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{{redirect|Biocatalyst|the use of natural catalysts in organic chemistry|Biocatalysis}}{{pp-vandalism|expiry=indef|small=yes}}{{pp-move-indef}}{{Use dmy dates|date=June 2015}}File:Glucosidase enzyme.png|thumb|400px|The enzyme glucosidase converts the sugar maltose to two glucose sugars. Active site residues in red, maltose substrate in black, and NAD cofactorcofactor{{Biochemistry sidebar}}Enzymes {{IPAc-en|ˈ|ɛ|n|z|aɪ|m|z}} are macromolecular biological catalysts. Enzymes accelerate chemical reactions. The molecules upon which enzymes may act are called substrates and 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.BOOK, Stryer L, Berg JM, Tymoczko JL, Biochemistry, W.H. Freeman, San Francisco, 2002, 5th, 0-7167-4955-6,weblink {{Open access}}{{rp|8.1}} Metabolic pathways depend upon enzymes to catalyze individual steps. The study of enzymes is called enzymology and a new field of pseudoenzyme analysis has recently grown up, recognising that during evolution, some enzymes have lost the ability to carry out biological catalysis, which is often reflected in their amino acid sequences and unusual 'pseudocatalytic' properties.JOURNAL, Murphy JM, Farhan H, Eyers PA, 2017, Bio-Zombie: the rise of pseudoenzymes in biology, Biochem Soc Trans, 45, 537–544, 10.1042/bst20160400, JOURNAL, Murphy JM, et al., A robust methodology to subclassify pseudokinases based on their nucleotide-binding properties, Biochemical Journal, 457, 2, 323–334, 2014, 24107129, 10.1042/BJ20131174, 5679212, Enzymes are known to catalyze more than 5,000 biochemical reaction types.JOURNAL, Schomburg I, Chang A, Placzek S, Söhngen C, Rother M, Lang M, Munaretto C, Ulas S, Stelzer M, Grote A, Scheer M, Schomburg D, BRENDA in 2013: integrated reactions, kinetic data, enzyme function data, improved disease classification: new options and contents in BRENDA, Nucleic Acids Research, 41, Database issue, D764–72, January 2013, 23203881, 3531171, 10.1093/nar/gks1049, Most enzymes are proteins, although a few are catalytic RNA molecules. The latter are called ribozymes. Enzymes' specificity comes from their unique three-dimensional structures.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 is orotidine 5'-phosphate decarboxylase, which allows a reaction that would otherwise take millions of years to occur in milliseconds.JOURNAL, Radzicka A, Wolfenden R, A proficient enzyme, Science, 267, 5194, 90–931, January 1995, 7809611, 10.1126/science.7809611, 1995Sci...267...90R, JOURNAL, Callahan BP, Miller BG, OMP decarboxylase—An enigma persists, Bioorganic Chemistry, 35, 6, 465–9, December 2007, 17889251, 10.1016/j.bioorg.2007.07.004, 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 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.

