzymes are small organic non-protein molecules that carry chemical groups between enzymes. ... Nicotinamide adenine dinucleotide (NAD+ or in older notation DPN+) is an important coenzyme found in cells. ... Nicotinamide adenine dinucleotide phosphate (NADP) is used in anabolic reactions, such as fatty acid and nucleic acid synthesis, which require NADPH as a reducing agent. ... Adenosine 5-triphosphate (ATP) is a multifunctional nucleotide that is most important as a molecular currency of intracellular energy transfer. ...

An example of an enzyme that contains a cofactor is carbonic anhydrase, and is shown in the ribbon diagram above with a zinc cofactor bound as part of its active site.^[43] These tightly-bound molecules are usually found in the active site and are involved in catalysis. For example, flavin and heme cofactors are often involved in redox reactions. Carbonic anhydrase (carbonate dehydratase) is a family of metalloenzymes (enzymes that contain one or more metal atoms as a functional component of the enzyme) that catalyze the rapid interconversion of carbon dioxide and water into carbonic acid, protons, and bicarbonate ions. ... ed|other uses|reduction}} Illustration of a redox reaction Redox (shorthand for reduction/oxidation reaction) describes all chemical reactions in which atoms have their oxidation number (oxidation state) changed. ...

Enzymes that require a cofactor but do not have one bound are called apoenzymes or apoproteins. An apoenzyme together with its cofactor(s) is called a holoenzyme (this is the active form). Most cofactors are not covalently attached to an enzyme, but are very tightly bound. However, organic prosthetic groups can be covalently bound (e.g., thiamine pyrophosphate in the enzyme pyruvate dehydrogenase). Thiamine mononitrate Thiamine or thiamin, also known as vitamin B1, is a colorless compound with chemical formula C12H17ClN4OS. It is soluble in water and insoluble in alcohol. ... Pyruvate dehydrogenase is an enzyme (E1) in the pyruvate dehydrogenase complex (PDC). ...

[edit] Coenzymes

Space-filling model of the coenzyme NADH

Coenzymes are small organic molecules that transport chemical groups from one enzyme to another.^[44] Some of these chemicals such as riboflavin, thiamine and folic acid are vitamins, this is when these compounds cannot be made in the body and must be acquired from the diet. The chemical groups carried include the hydride ion (H^-) carried by NAD or NADP⁺, the acetyl group carried by coenzyme A, formyl, methenyl or methyl groups carried by folic acid and the methyl group carried by S-adenosylmethionine. Image File history File links Download high-resolution version (986x1100, 284 KB) File links The following pages on the English Wikipedia link to this file (pages on other projects are not listed): Enzyme Nicotinamide adenine dinucleotide User:Benjah-bmm27/Gallery User:Ben Mills/Gallery ... Image File history File links Download high-resolution version (986x1100, 284 KB) File links The following pages on the English Wikipedia link to this file (pages on other projects are not listed): Enzyme Nicotinamide adenine dinucleotide User:Benjah-bmm27/Gallery User:Ben Mills/Gallery ... Molecular graphics is the discipline and philosophy of studying molecules and their properties through graphical representation. ... Riboflavin (E101), also known as vitamin B2, is an easily absorbed micronutrient with a key role in maintaining health in animals. ... For the similarly spelled nucleic acid, see Thymine Thiamine or thiamin, also known as vitamin B1, is one of the B vitamins. ... Folic acid and folate (the anion form) are forms of the water-soluble Vitamin B9. ... Retinol (Vitamin A) Vitamins are nutrients required in very small amounts for essential metabolic reactions in the body [1]. The term vitamin does not encompass other essential nutrients such as dietary minerals, essential fatty acids, or essential amino acids. ... Hydride is the name given to the negative ion of hydrogen, H−. Although this ion does not exist except in extraordinary conditions, the term hydride is widely applied to describe compounds of hydrogen with other elements, particularly those of groups 1–16. ... Nicotinamide adenine dinucleotide (NAD+ or in older notation DPN+) is an important coenzyme found in cells. ... Coenzyme A (CoA, CoASH, or HSCoA) is a coenzyme, notable for its role in the synthesis and oxidization of fatty acids, and the oxidation of pyruvate in the citric acid cycle. ... Folic acid and folate (the anion form) are forms of the water-soluble Vitamin B9. ... It has been suggested that this article or section be merged into S-Adenosyl methionine. ...

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 700 enzymes are known to use the coenzyme NADH.^[45]

Coenzymes are usually regenerated and their concentrations maintained at a steady level inside the cell: for example, NADPH is regenerated through the pentose phosphate pathway and S-adenosylmethionine by methionine adenosyltransferase. The pentose phosphate pathways Nonoxidative phase The pentose phosphate pathway (also called Phosphogluconate Pathway, or Hexose Monophosphate Shunt [HMP shunt]) is a process that serves to generate NADPH and the synthesis of pentose (5-carbon) sugars. ...

