Editing Adenosine triphosphate (section)

==Production from AMP and ADP==
===Production, aerobic conditions===
A typical intracellular [[concentration]] of ATP may be 1–10&nbsp;μmol per gram of tissue in a variety of eukaryotes.<ref>{{cite journal| last1 = Beis |first1=I. |last2= Newsholme |first2=E.&nbsp;A. | date = October 1, 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 |pmc=1172435| issue = 1 | doi=10.1042/bj1520023}}
</ref> The dephosphorylation of ATP and rephosphorylation of ADP and AMP occur repeatedly in the course of aerobic metabolism.<ref name="brit">{{cite web |title=Adenosine triphosphate |url=https://www.britannica.com/science/adenosine-triphosphate |publisher=Britannica |access-date=1 December 2023 |date=11 November 2023}}</ref>

ATP can be produced by a number of distinct cellular processes; the three main pathways in [[eukaryote]]s are (1) [[glycolysis]], (2) the [[citric acid cycle]]/[[oxidative phosphorylation]], and (3) [[beta-oxidation]]. The overall process of oxidizing [[glucose]] to [[carbon dioxide]], the combination of pathways 1 and 2, known as [[cellular respiration]], produces about 30 equivalents of ATP from each molecule of glucose.<ref name=Rich>{{cite journal |last=Rich |first=P.&nbsp;R. |title=The molecular machinery of Keilin's respiratory chain |journal=Biochem. Soc. Trans. |volume=31 |issue=6 |pages=1095–1105 |year=2003 |pmid=14641005 |doi=10.1042/BST0311095}}</ref>

ATP production by a non-[[photosynthetic]] aerobic eukaryote occurs mainly in the [[mitochondria]], which comprise nearly 25% of the volume of a typical cell.<ref name="Lodish">{{cite book |last1=Lodish |first1=H. |last2=Berk |first2=A. |last3=Matsudaira |first3=P. |last4=Kaiser |first4=C.&nbsp;A. |last5=Krieger |first5=M. |last6=Scott |first6=M.&nbsp;P. |last7=Zipursky |first7=S.&nbsp;L. |last8=Darnell |first8=J. |title=Molecular Cell Biology |edition=5th |publisher=W.&nbsp;H. Freeman |location=New York, NY |isbn=978-0-7167-4366-8 |year=2004 |url-access=registration |url=https://archive.org/details/molecularcellbio00harv }}</ref>

====Glycolysis====
{{Main|Glycolysis}}

In glycolysis, glucose and glycerol are metabolized to [[pyruvate]]. Glycolysis generates two equivalents of ATP through [[substrate-level phosphorylation|substrate phosphorylation]] catalyzed by two enzymes,  [[phosphoglycerate kinase]] (PGK) and [[pyruvate kinase]]. Two equivalents of [[nicotinamide adenine dinucleotide]] (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 [[citric acid cycle|Krebs Cycle]].<ref name=Voet>{{cite book |last1=Voet |first1=D. |last2=Voet |first2=J.&nbsp;G. | year=2004 | title=Biochemistry |volume=1 |edition=3rd | publisher= Wiley |location=Hoboken, NJ | isbn = 978-0-471-19350-0}}</ref>

Glycolysis is viewed as consisting of two phases with five steps each. In phase 1, "the preparatory phase", glucose is converted to 2 d-glyceraldehyde-3-phosphate (g3p). One ATP is invested in Step 1, and another ATP is invested in Step 3. Steps 1 and 3 of glycolysis are referred to as "Priming Steps". In Phase 2, two equivalents of g3p are converted to two pyruvates. In Step 7, two ATP are produced. Also, in Step 10, two further equivalents of ATP are produced. In Steps 7 and 10, ATP is generated from ADP. A net of two ATPs is formed in the glycolysis cycle. The glycolysis pathway is later associated with the Citric Acid Cycle which produces additional equivalents of ATP.<ref name="glycolysis_animation">{{cite web | vauthors = Mehta S | date = 20 September 2011 | url = http://pharmaxchange.info/press/2011/09/glycolysis-animation-and-notes/ | title = Glycolysis – Animation and Notes | work = PharmaXchange | access-date = 22 September 2011 | archive-date = 25 March 2012 | archive-url = https://web.archive.org/web/20120325151810/http://pharmaxchange.info/press/2011/09/glycolysis-animation-and-notes/ | url-status = dead }}</ref>