Etymology and history

missing image!
- Eduardbuchner.jpg -
alt=Photograph of Eduard Buchner.|Eduard Buchner
By the late 17th and early 18th centuries, the digestion of meat by stomach secretionsJOURNAL, de Réaumur RA, René Antoine Ferchault de Réaumur, 1752, Observations sur la digestion des oiseaux, Histoire de l'academie royale des sciences, 1752, 266, 461, and the conversion of starch to sugars by plant extracts and saliva were known but the mechanisms by which these occurred had not been identified.BOOK,weblink Williams, Henry Smith, A History of Science: in Five Volumes. Volume IV: Modern Development of the Chemical and Biological Sciences, Harper and Brothers, 1904, vanc, French chemist Anselme Payen was the first to discover an enzyme, diastase, in 1833.JOURNAL, Payen A, Persoz JF, 1833, Mémoire sur la diastase, les principaux produits de ses réactions et leurs applications aux arts industriels, French, Memoir on diastase, the principal products of its reactions, and their applications to the industrial arts, Annales de chimie et de physique, 2nd, 53,weblink 73–92, 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 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."JOURNAL, Manchester KL, Louis Pasteur (1822–1895)–chance and the prepared mind, Trends in Biotechnology, 13, 12, 511–5, December 1995, 8595136, 10.1016/S0167-7799(00)89014-9, In 1877, German physiologist Wilhelm Kühne (1837–1900) first used the term (wiktionary:enzyme|enzyme), which comes from Greek ἔνζυμον, "leavened" or "in yeast", to describe this process.Kühne coined the word "enzyme" in: JOURNAL, Kühne W, 1877,weblink German, Über das Verhalten verschiedener organisirter und sog. ungeformter Fermente, On the behavior of various organized and so-called unformed ferments, Verhandlungen des naturhistorisch-medicinischen Vereins zu Heidelberg, new series, 1, 3, 190–193, Relevant passage on page 190: "Um Missverständnissen vorzubeugen und lästige Umschreibungen zu vermeiden schlägt Vortragender vor, die ungeformten oder nicht organisirten Fermente, deren Wirkung ohne Anwesenheit von Organismen und ausserhalb derselben erfolgen kann, als Enzyme zu bezeichnen." (Translation: In order to obviate misunderstandings and avoid cumbersome periphrases, [the author, a university lecturer] suggests designating as "enzymes" the unformed or not organized ferments, whose action can occur without the presence of organisms and outside of the same.) The word enzyme 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.BOOK, John L., Heilbron, The Oxford Companion to the History of Modern Science, Frederic Lawrence, Holmes, Enzymes, 270,weblink Oxford University Press, Oxford, 2003, vanc, 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 the mixture.WEB,weblink Eduard Buchner, Nobel Laureate Biography, Nobelprize.org, 23 February 2015, He named the enzyme that brought about the fermentation of sucrose "zymase".WEB,weblink Eduard Buchner – Nobel Lecture: Cell-Free Fermentation, 1907, Nobelprize.org, 23 February 2015, 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 the type of reaction (e.g., DNA polymerase forms DNA polymers).The naming of enzymes by adding the suffix "-ase" to the substrate on which the enzyme acts, has been traced to French scientist Émile Duclaux (1840–1904), who intended to honor the discoverers of diastase – the first enzyme to be isolated – by introducing this practice in his book BOOK, Duclaux E, Traité de microbiologie: Diastases, toxines et venins, French, Microbiology Treatise: diastases, toxins and venoms, 1899, Masson and Co, Paris, France,weblink See Chapter 1, especially page 9.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.JOURNAL, Willstätter R, Faraday lecture. Problems and methods in enzyme research, Journal of the Chemical Society (Resumed), 1927, 1359, 10.1039/JR9270001359, quoted in JOURNAL, Blow D, So do we understand how enzymes work?, Structure, 8, 4, R77–R81, April 2000, 10801479, 10.1016/S0969-2126(00)00125-8,weblink pdf, In 1926, James B. Sumner showed that 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.WEB,weblink Nobel Prizes and Laureates: The Nobel Prize in Chemistry 1946, Nobelprize.org, 23 February 2015, The 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.JOURNAL, Blake CC, Koenig DF, Mair GA, North AC, Phillips DC, Sarma VR, Structure of hen egg-white lysozyme. A three-dimensional Fourier synthesis at 2 Ångström resolution, Nature, 206, 4986, 757–61, May 1965, 5891407, 10.1038/206757a0, 1965Natur.206..757B, 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.JOURNAL, Johnson LN, Petsko GA, David Phillips and the origin of structural enzymology, Trends Biochem. Sci., 24, 7, 287–9, 1999, 10390620, 10.1016/S0968-0004(99)01423-1,

