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((Short description|Metabolic reaction))
((multiple issues|
((More citations needed|date=November 2012))
((Confusing|date=November 2009))
))
[[File:Substrate-level phosphorylation generating ATP.svg|thumb|200px|Substrate-level phosphorylation exemplified with the conversion of [[Adenosine diphosphate|ADP]] to [[Adenosine triphosphate|ATP]]]]

'''Substrate-level phosphorylation''' is a metabolism reaction that results in the production of [[Adenosine triphosphate|ATP]] or [[Guanosine triphosphate|GTP]] supported by the energy released from another high-energy bond that leads to phosphorylation of [[Adenosine diphosphate|ADP]] or [[Guanosine diphosphate|GDP]] to [[Adenosine triphosphate|ATP]] or [[Guanosine triphosphate|GTP]] (note that the reaction catalyzed by creatine kinase is not considered as "substrate-level phosphorylation"). This process uses some of the released [[chemical energy]], the [[Gibbs free energy]], to transfer a [[phosphoryl]] (PO<sub>3</sub>) group to ADP or GDP. Occurs in [[glycolysis]] and in the citric acid cycle.<ref>((Cite book|last=Freeman, Scott|url=https://www.worldcat.org/oclc/1043972098|title=Biological science|others=Quillin, Kim, Allison, Lizabeth A., 1958-, Black, Michael (Lecturer in biology), Podgorski, Greg, Taylor, Emily (Lecturer in biological sciences), Carmichael, Jeff.|year=2020|isbn=978-0-13-467832-0|edition=Seventh |location=Hoboken, NJ|oclc=1043972098))</ref>

Unlike [[oxidative phosphorylation]], oxidation and phosphorylation are not coupled in the process of substrate-level phosphorylation, and reactive intermediates are most often gained in the course of [[oxidation]] processes in [[catabolism]]. Most ATP is generated by oxidative phosphorylation in [[Aerobic respiration|aerobic]] or [[anaerobic respiration]] while substrate-level phosphorylation provides a quicker, less efficient source of ATP, independent of external [[electron acceptor]]s. This is the case in human [[erythrocyte]]s, which have no [[Mitochondrion|mitochondria]], and in oxygen-depleted muscle.

==Overview==
Adenosine triphosphate (ATP) is a major "energy currency" of the cell.<ref name="SkulachevBogachev2012">((cite book|last1=Skulachev|first1=Vladimir P. |last2=Bogachev|first2=Alexander V. |last3=Kasparinsky|first3=Felix O. |title=Principles of Bioenergetics|url=https://books.google.com/books?id=-IJg4rgwXJQC|date=15 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-33430-6|page=252))</ref> The high energy bonds between the phosphate groups can be broken to power a variety of reactions used in all aspects of cell function.<ref name="AgtereschDagnelie1999">((cite journal|last1=Agteresch|first1=Hendrik J.|last2=Dagnelie|first2=Pieter C.|last3=van den Berg|first3=J Willem|last4=Wilson|first4=J H.|title=Adenosine Triphosphate|journal=Drugs|volume=58|issue=2|year=1999|pages=211–232|issn=0012-6667|doi=10.2165/00003495-199958020-00002|pmid=10473017|s2cid=46974766))</ref>

Substrate-level phosphorylation occurs in the cytoplasm of cells during [[glycolysis]] and in mitochondria either during the [[Krebs cycle]] or by [[MTHFD1L]] ([https://www.uniprot.org/uniprot/Q6UB35 EC 6.3.4.3]), an enzyme interconverting ADP + phosphate + 10-formyltetrahydrofolate to ATP + formate + tetrahydrofolate (reversibly), under both [[Cellular respiration#Aerobic respiration|aerobic]] and [[anaerobic respiration|anaerobic]] conditions. In the [[Glycolysis#Pay-off phase|pay-off phase of glycolysis]], a net of 2 ATP are produced by substrate-level phosphorylation.

==Glycolysis==
((Main|Glycolysis))
The first substrate-level phosphorylation occurs after the conversion of 3-phosphoglyceraldehyde and Pi and NAD+ to 1,3-bisphosphoglycerate via [[glyceraldehyde 3-phosphate dehydrogenase]]. 1,3-bisphosphoglycerate is then dephosphorylated via [[phosphoglycerate kinase]], producing 3-phosphoglycerate and ATP through a substrate-level phosphorylation.

