Adenosine triphosphate 1800 224471107 2008-07-09T00:01:09Z Bobo192 97951 Reverted edits by [[Special:Contributions/136.166.2.173|136.166.2.173]] ([[User talk:136.166.2.173|talk]]) to last version by DOI bot {{Chembox new | Name = Adenosine triphosphate | ImageFile = ATP structure.svg | ImageFile1 = ATP-xtal-3D-sticks.png | IUPACName = 5-(6-aminopurin-9-yl)<br />-3,4-dihydroxy-oxolan-2-yl<br />methoxy-hydroxy-phosphoryl<br />oxy-hydroxy-phosphoryl oxyphosphonic acid | Section1 = {{Chembox Identifiers | CASNo = 56-65-5 }} | Section2 = {{Chembox Properties | Formula = C<sub>10</sub>H<sub>16</sub>N<sub>5</sub>O<sub>13</sub>P<sub>3</sub> | MolarMass = 507.181 g/mol | MeltingPt = | Density = | pKa = 6.5 }} }} '''Adenosine-5'-triphosphate''' ('''ATP''') is a multifunctional [[nucleotide]] that is most important as a "[[molecule|molecular]] currency" of intracellular [[energy]] transfer.<ref>{{cite journal |author=Knowles JR |title=Enzyme-catalyzed phosphoryl transfer reactions |journal=Annu. Rev. Biochem. |volume=49 |issue= |pages=877–919 |year=1980 |pmid=6250450 | doi=10.1146/annurev.bi.49.070180.004305}}</ref> In this role, ATP transports chemical energy within [[cell (biology)|cells]] for [[metabolism]]. It is produced as an energy source during the processes of [[photosynthesis]] and [[cellular respiration]] and consumed by many [[enzyme]]s and a multitude of cellular processes including [[biosynthesis|biosynthetic reactions]], [[motility]] and [[cell division]]. In [[signal transduction]] pathways, ATP is used as a [[Substrate (biochemistry)|substrate]] by [[kinase]]s that [[phosphorylation|phosphorylate]] [[protein]]s and [[lipid]]s, as well as by [[adenylate cyclase]], which uses ATP to produce the [[second messenger]] molecule [[cyclic adenosine monophosphate|cyclic AMP]]. The structure of this molecule consists of a [[purine]] base ([[adenine]]) attached to the 1' carbon atom of a [[pentose]] sugar ([[ribose]]). Three phosphate groups are attached at the 5' carbon atom of the pentose sugar. ATP is also incorporated into [[nucleic acid]]s by [[polymerase]]s in the processes of [[DNA replication]] and [[transcription (genetics)|transcription]]. When ATP is used in DNA synthesis, the ribose sugar is first converted to [[deoxyribose]] by [[ribonucleotide reductase]]. ATP was discovered in 1929 by Karl Lohmann,<ref>Lohmann, K. (1929) ''Über die Pyrophosphatfraktion im Muskel.'' Naturwissenschaften 17, 624–625.</ref> and was proposed to be the main energy-transfer molecule in the cell by [[Fritz Albert Lipmann]] in 1941.<ref>Lipmann F. (1941) ''Adv. Enzymol.'' 1, 99–162.</ref> ==Physical and chemical properties== ATP consists of [[adenosine]] — itself composed of an [[adenine]] ring and a [[ribose]] sugar — and three [[phosphate]] groups (triphosphate). The phosphoryl groups, starting with the group closest to the ribose, are referred to as the alpha (α), beta (β), and gamma (γ) phosphates. ATP is highly soluble in water and is quite stable in solutions between pH&nbsp;6.8–7.4, but is rapidly [[hydrolysis|hydrolysed]] at extreme pH. Consequently, ATP is best stored as an anhydrous salt.<ref>{{cite book| author=Stecher P.G., ed. | date=1968 | title=The Merck Index: an encyclopedia of chemicals and drugs 8th edition |publisher= Merck and Co. Ltd.}}</ref> ATP is an unstable molecule and tends to be hydrolysed in water. If ATP and [[adenosine diphosphate|ADP]] are in [[chemical equilibrium]], almost all the ATP will be converted to ADP. Any system that is far from equilibrium contains [[potential energy]], and is capable of doing [[work (thermodynamics)|work]]. Biological cells maintain the ratio of ATP to ADP at a point ten orders of magnitude from equilibrium, with ATP concentrations a thousandfold higher than the concentration of ADP. This displacement from equilibrium means that the hydrolysis of ATP in the cell releases a great amount of energy.<ref name=Nicholls>Nicholls D.G. and Ferguson S.J. (2002) ''Bioenergetics'' Academic press 3rd edition ISBN 0-125-18121-3</ref> ATP is commonly referred to as a "high energy molecule"; however this is incorrect, as a mixture of ATP and ADP at equilibrium in water can do no useful work at all.<ref name=Nicholls/> ATP does not contain "high-energy bonds", and any other unstable molecule would serve as a way of storing energy, if the cell maintained its concentration far from equilibrium.