=====Regulation=====
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 active form of the enzyme is a [[tetramer protein|tetramer]] that exists in two conformations, only one of which binds the second substrate fructose-6-phosphate (F6P). The protein has two [[binding site]]s for ATP&nbsp;– 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" /> {{confusing|date=October 2024}}

====Citric acid cycle====
{{Main|Citric acid cycle|Oxidative phosphorylation}}

In the [[mitochondrion]], pyruvate is oxidized by the [[pyruvate dehydrogenase complex]] to the [[acetyl]] group, which is fully oxidized to carbon dioxide by the [[citric acid cycle]] (also known as the [[Hans Krebs (biochemist)|Krebs]] cycle). Every "turn" of the citric acid cycle produces two molecules of carbon dioxide, one equivalent of ATP [[guanosine triphosphate]] (GTP) through [[substrate-level phosphorylation]] catalyzed by [[succinyl-CoA synthetase]], as succinyl-CoA is converted to succinate, three equivalents of NADH, and one equivalent of [[Flavin group|FADH<sub>2</sub>]]. NADH and FADH<sub>2</sub> are recycled (to NAD<sup>+</sup> and [[Flavin adenine dinucleotide|FAD]], respectively) by [[oxidative phosphorylation]], generating additional ATP. The oxidation of NADH results in the synthesis of 2–3 equivalents of ATP, and the oxidation of one FADH<sub>2</sub> yields between 1–2 equivalents of ATP.<ref name="Rich" /> 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 used to recycle the NADH and FADH<sub>2</sub>. In the absence of oxygen, the citric acid cycle ceases.<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 releases the energy to pump [[proton]]s out of the mitochondrial matrix and into the intermembrane space. This pumping generates 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&nbsp;– that is, from the intermembrane space to the matrix&nbsp;– yields ATP by ATP synthase.<ref>{{cite journal |last1=Abrahams |first1=J. |last2=Leslie |first2=A. |last3=Lutter |first3=R. |last4=Walker |first4=J. | title = Structure at 2.8&nbsp;Å resolution of F1-ATPase from bovine heart mitochondria | journal = Nature | volume = 370 | issue = 6491 | pages = 621–628 | year = 1994 |pmid=8065448 | doi = 10.1038/370621a0 |bibcode=1994Natur.370..621A |s2cid=4275221 }}</ref> Three ATP are produced per turn.

Although oxygen consumption appears fundamental for the maintenance of the proton motive force, in the event of oxygen shortage ([[Hypoxia (medical)|hypoxia]]), intracellular acidosis (mediated by enhanced glycolytic rates and [[ATP hydrolysis]]), contributes to mitochondrial membrane potential and directly drives ATP synthesis.<ref>{{cite journal | pmid = 30713504 | volume=9, 1914 | title=Acidosis Maintains the Function of Brain Mitochondria in Hypoxia-Tolerant Triplefin Fish: A Strategy to Survive Acute Hypoxic Exposure? | pmc=6346031 | date=January 2019 | journal=Front Physiol | doi=10.3389/fphys.2018.01941 | last1 = Devaux | first1 = JBL | last2 = Hedges | first2 = CP | last3 = Hickey | first3 = AJR| page=1941 | doi-access=free }}</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. ATP outward movement is favored by the membrane's electrochemical potential because the cytosol has a relatively positive charge compared to the relatively negative matrix. For every ATP transported out, it costs 1 H<sup>+</sup>. Producing one ATP costs about 3  H<sup>+</sup>. Therefore, making and exporting one ATP requires  4H<sup>+.</sup> 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 |last1=Dahout-Gonzalez |first1=C. |last2=Nury |first2=H. |last3=Trézéguet |first3=V. |last4=Lauquin |first4=G. |last5=Pebay-Peyroula |first5=E. |last6=Brandolin |first6=G. | title = Molecular, functional, and pathological aspects of the mitochondrial ADP/ATP carrier | journal = Physiology | volume = 21 | pages = 242–249 | year = 2006| pmid = 16868313 | doi=10.1152/physiol.00005.2006 | issue = 4 }}</ref>