The second substrate-level phosphorylation occurs by dephosphorylating [[phosphoenolpyruvate]], catalyzed by [[pyruvate kinase]], producing [[pyruvate]] and ATP.

During the preparatory phase, each 6-carbon glucose molecule is broken into two 3-carbon molecules. Thus, in glycolysis dephosphorylation results in the production of 4 ATP. However, the prior preparatory phase consumes 2 ATP, so the net yield in glycolysis is 2 ATP. 2 molecules of NADH are also produced and can be used in oxidative phosphorylation to generate more ATP.

==Mitochondria==

ATP can be generated by substrate-level phosphorylation in [[mitochondria]] in a pathway that is independent from the [[proton motive force]]. In the [[mitochondrial matrix|matrix]] there are three reactions capable of substrate-level phosphorylation, utilizing either [[phosphoenolpyruvate carboxykinase]] or [[succinyl coenzyme A synthetase|succinate-CoA ligase]], or [[MTHFD1L|monofunctional C1-tetrahydrofolate synthase]].

===Phosphoenolpyruvate carboxykinase===
Mitochondrial phosphoenolpyruvate carboxykinase is thought to participate in the transfer of the phosphorylation potential from the matrix to the cytosol and vice versa.<ref>((cite journal |pmid=15234968 |name-list-style=vanc|year=2004 |last1=Lambeth |first1=DO |last2=Tews |first2=KN |last3=Adkins |first3=S |last4=Frohlich |first4=D |last5=Milavetz |first5=BI |title=Expression of two succinyl-CoA synthetases with different nucleotide specificities in mammalian tissues |volume=279 |issue=35 |pages=36621–4 |doi=10.1074/jbc.M406884200 |journal=The Journal of Biological Chemistry|doi-access=free ))</ref><ref>((cite journal |pmid=6263728 |name-list-style=vanc|year=1981 |last1=Ottaway |first1=JH |last2=McClellan |first2=JA |last3=Saunderson |first3=CL |title=Succinic thiokinase and metabolic control |volume=13 |issue=4 |pages=401–10 |journal=The International Journal of Biochemistry |doi=10.1016/0020-711x(81)90111-7))</ref><ref>((cite journal |pmid=12489642 |name-list-style=vanc|year=2002 |last1=Lambeth |first1=DO |title=What is the function of GTP produced in the Krebs citric acid cycle? |volume=54 |issue=3 |pages=143–4 |doi=10.1080/15216540214539 |journal=IUBMB Life|doi-access=free ))</ref><ref>((cite journal |pmid=6885788 |name-list-style=vanc|year=1983 |last1=Wilson |first1=DF |last2=Erecińska |first2=M |last3=Schramm |first3=VL |title=Evaluation of the relationship between the intra- and extramitochondrial ATP/ADP ratios using phosphoenolpyruvate carboxykinase |volume=258 |issue=17 |pages=10464–73 |journal=The Journal of Biological Chemistry|doi=10.1016/S0021-9258(17)44479-6|doi-access=free))</ref><ref>((cite journal |pmid=9765291 |name-list-style=vanc|year=1998 |last1=Johnson |first1=JD |last2=Mehus |first2=JG |last3=Tews |first3=K |last4=Milavetz |first4=BI |last5=Lambeth |first5=DO |title=Genetic evidence for the expression of ATP- and GTP-specific succinyl-CoA synthetases in multicellular eucaryotes |volume=273 |issue=42 |pages=27580–6 |journal=The Journal of Biological Chemistry |doi=10.1074/jbc.273.42.27580|doi-access=free ))</ref> However, it is strongly favored towards GTP hydrolysis, thus it is not really considered as an important source of intra-mitochondrial substrate-level phosphorylation.