<ref name=Nicholls/> The amount of energy released can be calculated from the changes in energy under non-natural conditions. The net change in heat energy ([[enthalpy]]) at [[Standard conditions for temperature and pressure|standard temperature and pressure]] of the decomposition of ATP into hydrated [[Adenosine diphosphate|ADP]] and hydrated inorganic phosphate is −20.5&nbsp;[[joule per mole|kJ/mol]], with a change in [[Thermodynamic free energy|free energy]] of 3.4&nbsp;kJ/mol.<ref>{{cite journal | author = Gajewski E, Steckler D, Goldberg R | title = Thermodynamics of the hydrolysis of adenosine 5'-triphosphate to adenosine 5'-diphosphate | url=http://www.jbc.org/cgi/reprint/261/27/12733.pdf | journal = J Biol Chem | volume = 261 | issue = 27 | pages = 12733–7 | year = 1986 | pmid = 3528161}}</ref> The energy released by cleaving either a phosphate (Pi) or pyrophosphate (PPi) unit from ATP, with all reactants and products at their [[standard state]]s of 1&nbsp;M concentration, are: :ATP + H<sub>2</sub>O → ADP(hydrated) + Pi(hydrated) + H<sup>+</sup>(hydrated) ΔG˚ = -30.54&nbsp;kJ/mol (−7.3&nbsp;kcal/mol) :ATP + H<sub>2</sub>O → AMP(hydrated) + PPi(hydrated) + H<sup>+</sup>(hydrated) ΔG˚ = -45.6&nbsp;kJ/mol (−10.9&nbsp;kcal/mol) These values can be used to calculate the change in energy under physiological conditions and the cellular ATP/ADP ratio. The values given for the [[Gibbs free energy]] for this reaction are dependent on a number of factors, including overall ionic strength and the presence of [[alkaline earth metal]] ions such as Mg<sup>2+</sup> and Ca<sup>2+</sup>. Under typical cellular conditions, ΔG is approximately −57&nbsp;kJ/mol (−14&nbsp;kcal/mol).<ref>{{cite book | author=Stryer, Lubert | title=Biochemistry, fifth edition | location=New York | publisher=W.H. Freeman and Company | year=2002 | id=ISBN 0-7167-1843-X}}</ref> ===Ionization in biological systems=== ATP has multiple ionizable groups with different [[acid dissociation constant]]s. In neutral solution, ATP is ionized and exists mostly as ATP<sup>4−</sup>, with a small proportion of ATP<sup>3−</sup>.<ref name=Storer>{{cite journal | author = Storer A, Cornish-Bowden A | title = Concentration of MgATP2− and other ions in solution. Calculation of the true concentrations of species present in mixtures of associating ions | url=http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1164030&blobtype=pdf | journal = Biochem J | volume = 159 | issue = 1 | pages = 1–5 | year = 1976 | pmid = 11772}}</ref> As ATP has several negatively-charged groups in neutral solution, it can [[chelation|chelate]] metals with very high affinity. The [[binding constant]] for various metal ions are (given as per mole) as [[magnesium|Mg<sup>2+</sup>]] (9 554), [[sodium|Na<sup>+</sup>]] (13), [[calcium|Ca<sup>2+</sup>]] (3 722), [[potassium|K<sup>+</sup>]] (8), [[strontium|Sr<sup>2+</sup>]] (1 381) and [[lithium|Li<sup>+</sup>]] (25).<ref>{{cite journal | author = Wilson J, Chin A | title = Chelation of divalent cations by ATP, studied by titration calorimetry | journal = Anal Biochem | volume = 193 | issue = 1 | pages = 16–9 | year = 1991 | pmid = 1645933| doi=10.1016/0003-2697(91)90036-S}}</ref> Due to the strength of these interactions, ATP exists in the cell mostly in a complex with Mg<sup>2+</sup>.<ref>{{cite journal | author = Garfinkel L, Altschuld R, Garfinkel D | title = Magnesium in cardiac energy metabolism | journal = J Mol Cell Cardiol | volume = 18 | issue = 10 | pages = 1003–13 | year = 1986 | pmid = 3537318 | doi = 10.1016/S0022-2828(86)80289-9 }}</ref><ref name=Storer/> ==Biosynthesis== The ATP [[concentration]] inside the cell is typically 1–10 [[molarity|mM]].<ref>{{cite journal| author = Beis I., and Newsholme E. A. | date=1975 | title= The contents of adenine nucleotides, phosphagens and some glycolytic intermediates in resting muscles from vertebrates and invertebrates | journal= Biochem J | volume=152 | pages= 23–32 | pmid=1212224 |url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1172435}} </ref> ATP can be produced by [[redox]] reactions using simple and complex [[sugars]] ([[carbohydrates]]) or [[lipids]] as an energy source. For ATP to be synthesized from complex fuels, they first need to be broken down into their basic components. Carbohydrates are [[hydrolysis|hydrolysed]] into simple sugars, such as [[glucose]] and [[fructose]]. Fats ([[triglyceride]]s) are metabolised to give [[fatty acids]] and [[glycerol]]. The overall process of oxidizing glucose to [[carbon dioxide]] is known as [[cellular respiration]] and can produce up to 36 molecules of ATP from a single molecule of glucose.<ref name="Lodish">{{cite book | author=Lodish, H, Berk A, Matsudaira P, Kaiser CA, Krieger M, Scott MP, Zipursky SL, Darnell J. |date-2004 | title=Molecular Cell Biology, 5th ed.