Naming conventions

An enzyme's name is often derived from its substrate or the chemical reaction it catalyzes, with the word ending in -ase.{{rp|8.1.3}} Examples are lactase, alcohol dehydrogenase and DNA polymerase. Different enzymes that catalyze the same chemical reaction are called isozymes.{{rp|10.3}}The International Union of Biochemistry and Molecular Biology have developed a nomenclature for enzymes, the EC numbers; each enzyme is described by a sequence of four numbers preceded by "EC", which stands for "Enzyme Commission". The first number broadly classifies the enzyme based on its mechanism.WEB,weblink Classification and Nomenclature of Enzymes by the Reactions they Catalyse, Nomenclature Committee, International Union of Biochemistry and Molecular Biology (NC-IUBMB), School of Biological and Chemical Sciences, Queen Mary, University of London, 6 March 2015,weblink" title="web.archive.org/web/20150317054348weblink">weblink 17 March 2015, yes, dmy-all, The top-level classification is: These sections are subdivided by other features such as the substrate, products, and chemical mechanism. An enzyme 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).WEB, EC 2.7.1.1,weblink Nomenclature Committee, International Union of Biochemistry and Molecular Biology (NC-IUBMB), School of Biological and Chemical Sciences, Queen Mary, University of London, 6 March 2015,weblink" title="web.archive.org/web/20141201224835weblink">weblink 1 December 2014, yes, dmy-all,

Structure

File:Q10 graph c.svg|thumb|400px|Enzyme activity initially increases with temperature (Q10 coefficient) until the enzyme's structure unfolds (denaturation), leading to an optimal alt=A graph showing that reaction rate increases exponentially with temperature until denaturation causes it to decrease again.{{see also|Protein structure}}Enzymes are generally globular proteins, acting alone or in larger complexes. The sequence of the amino acids specifies the structure which in turn determines the catalytic activity of the enzyme.JOURNAL, Anfinsen CB, Principles that govern the folding of protein chains, Science, 181, 4096, 223–30, July 1973, 4124164, 10.1126/science.181.4096.223, 1973Sci...181..223A, Although structure determines function, a novel enzymatic activity cannot yet be predicted from structure alone.JOURNAL, Dunaway-Mariano D, Enzyme function discovery, Structure, 16, 11, 1599–600, November 2008, 19000810, 10.1016/j.str.2008.10.001, Enzyme structures unfold (denature) when heated or exposed to chemical denaturants and this disruption to the structure typically causes a loss of activity.BOOK, Petsko, Gregory A., Ringe, Dagmar, vanc, Protein structure and function, 2003, New Science, London, 978-1405119221, Chapter 1: From sequence to structure,weblink 27, Enzyme denaturation is normally linked to temperatures above 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,JOURNAL, Chen LH, Kenyon GL, Curtin F, Harayama S, Bembenek ME, Hajipour G, Whitman CP, 4-Oxalocrotonate tautomerase, an enzyme composed of 62 amino acid residues per monomer, The Journal of Biological Chemistry, 267, 25, 17716–21, September 1992, 1339435, to over 2,500 residues in the animal fatty acid synthase.JOURNAL, Smith S, The animal fatty acid synthase: one gene, one polypeptide, seven enzymes, FASEB Journal, 8, 15, 1248–59, December 1994, 8001737, 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 comprise the enzyme's active site. The remaining majority of the enzyme structure serves to maintain the precise orientation and dynamics of the active site.BOOK, Suzuki H, How Enzymes Work: From Structure to Function, CRC Press, Boca Raton, FL, 2015, 978-981-4463-92-8, Chapter 7: Active Site Structure, 117–140, 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.BOOK, Krauss G, Biochemistry of Signal Transduction and Regulation, 2003, Wiley-VCH, Weinheim, 9783527605767, 3rd, 89–114, The Regulations of Enzyme Activity,weblink 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 is the ribosome which is a complex of protein and catalytic RNA components.{{rp|2.2}}

Mechanism

File:Enzyme structure.svg|thumb|400px|Organisation of enzyme structure and lysozyme example. Binding sites in blue, catalytic site in red and 9LYZ}})|alt=Lysozyme displayed as an opaque globular surface with a pronounced cleft which the substrate depicted as a stick diagram snuggly fits into.