[edit] Thermodynamics

The energies of the stages of a chemical reaction. Substrates need a lot of energy to reach a transition state, which then decays into products. The enzyme stabilizes the transition state, reducing the energy needed to form products.

Main articles: Activation energy, Thermodynamic equilibrium, and Chemical equilibrium

As all catalysts, enzymes do not alter the position of the chemical equilibrium of the reaction. Usually, in the presence of an enzyme, the reaction runs in the same direction as it would without the enzyme, just more quickly. However, in the absence of the enzyme, other possible uncatalyzed, "spontaneous" reactions might lead to different products, because in those conditions this different product is formed faster. For other uses, see Chemical reaction (disambiguation). ... The transition state of a chemical reaction is a particular configuration along the reaction coordinate. ... The sparks generated by striking steel against a flint provide the activation energy to initiate combustion in this Bunsen burner. ... In thermodynamics, a thermodynamic system is said to be in thermodynamic equilibrium when it is in thermal equilibrium, mechanical equilibrium, and chemical equilibrium. ... A burette, an apparatus for carrying out acid-base titration, is an important part of equilibrium chemistry. ...

Furthermore, enzymes can couple two or more reactions, so that a thermodynamically favorable reaction can be used to "drive" a thermodynamically unfavorable one. For example, the hydrolysis of ATP is often used to drive other chemical reactions. Adenosine 5-triphosphate (ATP) is a multifunctional nucleotide that is most important as a molecular currency of intracellular energy transfer. ...

Enzymes catalyze the forward and backward reactions equally. They do not alter the equilibrium itself, but only the speed at which it is reached. For example, carbonic anhydrase catalyzes its reaction in either direction depending on the concentration of its reactants. Carbonic anhydrase (carbonate dehydratase) is a family of metalloenzymes (enzymes that contain one or more metal atoms as a functional component of the enzyme) that catalyze the rapid interconversion of carbon dioxide and water into carbonic acid, protons, and bicarbonate ions. ...

(in tissues; high CO₂ concentration)

(in lungs; low CO₂ concentration)

Nevertheless, if the equilibrium is greatly displaced in one direction, that is, in a very exergonic reaction, the reaction is effectively irreversible. Under these conditions the enzyme will, in fact, only catalyze the reaction in the thermodynamically allowed direction. Biological tissue is a collection of interconnected cells that perform a similar function within an organism. ... For the village in Tibet, see Lung, Tibet. ... Look up exergonic in Wiktionary, the free dictionary. ...

[edit] Kinetics

Main article: Enzyme kinetics

Mechanism for a single substrate enzyme catalyzed reaction. The enzyme (E) binds a substrate (S) and produces a product (P).

Enzyme kinetics is the investigation of how enzymes bind substrates and turn them into products. The rate data used in kinetic analyses are obtained from enzyme assays. Dihydrofolate reductase from with its two substrates, dihydrofolate (right) and NADPH (left), bound in the active site. ... Image File history File links Simple_mechanism. ... Image File history File links Simple_mechanism. ... Enzyme assays are laboratory methods for measuring enzymatic activity. ...

In 1902 Victor Henri^[46] proposed a quantitative theory of enzyme kinetics, but his experimental data were not useful because the significance of the hydrogen ion concentration was not yet appreciated. After Peter Lauritz Sørensen had defined the logarithmic pH-scale and introduced the concept of buffering in 1909^[47] the German chemist Leonor Michaelis and his Canadian postdoc Maud Leonora Menten repeated Henri's experiments and confirmed his equation which is referred to as Henri-Michaelis-Menten kinetics (sometimes also Michaelis-Menten kinetics).^[48] Their work was further developed by G. E. Briggs and J. B. S. Haldane, who derived kinetic equations that are still widely used today.^[49] Leonor Michaelis (January 16, 1875 – October 8, 1947) was a German biochemist and physician famous for his work with Maud Menten in enzyme kinetics and Michaelis-Menten kinetics. ... Maud Leonora Menten (March 20, 1879 – July 26, 1960) was a Canadian medical scientist who made significant contributions to enzyme kinetics and histochemistry. ... Michaelis-Menten kinetics describe the rate of enzyme mediated reactions for many enzymes. ... Michaelis-Menten kinetics describes the kinetics of many enzymes. ... George Edward Briggs (25 June 1893 - 7 February 1985) was a British botanist. ... John Burdon Sanderson Haldane (November 5, 1892 – December 1, 1964), who normally used J.B.S. as a first name, was a British geneticist and evolutionary biologist. ...

The major contribution of Henri 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 complex. The enzyme then catalyzes the chemical step in the reaction and releases the product.