===Succinate-CoA ligase===
Succinate-CoA ligase is a heterodimer composed of an invariant α-subunit and a substrate-specific ß-subunit, encoded by either SUCLA2 or SUCLG2. This combination results in either an [[succinate-CoA ligase (ADP-forming)|ADP-forming succinate-CoA ligase]] (A-SUCL, EC 6.2.1.5) or a [[succinate-CoA ligase (GDP-forming)|GDP-forming succinate-CoA ligase]] (G-SUCL, EC 6.2.1.4). The ADP-forming succinate-CoA ligase is potentially the only matrix enzyme generating ATP in the absence of a proton motive force, capable of maintaining matrix ATP levels under energy-limited conditions, such as transient [[hypoxia (medical)|hypoxia]].

===Monofunctional C1-tetrahydrofolate synthase===
This enzyme is encoded by [[MTHFD1L]] and reversibly interconverts ADP + phosphate + 10-formyltetrahydrofolate to ATP + formate + tetrahydrofolate.

==Other mechanisms==
In working skeletal muscles and the brain, [[Phosphocreatine]] is stored as a readily available high-energy phosphate supply, and the enzyme [[creatine phosphokinase]] transfers a phosphate from phosphocreatine to ADP to produce ATP. Then the ATP releases giving chemical energy. This is sometimes erroneously considered to be substrate-level phosphorylation, although it is a [[transphosphorylation]].

==Importance of substrate-level phosphorylation in anoxia==
During [[Hypoxia (medical)|anoxia]], provision of ATP by substrate-level phosphorylation in the matrix is important not only as a mere means of energy, but also to prevent mitochondria from straining glycolytic ATP reserves by maintaining the [[adenine nucleotide translocator]] in ‘forward mode’ carrying ATP towards the cytosol.<ref>((cite journal | pmid = 20207940 | doi=10.1096/fj.09-149898 | volume=24 | title=Forward operation of adenine nucleotide translocase during F0F1-ATPase reversal: critical role of matrix substrate-level phosphorylation | pmc=2887268 | year=2010 | journal=FASEB J | pages=2405–16 | last1 = Chinopoulos | first1 = C | last2 = Gerencser | first2 = AA | last3 = Mandi | first3 = M | last4 = Mathe | first4 = K | last5 = Töröcsik | first5 = B | last6 = Doczi | first6 = J | last7 = Turiak | first7 = L | last8 = Kiss | first8 = G | last9 = Konràd | first9 = C | last10 = Vajda | first10 = S | last11 = Vereczki | first11 = V | last12 = Oh | first12 = RJ | last13 = Adam-Vizi | first13 = V| issue=7 ))</ref><ref>((cite journal | pmid = 21486564 | doi=10.1016/j.febslet.2011.04.004 | volume=585 | title=Mitochondrial consumption of cytosolic ATP: not so fast | year=2011 | journal=FEBS Lett | pages=1255–9 | last1 = Chinopoulos | first1 = C| issue=9 | s2cid=24773903 | doi-access=free ))</ref><ref>((cite journal | pmid = 21541983 | doi=10.1002/jnr.22659 | volume=89 | title=The "B space" of mitochondrial phosphorylation | year=2011 | journal=J Neurosci Res | pages=1897–904 | last1 = Chinopoulos | first1 = C| issue=12 | doi-access=free ))</ref>

==Oxidative phosphorylation==
((Main|Oxidative phosphorylation))
An alternative method used to create ATP is through [[oxidative phosphorylation]], which takes place during [[cellular respiration]]. This process utilizes the oxidation of [[NADH]] to NAD<sup>+</sup>, yielding 3 ATP, and of FADH<sub>2</sub> to FAD, yielding 2 ATP. The [[potential energy]] stored as an [[electrochemical gradient]] of protons (H<sup>+</sup>) across the inner mitochondrial membrane is required to generate ATP from ADP and P<sub>i</sub> (inorganic phosphate molecule), a key difference from substrate-level phosphorylation. This gradient is exploited by [[ATP synthase]] acting as a pore, allowing H<sup>+</sup> from the mitochondrial [[intermembrane space]] to move down its electrochemical gradient into the matrix and coupling the release of free energy to ATP synthesis. Conversely, electron transfer provides the energy required to actively pump H<sup>+</sup> out of the matrix.

==References==
((Portal|Biology))
((reflist))

[[Category:Metabolism]]
[[Category:Phosphorus]]

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