Substrate binding

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 the substrates. Enzymes can therefore distinguish between very similar substrate molecules to be chemoselective, regioselective and stereospecific.JOURNAL, Jaeger KE, Eggert T, Enantioselective biocatalysis optimized by directed evolution, Current Opinion in Biotechnology, 15, 4, 305–13, August 2004, 15358000, 10.1016/j.copbio.2004.06.007, 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 a first step and then checks that the product is correct in a second step.JOURNAL, Shevelev IV, Hübscher U, The 3' 5' exonucleases, Nature Reviews Molecular Cell Biology, 3, 5, 364–76, May 2002, 11988770, 10.1038/nrm804, This two-step process results in average error rates of less than 1 error in 100 million reactions in high-fidelity mammalian polymerases.{{rp|5.3.1}} Similar proofreading mechanisms are also found in RNA polymerase,JOURNAL, Zenkin N, Yuzenkova Y, Severinov K, Transcript-assisted transcriptional proofreading, Science, 313, 5786, 518–20, July 2006, 16873663, 10.1126/science.1127422, 2006Sci...313..518Z, aminoacyl tRNA synthetasesJOURNAL, Ibba M, Soll D, Aminoacyl-tRNA synthesis, Annual Review of Biochemistry, 69, 617–50, 10966471, 10.1146/annurev.biochem.69.1.617, 2000, and ribosomes.JOURNAL, Rodnina MV, Wintermeyer W, Fidelity of aminoacyl-tRNA selection on the ribosome: kinetic and structural mechanisms, Annual Review of Biochemistry, 70, 415–35, 11395413, 10.1146/annurev.biochem.70.1.415, 2001, Conversely, some enzymes display enzyme promiscuity, having broad specificity and acting on 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.JOURNAL, Khersonsky O, Tawfik DS, Enzyme promiscuity: a mechanistic and evolutionary perspective, Annual Review of Biochemistry, 79, 471–505, 20235827, 10.1146/annurev-biochem-030409-143718, 2010, JOURNAL, O'Brien PJ, Herschlag D, Catalytic promiscuity and the evolution of new enzymatic activities, Chemistry & Biology, 6, 4, R91–R105, April 1999, 10099128, 10.1016/S1074-5521(99)80033-7, File:Hexokinase induced fit.svg|alt=Hexokinase displayed as an opaque surface with a pronounced open binding cleft next to unbound substrate (top) and the same enzyme with more closed cleft that surrounds the bound substrate (bottom)|thumb|400px|Enzyme changes shape by induced fit upon substrate binding to form enzyme-substrate complex. Hexokinase has a large induced fit motion that closes over the substrates adenosine triphosphate and xylose. Binding sites in blue, substrates in black and Mg2+Mg2+

"Lock and key" model

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.JOURNAL, Fischer E, 1894, Einfluss der Configuration auf die Wirkung der Enzyme, German, Influence of configuration on the action of enzymes, Berichte der Deutschen chemischen Gesellschaft zu Berlin, 27, 3, 2985–93,weblink 10.1002/cber.18940270364, From page 2992: "Um ein Bild zu gebrauchen, will ich sagen, dass Enzym und Glucosid wie Schloss und Schlüssel zu einander passen müssen, um eine chemische Wirkung auf einander ausüben zu können." (To use an image, I will say that an enzyme and a glucoside [i.e., glucose derivative] must fit like a lock and key, in order to be able to exert a chemical effect on each other.) This is often referred to as "the lock and key" model.{{rp|8.3.2}} This early model explains enzyme specificity, but fails to explain the stabilization of the transition state that enzymes achieve.BOOK, Cooper GM, The Cell: a Molecular Approach, 2000, ASM Press, Washington (DC ), 0-87893-106-6, 2nd, Chapter 2.2: The Central Role of Enzymes as Biological Catalysts,weblink

Induced fit model

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 the enzyme.JOURNAL, Koshland DE, Application of a Theory of Enzyme Specificity to Protein Synthesis, Proceedings of the National Academy of Sciences of the United States of America, 44, 2, 98–104, February 1958, 16590179, 335371, 10.1073/pnas.44.2.98, 1958PNAS...44...98K, 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.JOURNAL, Vasella A, Davies GJ, Böhm M, Glycosidase mechanisms, Current Opinion in Chemical Biology, 6, 5, 619–29, October 2002, 12413546, 10.1016/S1367-5931(02)00380-0, The active site continues to change until the substrate is completely bound, at which point the final shape and charge distribution is determined.BOOK, Boyer, Rodney, Concepts in Biochemistry, 2nd, John Wiley & Sons, Inc., New York, Chichester, Weinheim, Brisbane, Singapore, Toronto., 0-470-00379-0, 137–8, Chapter 6: Enzymes I, Reactions, Kinetics, and Inhibition, 2002, 51720783, vanc, Induced fit may enhance the fidelity of molecular recognition in the presence of competition and noise via the conformational proofreading mechanism.JOURNAL, Savir Y, Tlusty T, Conformational proofreading: the impact of conformational changes on the specificity of molecular recognition, PLoS ONE, 2, 5, e468, 2007, 17520027, 1868595, 10.1371/journal.pone.0000468,weblink Scalas, Enrico, vanc, 2007PLoSO...2..468S,