| publisher= New York: WH Freeman|isbn = 9780716743668}}</ref> ATP can be produced by a number of distinct cellular processes; the three main pathways used to generate energy in [[eukaryote|eukaryotic]] organisms are [[glycolysis]] and the [[citric acid cycle]]/[[oxidative phosphorylation]], both components of [[cellular respiration]]; and [[beta-oxidation]]. The majority of this ATP production by a non-[[photosynthetic]] aerobic eukaryote takes place in the [[mitochondria]], which can make up nearly 25% of the total volume of a typical cell.<ref name="Lodish" /> ===Glycolysis=== {{main|glycolysis}} In glycolysis, glucose and glycerol are metabolized to [[pyruvate]] via the glycolytic pathway. In most organisms this process occurs in the [[cytosol]], but in some protozoa such as the [[kinetoplastid]]s, this is carried out in a specialized [[organelle]] called the [[glycosome]].<ref>{{cite journal | author = Parsons M | title = Glycosomes: parasites and the divergence of peroxisomal purpose | journal = Mol Microbiol | volume = 53 | issue = 3 | pages = 717–24 | year = 2004 | pmid = 15255886 | doi=10.1111/j.1365-2958.2004.04203.x }}</ref> Glycolysis generates a net two molecules of ATP through [[substrate-level phosphorylation|substrate phosphorylation]] catalyzed by two enzymes: [[Phosphoglycerate kinase|PGK]] and [[pyruvate kinase]]. Two molecules of [[NADH]] are also produced, which can be oxidized via the [[electron transport chain]] and result in the generation of additional ATP by [[ATP synthase]]. The pyruvate generated as an end-product of glycolysis is a substrate for the [[Krebs Cycle]]. ===Citric acid cycle=== {{main|Citric acid cycle|oxidative phosphorylation}} In the [[mitochondrion]], pyruvate is oxidized by the [[pyruvate dehydrogenase complex]] to [[acetyl CoA]], which is fully oxidized to carbon dioxide by the citric acid cycle (also known as the Krebs Cycle). Every "turn" of the citric acid cycle produces two molecules of [[carbon dioxide]], one molecule of the ATP equivalent [[guanosine triphosphate]] (GTP) through [[substrate-level phosphorylation]] catalyzed by [[succinyl CoA synthetase]], three molecules of the reduced [[coenzyme]] [[NADH]], and one molecule of the reduced coenzyme [[flavin|FADH<sub>2</sub>]]. Both of these latter molecules are recycled to their oxidized states (NAD<sup>+</sup> and [[FAD]], respectively) via the [[electron transport chain]], which generates additional ATP by [[oxidative phosphorylation]]. The oxidation of an NADH molecule results in the synthesis of about 3 ATP molecules, and the oxidation of one FADH<sub>2</sub> yields about 2 ATP molecules.<ref name="Voet">{{cite book | author=Voet D, Voet JG. | date=2004 | title=Biochemistry Vol 1 3rd ed. | publisher= Wiley: Hoboken, NJ. | isbn = 978-0-471-19350-0}}</ref> The majority of cellular ATP is generated by this process. Although the citric acid cycle itself does not involve molecular [[oxygen]], it is an obligately [[aerobic glycolysis|aerobic]] process because O<sub>2</sub> is needed to recycle the reduced NADH and FADH<sub>2</sub> to their oxidized states. In the absence of oxygen the citric acid cycle will cease to function due to the lack of available NAD<sup>+</sup> and FAD.<ref name="Lodish" /> The generation of ATP by the mitochondrion from cytosolic NADH relies on the [[malate-aspartate shuttle]] (and to a lesser extent, the [[glycerol-phosphate shuttle]]) because the inner mitochondrial membrane is impermeable to NADH and NAD<sup>+</sup>. Instead of transferring the generated NADH, a [[malate dehydrogenase]] enzyme converts [[oxaloacetate]] to [[malate]], which is translocated to the mitochondrial matrix. Another malate dehydrogenase-catalyzed reaction occurs in the opposite direction, producing oxaloacetate and NADH from the newly transported malate and the mitochondrion's interior store of NAD<sup>+</sup>. A [[transaminase]] converts the oxaloacetate to [[aspartate]] for transport back across the membrane and into the intermembrane space.<ref name="Lodish" /><!--will put the antiporter/full cycle in the shuttle article--> In oxidative phosphorylation, the passage of electrons from NADH and FADH<sub>2</sub> through the electron transport chain powers the pumping of [[proton]]s out of the mitochondrial matrix and into the intermembrane space. This creates a [[proton motive force]] that is the net effect of a [[pH]] gradient and an [[electric potential]] gradient across the inner mitochondrial membrane. Flow of protons down this potential gradient — that is, from the intermembrane space to the matrix — provides the driving force for ATP synthesis by [[ATP synthase]]. This [[enzyme]] contains a rotor subunit that physically rotates relative to the static portions of the protein during ATP synthesis.