Saturation curve for an enzyme reaction showing the relation between the substrate concentration (S) and rate (v).

Enzymes can catalyze up to several million reactions per second. For example, the reaction catalyzed by orotidine 5'-phosphate decarboxylase will consume half of its substrate in 78 million years if no enzyme is present. However, when the decarboxylase is added, the same process takes just 25 milliseconds.^[50] Enzyme rates depend on solution conditions and substrate concentration. Conditions that denature the protein abolish enzyme activity, such as high temperatures, extremes of pH or high salt concentrations, while raising substrate concentration tends to increase activity. To find the maximum speed of an enzymatic reaction, the substrate concentration is increased until a constant rate of product formation 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 form. At the maximum velocity (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. However, V_max is only one kinetic constant of enzymes. 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 velocity. Each enzyme has a characteristic K_m for a given substrate, and this can show how tight the binding of the substrate is to the enzyme. Another useful constant is k_cat, which is the number of substrate molecules handled by one active site per second. Image File history File links Michaelis-Menten_saturation_curve_of_an_enzyme_reaction. ... Image File history File links Michaelis-Menten_saturation_curve_of_an_enzyme_reaction. ... Orotidine 5-phosphate decarboxylase is an enzyme involved in pyrimidine metabolism. ... Michaelis-Menten kinetics describe the rate of enzyme mediated reactions for many enzymes. ...

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. Because the specificity constant reflects both affinity and catalytic ability, it 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 10⁸ to 10⁹ (M^-1 s^-1). 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. In chemical kinetics a reaction rate constant quantifies the speed of a chemical reaction. ... Catalytically perfect enzyme or kineticall perfect enzyme is an enzyme that catalyzes so efficiently, that almost every time enzyme meets its substrate, the reaction occurs. ... Triose-phosphate isomerase (TIM), is an enzyme (EC 5. ... Carbonic anhydrase (carbonate dehydratase) is a family of metalloenzymes (enzymes that contain one or more metal atoms as a functional component of the enzyme) that catalyze the rapid interconversion of carbon dioxide and water into carbonic acid, protons, and bicarbonate ions. ... In biochemistry, cholinesterase is a term which refers to one of the two enzymes (EC 3. ... RNA expression pattern Orthologs Human Mouse Entrez Ensembl Uniprot Refseq Location Pubmed search Catalase is a common enzyme found in nearly all living organisms. ... Structure of the monomeric unit of human superoxide dismutase 2 The enzyme superoxide dismutase (SOD, EC 1. ...

Michaelis-Menten kinetics relies on the law of mass action, which is derived from the assumptions of free diffusion and thermodynamically-driven random collision. However, many biochemical or cellular processes deviate significantly from these conditions, because of very high concentrations, phase-separation of the enzyme/substrate/product, or one or two-dimensional molecular movement.^[51] In these situations, a fractal Michaelis-Menten kinetics may be applied.^{[52][53][54][55]} Mass action in science is the idea that a large number of small units (especially atoms or molecules) acting randomly by themselves can in fact have a larger pattern. ... diffusion (disambiguation). ... The boundary of the Mandelbrot set is a famous example of a fractal. ... Michaelis-Menten kinetics describes the kinetics of many enzymes. ...

Some enzymes operate with kinetics which are faster than diffusion rates, which would seem to be impossible. Several mechanisms have been invoked to explain this phenomenon. Some proteins are believed to accelerate catalysis by drawing their substrate in and pre-orienting them by using dipolar electric fields. Other models invoke a quantum-mechanical tunneling explanation, whereby a proton or an electron can tunnel through activation barriers, although for proton tunneling this model remains somewhat controversial.^[56][57] Quantum tunneling for protons has been observed in tryptamine.^[58] This suggests that enzyme catalysis may be more accurately characterized as "through the barrier" rather than the traditional model, which requires substrates to go "over" a lowered energy barrier. Quantum tunneling is the quantum-mechanical effect of transitioning through a classically-forbidden energy state. ... Tryptamine (3-(2-aminoethyl)indole) is a monoamine compound that is widespread in nature. ...

[edit] Inhibition

Competitive inhibitors bind reversibly to the enzyme, preventing the binding of substrate. On the other hand, binding of substrate prevents binding of the inhibitor. Substrate and inhibitor compete for the enzyme.

Types of inhibition. This classification was introduced by W.W. Cleland.^[59]

Main article: Enzyme inhibitor

Enzyme reaction rates can be decreased by various types of enzyme inhibitors. Image File history File links Competitive_inhibition. ... Image File history File links Competitive_inhibition. ... Image File history File links Size of this preview: 449 × 599 pixelsFull resolution (640 × 854 pixel, file size: 28 KB, MIME type: image/png) self-created image I, the copyright holder of this work, hereby release it into the public domain. ... Image File history File links Size of this preview: 449 × 599 pixelsFull resolution (640 × 854 pixel, file size: 28 KB, MIME type: image/png) self-created image I, the copyright holder of this work, hereby release it into the public domain. ... HIV protease in a complex with the protease inhibitor ritonavir. ... HIV protease in a complex with the protease inhibitor ritonavir. ...