Catalysis

{{See also|Enzyme catalysis|Transition state theory}}Enzymes can accelerate reactions in several ways, all of which lower the activation energy (ΔG‡, Gibbs free energy)BOOK, Fersht A, Enzyme Structure and Mechanism, W.H. Freeman, San Francisco, 1985, 50–2, 978-0-7167-1615-0,
  1. By stabilizing the transition state:
    • Creating an environment with a charge distribution complementary to that of the transition state to lower its energyJOURNAL, Warshel A, Sharma PK, Kato M, Xiang Y, Liu H, Olsson MH, Electrostatic basis for enzyme catalysis, Chemical Reviews, 106, 8, 3210–35, August 2006, 16895325, 10.1021/cr0503106,
  2. By providing an alternative reaction pathway:
    • Temporarily reacting with the substrate, forming a covalent intermediate to provide a lower energy transition stateBOOK, Cox, Michael M., Nelson, David L., vanc, Lehninger Principles of Biochemistry, 2013, W.H. Freeman, New York, N.Y., 978-1464109621, 6th, Chapter 6.2: How enzymes work, 195,weblink
  3. By destabilising the substrate ground state:
    • Distorting bound substrate(s) into their transition state form to reduce the energy required to reach the transition stateJOURNAL, Benkovic SJ, Hammes-Schiffer S, A perspective on enzyme catalysis, Science, 301, 5637, 1196–202, August 2003, 12947189, 10.1126/science.1085515, 2003Sci...301.1196B,
    • By orienting the substrates into a productive arrangement to reduce the reaction entropy changeBOOK, Jencks WP, Catalysis in Chemistry and Enzymology, Dover, Mineola, N.Y, 1987, 978-0-486-65460-7, (the contribution of this mechanism to catalysis is relatively small)JOURNAL, Villa J, Strajbl M, Glennon TM, Sham YY, Chu ZT, Warshel A, How important are entropic contributions to enzyme catalysis?, Proceedings of the National Academy of Sciences of the United States of America, 97, 22, 11899–904, October 2000, 11050223, 17266, 10.1073/pnas.97.22.11899, 2000PNAS...9711899V,
Enzymes may use several of these mechanisms simultaneously. For example, proteases such as trypsin perform covalent catalysis using a catalytic triad, stabilise charge build-up on the transition states using an oxyanion hole, complete hydrolysis using an oriented water substrate.JOURNAL, Polgár, L., 2005-07-07, The catalytic triad of serine peptidases, Cellular and Molecular Life Sciences, en, 62, 19–20, 2161–2172, 10.1007/s00018-005-5160-x, 16003488, 1420-682X,

Dynamics

{{See also|Protein dynamics}}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 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.JOURNAL, Ramanathan A, Savol A, Burger V, Chennubhotla CS, Agarwal PK, Protein conformational populations and functionally relevant substates, Acc. Chem. Res., 47, 1, 149–56, 2014, 23988159, 10.1021/ar400084s,

Allosteric modulation

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 the reaction rate of the enzyme.JOURNAL, Tsai CJ, Del Sol A, Nussinov R, Protein allostery, signal transmission and dynamics: a classification scheme of allosteric mechanisms, Mol Biosyst, 5, 3, 207–16, 2009, 19225609, 2898650, 10.1039/b819720b,weblink 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.JOURNAL, Changeux JP, Edelstein SJ, Allosteric mechanisms of signal transduction, Science, 308, 5727, 1424–8, June 2005, 15933191, 10.1126/science.1108595, 2005Sci...308.1424C,