<ref>{{cite journal | author = Abrahams J, Leslie A, Lutter R, Walker J | title = Structure at 2.8 A resolution of F1-ATPase from bovine heart mitochondria | journal = Nature | volume = 370 | issue = 6491 | pages = 621–8 | year = 1994 |pmid=8065448 | doi = 10.1038/370621a0 }}</ref> Most of the ATP synthesized in the mitochondria will be used for cellular processes in the cytosol; thus it must be exported from its site of synthesis in the mitochondrial matrix. The inner membrane contains an [[antiporter]], the ADP/ATP translocase, which is an [[integral membrane protein]] used to exchange newly-synthesized ATP in the matrix for ADP in the intermembrane space.<ref name=Brandolin>{{cite journal | author = Dahout-Gonzalez C, Nury H, Trézéguet V, Lauquin G, Pebay-Peyroula E, Brandolin G | title = Molecular, functional, and pathological aspects of the mitochondrial ADP/ATP carrier | journal = Physiology (Bethesda) | volume = 21 | issue = | pages = 242–9 | year = 2006| pmid = 16868313 | doi=10.1152/physiol.00005.2006 | url=http://physiologyonline.physiology.org/cgi/content/full/21/4/242 }}</ref> This translocase is driven by the membrane potential, as it results in the movement of about 4 negative charges out of the mitochondrial membrane in exchange for 3 negative charges moved inside. However, it is also necessary to transport phosphate into the mitochondrion; the phosphate carrier moves a proton in with each phosphate, partially dissipating the proton gradient. ===Beta-oxidation=== {{main|beta-oxidation}} Fatty acids can also be broken down to [[acetyl-CoA]] by [[beta-oxidation]]. Each round of this cycle reduces the length of the acyl chain by two carbon atoms and produces one NADH and one FADH<sub>2</sub> molecule, which are used to generate ATP by oxidative phosphorylation. Because NADH and FADH<sub>2</sub> are energy-rich molecules, dozens of ATP molecules can be generated by the beta-oxidation of a single long acyl chain. The high energy yield of this process and the compact storage of fat explain why it is the most dense source of dietary [[calorie]]s.<ref>{{cite journal | author = Ronnett G, Kim E, Landree L, Tu Y | title = Fatty acid metabolism as a target for obesity treatment | journal = Physiol Behav | volume = 85 | issue = 1 | pages = 25–35 | year = 2005 | pmid = 15878185 | doi=10.1016/j.physbeh.2005.04.014 }}</ref> ===Anaerobic respiration=== {{main|anaerobic respiration}} Anaerobic respiration or [[fermentation (biochemistry)|fermentation]] entails the generation of energy via the process of [[oxidation]] in the absence of [[oxygen|O<sub>2</sub>]] as an [[electron acceptor]]. In most eukaryotes, glucose is used as both an energy store and an electron donor. The equation for the oxidation of glucose to [[lactic acid]] is: : C<sub>6</sub>H<sub>12</sub>O<sub>6</sub><math>\to</math> 2CH<sub>3</sub>CH(OH)COOH + 2 ATP In prokaryotes, multiple electron acceptors can be used in anaerobic respiration. These include [[nitrate]], [[sulfate]] or carbon dioxide. These processes lead to the ecologically-important processes of [[denitrification]], sulfate reduction and [[acetogenesis]], respectively.<ref>{{cite journal | author = Zumft W | title = Cell biology and molecular basis of denitrification | url=http://mmbr.asm.org/cgi/reprint/61/4/533?view=long&pmid=9409151 | journal = Microbiol Mol Biol Rev | volume = 61 | issue = 4 | pages = 533 – 616 | year = 1997 | pmid = 9409151}}</ref><ref>{{cite journal | author = Drake H, Daniel S, Küsel K, Matthies C, Kuhner C, Braus-Stromeyer S | title = Acetogenic bacteria: what are the in situ consequences of their diverse metabolic versatilities? | journal = Biofactors | volume = 6 | issue = 1 | pages = 13 – 24 | year = 1997 | pmid = 9233536}}</ref> ===ATP replenishment by nucleoside diphosphate kinases=== ATP can also be synthesized through several so-called "replenishment" reactions catalyzed by the enzyme families of [[nucleoside diphosphate kinase]]s (NDKs), which use other nucleoside triphosphates as a high-energy phosphate donor, and the ATP:guanido-phosphotransferase family, which uses [[creatine]]. :[[adenosine diphosphate|ADP]] + [[guanosine triphosphate|GTP]]<math>\to</math> ATP + [[guanosine diphosphate|GDP]] ===ATP production during photosynthesis=== In plants, ATP is synthesized in [[thylakoid membrane]] of the [[chloroplast]] during the [[light-dependent reaction]]s of [[photosynthesis]] in a process called photophosphorylation. Here, light energy is used to pump protons across the chloroplast membrane. This produces a proton-motive force and this drives the ATP synthase, exactly as in oxidative phosphorylation.