=====Regulation=====
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]]&nbsp;– the ion that gives its name to the cycle&nbsp;– 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" /> {{confusing|date=October 2024}}

====Beta oxidation====
{{Main|Beta-oxidation}}
In the presence of air and various cofactors and enzymes, fatty acids are converted to [[acetyl-CoA]]. The pathway is called [[beta-oxidation]]. Each cycle of beta-oxidation shortens the fatty acid chain by two carbon atoms and produces one equivalent each of acetyl-CoA, NADH, and FADH<sub>2</sub>. The acetyl-CoA is metabolized by the citric acid cycle to generate ATP, while the NADH and FADH<sub>2</sub> are used  by oxidative phosphorylation to generate ATP.  Dozens of ATP equivalents are generated by the beta-oxidation of a single long acyl chain.<ref>{{cite journal |last1=Ronnett |first1=G. |last2=Kim |first2=E. |last3=Landree |first3=L. |last4=Tu |first4=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 |s2cid=24865576 }}</ref>

=====Regulation=====
In oxidative phosphorylation, the key control point is the reaction catalyzed by [[cytochrome c oxidase]], which is regulated by the availability of its substrate&nbsp;– the reduced form of [[cytochrome c]]. The amount of reduced cytochrome c available is directly related to the amounts of other substrates:

:<math chem="">
\frac12 \ce{NADH} + \ce{cyt}\ \ce{c_{ox}} + \ce{ADP} + \ce{P_{i}} \rightleftharpoons
\frac12 \ce{NAD^+} + \ce{cyt}\ \ce{c_{red}} + \ce{ATP}
</math>

which directly implies this equation:

:<math>
\frac{[\mathrm{cyt~c_{red}}]}{[\mathrm{cyt~c_{ox}}]} = \left(\frac{[\mathrm{NADH}]}{[\mathrm{NAD}]^{+}}\right)^{\frac{1}{2}}\left(\frac{[\mathrm{ADP}] [\mathrm{P_i}]}{[\mathrm{ATP}]}\right)K_\mathrm{eq}
</math>

Thus, a high ratio of [NADH] to [NAD<sup>+</sup>] or a high 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" />

====Ketosis====
{{Main|Ketone bodies}}

Ketone bodies can be used as fuels, yielding 22 ATP and 2 [[Guanosine triphosphate|GTP]] molecules per acetoacetate molecule when oxidized in the mitochondria. Ketone bodies are transported from the [[liver]] to other tissues, where [[acetoacetate]] and [[beta-Hydroxybutyric acid|''beta''-hydroxybutyrate]] can be reconverted to acetyl-CoA to produce reducing equivalents (NADH and FADH<sub>2</sub>), via the citric acid cycle. Ketone bodies cannot be used as fuel by the liver, because the liver lacks the enzyme β-ketoacyl-CoA transferase, also called [[thiolase]]. [[Acetoacetate]] in low concentrations is taken up by the liver and undergoes detoxification through the methylglyoxal pathway which ends with lactate. Acetoacetate in high concentrations is absorbed by cells other than those in the liver and enters a different pathway via [[1,2-propanediol]].  Though the pathway follows a different series of steps requiring ATP, 1,2-propanediol can be turned into pyruvate.<ref name="Environmental Protection Agency; TOXICOLOGICAL REVIEW OF ACETONE (CAS No. 67-64-1)">{{Cite web| url=http://www.epa.gov/iris/toxreviews/0128tr.pdf| title=Integrated Risk Information System| date=2013-03-15| access-date=2019-02-01| archive-url=https://web.archive.org/web/20150924074331/http://www.epa.gov/iris/toxreviews/0128tr.pdf| archive-date=2015-09-24| url-status=live}}</ref>