Cofactors

File:Transketolase + TPP.png|thumb|400px|alt=Thiamine pyrophosphate displayed as an opaque globular surface with an open binding cleft where the substrate and cofactor both depicted as stick diagrams fit into.|Chemical structure for thiamine pyrophosphate and protein structure of transketolase. Thiamine pyrophosphate cofactor in yellow and 4KXV}})Some enzymes do not need additional components to show full activity. Others require non-protein molecules called cofactors to be bound for activity.WEB,weblink Glossary of Terms Used in Bioinorganic Chemistry: Cofactor, 30 October 2007, de Bolster, M.W.G., 1997, International Union of Pure and Applied Chemistry, vanc,weblink" title="web.archive.org/web/20170121172848weblink">weblink 21 January 2017, yes, dmy-all, 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 the active site.BOOK, Fundamentals of Biochemistry, Voet, Donald, Voet, Judith, Pratt, Charlotte, vanc, John Wiley & Sons, Inc., 2016, 978-1-118-91840-1, Hoboken, New Jersey, 336, 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).JOURNAL, Chapman-Smith A, Cronan JE, The enzymatic biotinylation of proteins: a post-translational modification of exceptional specificity, Trends Biochem. Sci., 24, 9, 359–63, 1999, 10470036, 10.1016/s0968-0004(99)01438-3, An example of an enzyme that contains a cofactor is carbonic anhydrase, which is shown in the ribbon diagram above with a zinc cofactor bound as part of its active site.JOURNAL, Fisher Z, Hernandez Prada JA, Tu C, Duda D, Yoshioka C, An H, Govindasamy L, Silverman DN, McKenna R, Structural and kinetic characterization of active-site histidine as a proton shuttle in catalysis by human carbonic anhydrase II, Biochemistry, 44, 4, 1097–115, February 2005, 15667203, 10.1021/bi0480279, These tightly bound ions or molecules are usually found in the active site and are involved in catalysis.{{rp|8.1.1}} For example, flavin and heme cofactors are often involved in redox reactions.{{rp|17}}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 the DNA polymerases; here the holoenzyme is the complete complex containing all the subunits needed for activity.{{rp|8.1.1}}

Coenzymes

Coenzymes are small organic molecules that can be loosely or tightly bound to an enzyme. Coenzymes transport chemical groups from one enzyme to another.BOOK, Wagner AL, Vitamins and Coenzymes, Krieger Pub Co, 1975, 0-88275-258-8, 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 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.WEB,weblink BRENDA The Comprehensive Enzyme Information System, Technische Universität Braunschweig, 23 February 2015, Coenzymes are usually continuously 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. 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.JOURNAL, Törnroth-Horsefield S, Neutze R, Opening and closing the metabolite gate, Proceedings of the National Academy of Sciences of the United States of America, 105, 50, 19565–6, December 2008, 19073922, 2604989, 10.1073/pnas.0810654106, 2008PNAS..10519565T,

Thermodynamics

File:Enzyme catalysis energy levels 2.svg|thumb|400px|alt=A two dimensional plot of reaction coordinate (x-axis) vs. energy (y-axis) for catalyzed and uncatalyzed reactions. The energy of the system steadily increases from reactants (x = 0) until a maximum is reached at the transition state (x = 0.5), and steadily decreases to the products (x = 1). However, in an enzyme catalysed reaction, binding generates an enzyme-substrate complex (with slightly reduced energy) then increases up to a transition state with a smaller maximum than the uncatalysed reaction.|The energies of the stages of a chemical reaction. Uncatalysed (dashed line), substrates need a lot of activation energy to reach a transition statetransition stateAs with all catalysts, enzymes do not alter the position of 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.{{rp|8.2.3}} For example, carbonic anhydrase catalyzes its reaction in either direction depending on the concentration of its reactants:BOOK, McArdle WD, Katch F, Katch VL, Essentials of Exercise Physiology, 2006, Lippincott Williams & Wilkins, Baltimore, Maryland, 978-0781749916, 312–3, 3rd, Chapter 9: The Pulmonary System and Exercise,weblink {{NumBlk|:| CO2{} + H2O ->[text{Carbonic anhydrase}] H2CO3 (in tissues; high CO2 concentration)|{{EquationRef|1}}}}{{NumBlk|:| CO2{} + H2O

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