<ref>{{cite journal | author = Allen J | title = Photosynthesis of ATP-electrons, proton pumps, rotors, and poise | journal = Cell | volume = 110 | issue = 3 | pages = 273–6 | year = 2002 | pmid = 12176312 | doi = 10.1016/S0092-8674(02)00870-X }}</ref> Some of the ATP produced in the chloroplasts is consumed in the [[Calvin cycle]], which produces [[triose]] sugars. ===ATP recycling=== The total quantity of ATP in the human body is about 0.1&nbsp;[[Mole (unit)|mole]]. The majority of ATP is not usually synthesised ''de novo'', but is generated from ADP by the aforementioned processes. Thus, at any given time, the total amount of ATP + ADP remains fairly constant. The energy used by human cells requires the [[hydrolysis]] of 100 to 150&nbsp;moles of ATP daily which is around 50 to 75&nbsp;kg. Typically, a human will use up their body weight of ATP over the course of the day.<ref name="Di Carlo">{{cite journal | author=Di Carlo, S. E. and Coliins, H. L. | date=2001 | journal= Advan. Physiol. Edu. | volume = 25 | pages= 70–71 | title= Submitting illuminations for review | url= http://advan.physiology.org/cgi/content/full/25/2/70}}</ref> This means that each ATP molecule is recycled 1000 to 1500 times during a single day (100 / 0.1 = 1000). ATP cannot be stored, hence its consumption closely follows its synthesis. ==Regulation of biosynthesis== ATP production in an aerobic eukaryotic cell is tightly regulated by [[allosteric]] mechanisms, by [[feedback]] effects, and by the substrate concentration dependence of individual enzymes within the glycolysis and oxidative phosphorylation pathways. Key control points occur in enzymatic reactions that are so energetically favorable that they are effectively irreversible under physiological conditions. In glycolysis, [[hexokinase]] is directly inhibited by its product, glucose-6-phosphate, and [[pyruvate kinase]] is inhibited by ATP itself. The main control point for the glycolytic pathway is [[phosphofructokinase]] (PFK), which is allosterically inhibited by high concentrations of ATP and activated by high concentrations of AMP. The inhibition of PFK by ATP is unusual, since ATP is also a substrate in the reaction catalyzed by PFK; the biologically active form of the enzyme is a [[tetramer]] that exists in two possible conformations, only one of which binds the second substrate fructose-6-phosphate (F6P). The protein has two [[binding site]]s for ATP - the [[active site]] is accessible in either protein conformation, but ATP binding to the inhibitor site stabilizes the conformation that binds F6P poorly.<ref name="Voet" /> A number of other small molecules can compensate for the ATP-induced shift in equilibrium conformation and reactivate PFK, including [[cyclic AMP]], [[ammonium]] ions, inorganic phosphate, and fructose 1,6 and 2,6 biphosphate.<ref name="Voet" /> The citric acid cycle is regulated mainly by the availability of key substrates, particularly the ratio of NAD<sup>+</sup> to NADH and the concentrations of [[calcium]], inorganic phosphate, ATP, ADP, and AMP. [[Citrate]] - the molecule that gives its name to the cycle - is a feedback inhibitor of [[citrate synthase]] and also inhibits PFK, providing a direct link between the regulation of the citric acid cycle and glycolysis.<ref name="Voet" /> In oxidative phosphorylation, the key control point is the reaction catalyzed by [[cytochrome c oxidase]], which is regulated by the availability of its substrate—the reduced form of [[cytochrome c]]. The amount of reduced cytochrome c available is directly related to the amounts of other substrates: :<math> \frac{1}{2}NADH + cyt~c_{ox} + ADP + P_{i} \iff \frac{1}{2}NAD^{+} + cyt~c_{red} + ATP </math> which directly implies this equation: :<math> \frac{cyt~c_{red}}{cyt~c_{ox}} = \left(\frac{[NADH]}{[NAD]^{+}}\right)^{\frac{1}{2}}\left(\frac{[ADP] [P {i}]}{[ATP]}\right)K_{eq} </math> Thus, a high ratio of [NADH] to [NAD<sup>+</sup>] or a low ratio of [ADP] [P<sub>i</sub>] to [ATP] imply a high amount of reduced cytochrome c and a high level of cytochrome c oxidase activity.<ref name="Voet" /> An additional level of regulation is introduced by the transport rates of ATP and NADH between the mitochondrial matrix and the cytoplasm.