Competitive inhibition

In competitive inhibition, the inhibitor and substrate compete for the enzyme (i.e., they can not bind at the same time). Often competitive inhibitors strongly resemble the real substrate of the enzyme. For example, methotrexate is a competitive inhibitor of the enzyme dihydrofolate reductase, which catalyzes the reduction of dihydrofolate to tetrahydrofolate. The similarity between the structures of folic acid and this drug are shown in the figure to the right bottom. Note that binding of the inhibitor need not be to the substrate binding site (as frequently stated), if binding of the inhibitor changes the conformation of the enzyme to prevent substrate binding and vice versa. In competitive inhibition the maximal velocity of the reaction is not changed, but higher substrate concentrations are required to reach a given velocity, increasing the apparent K_m. Amethopterin redirects here. ... Categories: Biochemistry stubs | EC 1. ... Folic acid and folate (the anion form) are forms of the water-soluble Vitamin B9. ... Folic acid and folate (the anion form) are forms of the water-soluble Vitamin B9. ...

Uncompetitive inhibition

In uncompetitive inhibition the inhibitor can not bind to the free enzyme, but only to the ES-complex. The EIS-complex thus formed is enzymatically inactive. This type of inhibition is rare, but may occur in multimeric enzymes.

Non-competitive inhibition

Non-competitive inhibitors can bind to the enzyme at the same time as the substrate, i.e. they never bind to the active site. Both the EI and EIS complexes are enzymatically inactive. Because the inhibitor can not be driven from the enzyme by higher substrate concentration (in contrast to competitive inhibition), the apparent V_max changes. But because the substrate can still bind to the enzyme, the K_m stays the same.

Mixed inhibition

This type of inhibition resembles the non-competitive, except that the EIS-complex has residual enzymatic activity.

In many organisms inhibitors may act as part of a feedback mechanism. If an enzyme produces too much of one substance in the organism, that substance may act as an inhibitor for the enzyme at the beginning of the pathway that produces it, causing production of the substance to slow down or stop when there is sufficient amount. This is a form of negative feedback. Enzymes which are subject to this form of regulation are often multimeric and have allosteric binding sites for regulatory substances. Their substrate/velocity plots are not hyperbolar, but sigmoidal (S-shaped). For other uses, see Feedback (disambiguation). ... This article does not cite any references or sources. ...

The coenzyme folic acid (left) and the anti-cancer drug methotrexate (right) are very similar in structure. As a result, methotrexate is a competitive inhibitor of many enzymes that use folates.

Irreversible inhibitors react with the enzyme and form a covalent adduct with the protein. The inactivation is irreversible. These compounds include eflornithine a drug used to treat the parasitic disease sleeping sickness.^[60] Penicillin and Aspirin also act in this manner. With these drugs, the compound is bound in the active site and the enzyme then converts the inhibitor into an activated form that reacts irreversibly with one or more amino acid residues. Image File history File links Methotrexate_and_folic_acid_compared. ... Image File history File links Methotrexate_and_folic_acid_compared. ... HIV protease in a complex with the protease inhibitor ritonavir. ... Covalent redirects here. ... Eflornithine (α-difluoromethylornithine or DFMO) is a drug manufactured by Aventis which has various uses. ... Sleeping sickness or African trypanosomiasis is a parasitic disease in people and animals, caused by protozoa of genus Trypanosoma and transmitted by the tsetse fly. ... Penicillin core structure Penicillin (abbreviated PCN) is a group of β-lactam antibiotics used in the treatment of bacterial infections caused by susceptible, usually Gram-positive, organisms. ... This article is about the drug. ...

[edit] Uses of inactivators

Inhibitors are often used as drugs, but they can also act as poisons. However, the difference between a drug and a poison is usually only a matter of amount, since most drugs are toxic at some level, as Paracelsus wrote, "In all things there is a poison, and there is nothing without a poison."^[61] Equally, antibiotics and other anti-infective drugs are just specific poisons that kill a pathogen but not its host. Presumed portrait of Paracelsus, attributed to the school of Quentin Matsys. ... An antibiotic is a drug that kills or slows the growth of bacteria. ...

An example of an inactivator being used as a drug is aspirin, which inhibits the COX-1 and COX-2 enzymes that produce the inflammation messenger prostaglandin, thus suppressing pain and inflammation. The poison cyanide is an irreversible enzyme inactivator that combines with the copper and iron in the active site of the enzyme cytochrome c oxidase and blocks cellular respiration.