===Production, anaerobic conditions===
[[fermentation (biochemistry)|Fermentation]] is the metabolism of organic compounds in the absence of air. It involves [[substrate-level phosphorylation]] in the absence of a respiratory [[electron transport chain]]. 

The equation for the reaction of glucose to form [[lactic acid]] is:
: {{chem|C|6|H|12|O|6}} + 2&nbsp;ADP + 2&nbsp;P<sub>i</sub> → 2&nbsp;{{chem|CH|3|CH(OH)COOH}} + 2&nbsp;ATP + 2&nbsp;{{chem|H|2|O}}

[[Anaerobic respiration]] is respiration in the absence of {{chem|link=oxygen|O|2}}. Prokaryotes can utilize a variety of electron acceptors. These include [[nitrate]], [[sulfate]], and carbon dioxide. In
anaerobic organisms and prokaryotes, different pathways result in ATP. ATP is produced in the chloroplasts of green plants in a process similar to oxidative phosphorylation, called photophosphorylation.<ref name="Myers" />

====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|ATP:guanido-phosphotransferase]] family.{{citation needed|date=April 2023}}

===ATP production during photosynthesis===
In plants, ATP is synthesized in the [[thylakoid membrane]] of the [[chloroplast]]. The process is called [[photophosphorylation]]. The "machinery" is similar to that in mitochondria except that light energy is used to pump protons across a membrane to produce a proton-motive force. ATP synthase then ensues exactly as in oxidative phosphorylation.<ref>{{cite journal | last = Allen | first = J. | title = Photosynthesis of ATP-electrons, proton pumps, rotors, and poise | journal = Cell | volume = 110 | issue = 3 | pages = 273–276 | year = 2002 | pmid = 12176312 | doi = 10.1016/S0092-8674(02)00870-X | s2cid = 1754660 | doi-access = free }}</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;[[Molar concentration|mol/L]].<ref name="Fuhrman-1061">{{cite book |last1=Fuhrman |first1=Bradley P. |last2=Zimmerman |first2=Jerry J. |title=Pediatric Critical Care |date=2011 |publisher=Elsevier |isbn=978-0-323-07307-3 |pages=1061 |url=https://www.sciencedirect.com/science/article/pii/B9780323073073100746#s0025 |access-date=16 May 2020}}</ref> The majority of ATP is recycled 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 in an adult requires the hydrolysis of 100 to 150&nbsp;mol/L of ATP daily, which means a human will typically use their body weight worth of ATP over the course of the day.<ref name="Fuhrman">{{cite book |last1=Fuhrman |first1=Bradley P. |last2=Zimmerman |first2=Jerry J. |title=Pediatric Critical Care |date=2011 |publisher=Elsevier |isbn=978-0-323-07307-3 |pages=1058–1072 |url=https://www.sciencedirect.com/science/article/pii/B9780323073073100746#s0025 |access-date=16 May 2020}}</ref> Each equivalent of ATP is recycled 1000–1500 times during a single day ({{nowrap|150 / 0.1 {{=}} 1500}}),<ref name="Fuhrman-1061" /> at approximately 9×10<sup>20</sup> molecules/s.<ref name="Fuhrman-1061" />

[[Image:Rossmann-fold-1g5q.png|thumb|An example of the Rossmann fold, a [[structural domain]] of a [[decarboxylase]] enzyme from the bacterium ''[[Staphylococcus epidermidis]]'' ({{PDB|1G5Q}}) with a bound [[flavin mononucleotide]] cofactor]]