<ref name=Brandolin/> ==Functions in cells== ATP is generated in the cell by energy-consuming processes and is broken down by energy-releasing processes. In this way ATP transfers energy between spatially-separate [[metabolism|metabolic reactions]]. ATP is the main energy source for the majority of cellular functions. This includes the synthesis of macromolecules, including [[DNA replication|DNA]], [[Transcription (genetics)|RNA]], and [[Translation (genetics)|proteins]]. ATP also plays a critical role in the transport of macromolecules across cell membranes, e.g. [[exocytosis]] and [[endocytosis]]. In the synthesis of the [[nucleic acid]] [[RNA]], ATP is one of the four nucleotides incorporated directly into RNA molecules by [[RNA polymerase]]s. The energy driving this polymerization comes from cleaving off a pyrophosphate (two phosphate groups).<ref>{{cite journal |author=Joyce CM, Steitz TA |title=Polymerase structures and function: variations on a theme? |journal=J. Bacteriol. |volume=177 |issue=22 |pages=6321–9 |year=1995 |pmid=7592405 |url=http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=177480&blobtype=pdf}}</ref> The process is similar in DNA biosynthesis, except that ATP is reduced to the [[deoxyribonucleotide]] dATP, before incorporation into DNA. ATP is critically involved in maintaining cell structure by facilitating assembly and disassembly of elements of the [[cytoskeleton]]. In a related process, ATP is required for the [[Sliding filament mechanism|shortening of actin and myosin filament crossbridges]] required for [[muscle contraction]]. This latter process is one of the main energy requirements of animals and is essential for [[Animal locomotion|locomotion]] and [[Respiratory system|respiration]]. ===Cell signaling=== ====Extracellular signaling==== ATP is also a [[signaling molecule]]. ATP, ADP, or adenosine are recognized by [[purinergic receptors]]. In humans, this signaling role is important in both the central and peripheral nervous system. Activity-dependent release of ATP from synapses, axons and glia activates purinergic membrane receptors known as P2.<ref>{{cite journal | author=Fields, R.D. and Burnstock G. | date=2006 | title= Purinergic signalling in neuron-glia interactions | journal = Nature Reviews Neuroscience | volume= 7 | pages=423–436 | pmid=16715052 | url= http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16715052 | doi = 10.1038/nrn1928 }}</ref> The ''[[P2Y receptors|P2Y]]'' receptors are ''metabotropic'', i.e. [[G protein-coupled receptor|G protein-coupled]] and modulate mainly intracellular calcium and sometimes cyclic AMP levels. Though named between P2Y<sub>1</sub> and P2Y<sub>15</sub>, only nine members of the P2Y family have been cloned, and some are only related through weak homology and several (P2Y<sub>5</sub>, P2Y<sub>7</sub>, P2Y<sub>9</sub>, P2Y<sub>10</sub>) do not function as receptors that raise cytosolic calcium. The ''[[P2X receptors|P2X]] ionotropic'' receptor subgroup comprises seven members (P2X<sub>1</sub>–P2X<sub>7</sub>) which are ligand-gated Ca<sup>2+</sup>-permeable ion channels that open when bound to an extracellular purine nucleotide. In contrast to P2 receptors (agonist order ATP > ADP > AMP > ADO), purinergic [[nucleotide]]s like ATP are not strong agonists of P1 receptors which are strongly activated by [[adenosine]] and other [[nucleoside]]s (ADO > AMP > ADP > ATP). P1 receptors have A1, A2a, A2b, and A3 subtypes ("A" as a remnant of old nomenclature of ''adenosine receptor''), all of which are G protein-coupled receptors, A1 and A3 being coupled to Gi, and A2a and A2b being coupled to Gs.<ref>{{cite journal| author= Fredholm, BB, Abbracchio, MP, Burnstock, G, Daly, JW, Harden, TK, Jacobson, KA, Leff, P, Williams, M | title=Nomenclature and classification of purinoceptors | journal= Pharmacol Rev | date=1994 | volume=46 | pages= 143–156 | pmid= 938164 | url= http://pharmrev.aspetjournals.org/cgi/reprint/46/2/143 }}</ref> <!--This is an awful lot of detail on the receptors without a lot of information on the function of the receptors and their importance--> ====Intracellular signaling==== ATP is critical in [[signal transduction]] processes. It is used by [[kinase]]s as the source of phosphate groups in their phosphate transfer reactions. Kinase activity on substrates such as proteins or membrane lipids are a common form of signal transduction. [[Phosphorylation]] of a protein by a kinase can activate this cascade such as the [[mitogen-activated protein kinase]] cascade.<ref>{{cite journal | author = Mishra N, Tuteja R, Tuteja N | title = Signaling through MAP kinase networks in plants | journal = Arch Biochem Biophys | volume = 452 | issue = 1 | pages = 55–68 | year = 2006 | pmid = 16806044 | doi = 10.1016/j.abb.2006.05.001 }}</ref> ATP is also used by [[adenylate cyclase]] and is transformed to the [[second messenger]] molecule cyclic AMP, which is involved in triggering calcium signals by the release of calcium from intracellular stores.<ref>{{cite journal | author = Kamenetsky M, Middelhaufe S, Bank E, Levin L, Buck J, Steegborn C | title = Molecular details of cAMP generation in mammalian cells: a tale of two systems | journal = J Mol Biol | volume = 362 | issue = 4 | pages = 623–39 | year = 2006 | pmid = 16934836 | doi = 10.1016/j.jmb.2006.07.045}}</ref> This form of signal transduction is particularly important in brain function, although it is involved in the regulation of a multitude of other cellular processes.<ref>{{cite journal | author = Hanoune J, Defer N | title = Regulation and role of adenylyl cyclase isoforms | journal = Annu Rev Pharmacol Toxicol | volume = 41 | issue = | pages = 145–74 | year = 2001| pmid = 11264454 | doi = 10.1146/annurev.pharmtox.41.1.145 }}</ref> ===Deoxyribonucleotide synthesis=== In all known organisms, the deoxyribonucleotides that make up [[DNA]] are synthesized by the action of [[ribonucleotide reductase]] (RNR) enzymes on their corresponding ribonucleotides.<ref name=Stubbe>{{cite journal | author = Stubbe J | title = Ribonucleotide reductases: amazing and confusing | url=http://www.jbc.org/cgi/reprint/265/10/5329 | journal = J Biol Chem | volume = 265 | issue = 10 | pages = 5329–32 | year = 1990 | pmid = 2180924}}</ref> This enzyme reduces the 2' [[hydroxyl]] group on the [[ribose]] sugar to [[deoxyribose]], forming a deoxyribonucleotide (denoted dATP). All ribonucleotide reductase enzymes use a common [[sulfhydryl]] [[radical (chemistry)|radical]] mechanism reliant on reactive [[cysteine]] residues that oxidize to form [[disulfide bond]]s in the course of the reaction.<ref name=Stubbe/> RNR enzymes are recycled by reaction with [[thioredoxin]] or [[glutaredoxin]].<ref name="Voet" /> The regulation of RNR and related enzymes maintains a balance of dNTPs relative to each other and relative to NTPs in the cell. Very low dNTP concentration inhibits [[DNA replication|DNA synthesis]] and [[DNA repair]] and is lethal to the cell, while an abnormal ratio of dNTPs is [[mutagen]]ic due to the increased likelihood of the [[DNA polymerase]] incorporating the wrong dNTP during DNA synthesis.<ref name="Voet" /> Regulation of or differential specificity of RNR has been proposed as a mechanism for alterations in the relative sizes of intracellular dNTP pools under cellular stress such as [[Hypoxia (medical)|hypoxia]].<ref name="Chimploy">{{cite journal | author = Chimploy K, Tassotto M, Mathews C | title = Ribonucleotide reductase, a possible agent in deoxyribonucleotide pool asymmetries induced by hypoxia | url=http://www.jbc.org/cgi/content/full/275/50/39267 | doi = 10.1074/jbc.M006233200 <!--Retrieved from url by DOI bot--> | journal = J Biol Chem | volume = 275 | issue = 50 | pages = 39267–71 | year = 2000 | pmid = 11006282}}</ref> ==Binding to proteins== [[Image:Rossmann-fold-1g5q.png|thumb|300px|An example of the Rossmann fold, a [[structural domain]] of a [[decarboxylase]] enzyme from the bacterium ''[[Staphylococcus epidermidis]]'' (PDB ID 1G5Q) with a bound [[flavin mononucleotide]] cofactor.]] Some proteins that bind ATP do so in a characteristic [[tertiary structure|protein fold]] known as the [[Rossmann fold]], which is a general [[nucleotide]]-binding [[structural domain]] that can also bind the cofactor [[Nicotinamide adenine dinucleotide|NAD]].<ref>{{cite journal | author = Rao S, Rossmann M | title = Comparison of super-secondary structures in proteins | journal = J Mol Biol | volume = 76 | issue = 2 | pages = 241–56 | year = 1973 | pmid = 4737475 | doi=10.1016/0022-2836(73)90388-4 }}</ref> The most common ATP-binding proteins, known as [[kinases]], share a small number of common folds; the [[protein kinase]]s, the largest kinase superfamily, all share common structural features specialized for ATP binding and phosphate transfer.<ref name="Scheeff">{{cite journal | author = Scheeff E, Bourne P | title = Structural evolution of the protein kinase-like superfamily | url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16244704 | doi = 10.1371/journal.pcbi.0010049 <!--Retrieved from url by DOI bot--> | journal = PLoS Comput Biol | volume = 1 | issue = 5 | pages = e49 | year = 2005 | pmid = 16244704}}</ref> ATP in complexes with proteins generally requires the presence of a [[divalent]] [[cation]], almost always [[magnesium]], which binds to the ATP phosphate groups. The presence of magnesium greatly decreases the [[dissociation constant]] of ATP from its protein binding partner without affecting the ability of the enzyme to catalyze its reaction once the ATP has bound.<ref name="Saylor">{{cite journal | author = Saylor P, Wang C, Hirai T, Adams J | title = A second magnesium ion is critical for ATP binding in the kinase domain of the oncoprotein v-Fps | journal = Biochemistry | volume = 37 | issue = 36 | pages = 12624–30 | year = 1998 | pmid = 9730835 | doi = 10.1021/bi9812672 }}</ref> The presence of magnesium ions can serve as a mechanism for kinase regulation.<ref name="Lin">{{cite journal | author = Lin X, Ayrapetov M, Sun G | title = Characterization of the interactions between the active site of a protein tyrosine kinase and a divalent metal activator | url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16305747 | doi = 10.1186/1471-2091-6-25 <!--Retrieved from url by DOI bot--> | journal = BMC Biochem | volume = 6 | issue = | pages = 25 | year = | pmid = 16305747}}</ref> ==ATP analogs== Biochemistry laboratories often use ''[[in vitro]]'' studies to explore ATP-dependent molecular processes. [[Enzyme inhibitor]]s of ATP-dependent enzymes such as [[kinase]]s are needed to examine the [[binding site]]s and [[transition state]]s involved in ATP-dependent reactions. ATP analogs are also used in [[X-ray crystallography]] to determine a [[protein structure]] in complex with ATP, often together with other substrates. Most useful ATP analogs cannot be hydrolyzed as ATP would be; instead they trap the enzyme in a structure closely related to the ATP-bound state. Adenosine 5'-(gamma-thiotriphosphate) is an extremely common ATP analog in which one of the gamma-phosphate oxygens is replaced by a [[sulfur]] atom; this molecule is hydrolyzed at a dramatically slower rate than ATP itself and functions as an inhibitor of ATP-dependent processes. In crystallographic studies, hydrolysis transition states are modeled by the bound [[vanadate]] ion. However, caution is warranted in interpreting the results of experiments using ATP analogs, since some enzymes can hydrolyze them at appreciable rates at high concentration.<ref name="Resetar">{{cite journal | author=Resetar AM, Chalovich JM. | date=1995 | title= Adenosine 5'-(gamma-thiotriphosphate): an ATP analog that should be used with caution in muscle contraction studies | volume=34 | issue=49 | pages=16039–45 | pmid=8519760 | doi = 10.1021/bi00049a018 | journal= Biochemistry}} </ref> ==See also== * [[Adenosine diphosphate]] (ADP) * [[Adenosine monophosphate]] (AMP) * [[Cyclic adenosine monophosphate]] (cAMP) * [[ATPases]] * [[ATP hydrolysis]] * [[Citric acid cycle]] (also called the Krebs cycle or TCA cycle) * [[Phosphagen]] * [[Nucleotide exchange factor]] * [[Mitochondria]] * [[Photophosphorylation]] ==References== <div class="references-small" style="-moz-column-count:2; column-count:2;"> <references/> </div> ==External links== * [http://www.cliffsnotes.com/WileyCDA/CliffsReviewTopic/Adenosine-Triphosphate-ATP-.topicArticleId-8741,articleId-8593.html CliffNotes - Adenosine Triphosphate (ATP)] * [http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5957 PubChem entry for Adenosine Triphosphate] * [http://www.genome.jp/dbget-bin/www_bget?cpd:C00002 KEGG entry for Adenosine Triphosphate] {{Nucleobases, nucleosides, and nucleotides}} {{Enzyme cofactors}} [[Category:Cellular respiration]] [[Category:Exercise physiology]] [[Category:Nucleotides]] [[Category:Coenzymes]] [[ar:أدينوسين ثلاثي الفوسفات]] [[be:Адэназінтрыфосфарная кіслата]] [[bg:Аденозинтрифосфат]] [[ca:Trifosfat d'adenosina]] [[cs:Adenosintrifosfát]] [[da:Adenosintrifosfat]] [[de:Adenosintriphosphat]] [[et:Adenosiintrifosfaat]] [[es:Adenosín trifosfato]] [[eo:Adenozina trifosfato]] [[fr:Adénosine triphosphate]] [[gl:ATP]] [[ko:아데노신 삼인산]] [[hr:Adenozin trifosfat]] [[id:Adenosin trifosfat]] [[is:Adenósínþrífosfat]] [[it:Adenosintrifosfato]] [[he:ATP]] [[ka:ადენოზინტრიფოსფორმჟავა]] [[lb:Adenosintriphosphat]] [[lt:ATP]] [[hu:Adenozin-trifoszfát]] [[mk:Аденозин трифосфат]] [[ms:Adenosina trifosfat]] [[nl:Adenosinetrifosfaat]] [[ja:アデノシン三リン酸]] [[no:Adenosintrifosfat]] [[oc:Adenosina trifosfat]] [[pl:Adenozynotrifosforan]] [[pt:Trifosfato de adenosina]] [[ksh:Adenosiin Trifoßfaat]] [[ro:Adenozintrifosfat]] [[ru:Аденозинтрифосфорная кислота]] [[simple:Adenosine Triphosphate]] [[sk:Adenozíntrifosfát]] [[sl:Adenozin trifosfat]] [[sr:Аденозин трифосфат]] [[sh:Adenozin trifosfat]] [[su:Adénosin trifosfat]] [[fi:Adenosiinitrifosfaatti]] [[sv:Adenosintrifosfat]] [[vi:Adenosine triphosphate]] [[tr:Adenozin trifosfat]] [[uk:Аденозинтрифосфат]] [[zh:三磷酸腺苷]]