Editing Cori cycle

{{Short description|Series of interconnected biochemical reactions}}
{{distinguish|Cori disease}}
[[File:Cori Cycle.SVG|right|thumb|460px|Cori cycle]]
The '''Cori cycle''' (also known as the '''lactic acid cycle'''), named after its discoverers, [[Carl Ferdinand Cori]] and [[Gerty Cori]],<ref name="acs">{{cite web |title=Carl and Gerty Cori and Carbohydrate Metabolism |url=https://www.acs.org/content/acs/en/education/whatischemistry/landmarks/carbohydratemetabolism.html | work = National Historic Chemical Landmark | publisher = American Chemical Society |access-date=12 May 2020 |language=en |date=2004}}</ref> is a metabolic pathway in which [[lactic acid|lactate]], produced by anaerobic [[glycolysis]] in muscles, is transported to the liver and converted to glucose, which then returns to the muscles and is cyclically metabolized back to lactate.<ref>{{cite book | vauthors = Nelson DL, Cox MM | date = 2005 | title = Lehninger Principles of Biochemistry | edition = Fourth | location = New York | publisher = W.H. Freeman and Company | page = 543 | isbn = 978-0-7167-4339-2 }}</ref>

==Process==
[[File:Gerty Theresa Radnitz Cori (1896-1957) and Carl Ferdinand Cori - restoration1.jpg|thumb|[[Carl Cori]] and [[Gerty Cori]] jointly won the 1947 [[Nobel Prize in Physiology or Medicine]], for their discovery of the course of the catalytic conversion of glycogen, of which the Cori cycle is a part.]]
Muscular activity requires [[Adenosine triphosphate|ATP]], which is provided by the breakdown of [[glycogen]] in the [[skeletal muscles]]. The breakdown of glycogen, known as [[glycogenolysis]], releases [[glucose]] in the form of [[glucose-1-phosphate|glucose 1-phosphate]] (G1P). The G1P is converted to [[G6P]] by [[phosphoglucomutase]]. G6P is readily fed into [[glycolysis]], (or can go into the [[pentose phosphate pathway]] if G6P concentration is high) a process that provides ATP to the [[muscle cells]] as an energy source. During muscular activity, the store of ATP needs to be constantly replenished. When the supply of [[dioxygen|oxygen]] is sufficient, this energy comes from feeding [[pyruvate]], one product of glycolysis, into the [[citric acid cycle]], which ultimately generates ATP through oxygen-dependent [[oxidative phosphorylation]].

When oxygen supply is insufficient, typically during intense muscular activity, energy must be released through [[anaerobic metabolism]]. [[Lactic acid fermentation]] converts pyruvate to [[lactic acid|lactate]] by [[lactate dehydrogenase]]. Most importantly, fermentation regenerates [[Nicotinamide adenine dinucleotide|NAD<sup>+</sup>]], maintaining its concentration so additional glycolysis reactions can occur. The fermentation step oxidizes the [[NADH]] produced by glycolysis back to NAD<sup>+</sup>, transferring two electrons from [[NADH]] to reduce pyruvate into lactate. (Refer to the main articles on [[glycolysis]] and [[fermentation (biochemistry)|fermentation]] for the details.)

Instead of accumulating inside the muscle cells, lactate produced by anaerobic fermentation is taken up by the [[liver]]. This initiates the other half of the Cori cycle. In the liver, [[gluconeogenesis]] occurs. From an intuitive perspective, gluconeogenesis reverses both glycolysis and fermentation by converting lactate first into pyruvate, and finally back to glucose. The glucose is then supplied to the muscles through the [[bloodstream]]; it is ready to be fed into further glycolysis reactions. If muscle activity has stopped, the glucose is used to replenish the supplies of glycogen through [[glycogenesis]].<ref name="Elmhurst">"{{cite web | url = http://www.elmhurst.edu/~chm/vchembook/615coricycle.html | vauthors = Ophardt CE | title = Cori Cycle | archive-url = https://web.archive.org/web/20080423042037/http://www.elmhurst.edu/~chm/vchembook/615coricycle.html | archive-date= 23 April 2008 | access-date = 3 May 2008 | date = 2003 | work = Virtual Chem Book | publisher = Elmhurst College| pages = 1–3 }}</ref>

Overall, the glycolysis steps of the cycle produce 2 ATP molecules at a cost of 6 ATP molecules consumed in the gluconeogenesis steps. Each iteration of the cycle must be maintained by a net consumption of 4 ATP molecules. As a result, the cycle cannot be sustained indefinitely. The intensive consumption of ATP molecules in the Cori cycle shifts the [[metabolic]] burden from the muscles to the liver.

==Significance==
The cycle's importance is based on preventing [[lactic acidosis]] during anaerobic conditions in the muscle. However, normally, before this happens, the lactic acid is moved out of the muscles and into the liver.<ref name="Elmhurst" />

Additionally, this cycle is important in ATP production, an energy source, during muscle exertion. The end of muscle exertion allows the Cori cycle to function more effectively. This repays the oxygen debt so both the electron transport chain and citric acid cycle can produce energy at optimum effectiveness.<ref name="Elmhurst" />

The Cori cycle is a much more important source of substrate for [[gluconeogenesis]] than food.<ref name="pmid11213896">{{cite journal | vauthors = Gerich JE, Meyer C, Woerle HJ, Stumvoll M | title = Renal gluconeogenesis: its importance in human glucose homeostasis | journal = Diabetes Care | volume = 24 | issue = 2 | pages = 382–91 | date = February 2001 | pmid = 11213896 | doi = 10.2337/diacare.24.2.382 | doi-access = free }}</ref><ref name="pmid18561209">{{cite journal | vauthors = Nuttall FQ, Ngo A, Gannon MC | title = Regulation of hepatic glucose production and the role of gluconeogenesis in humans: is the rate of gluconeogenesis constant? | journal = Diabetes/Metabolism Research and Reviews | volume = 24 | issue = 6 | pages = 438–58 | date = September 2008 | pmid = 18561209 | doi = 10.1002/dmrr.863 | s2cid = 24330397 }}</ref> The contribution of Cori cycle lactate to overall glucose production increases with [[fasting]] duration before plateauing.<ref name="pmid9725823">{{cite journal | vauthors = Katz J, Tayek JA | title = Gluconeogenesis and the Cori cycle in 12-, 20-, and 40-h-fasted humans | journal = The American Journal of Physiology | volume = 275 | issue = 3 | pages = E537-42 | date = September 1998 | pmid = 9725823 | doi = 10.1152/ajpendo.1998.275.3.E537 }}</ref> Specifically, after 12, 20, and 40 hours of fasting by human volunteers, gluconeogenesis accounts for 41%, 71%, and 92% of glucose production, but the contribution of Cori cycle lactate to gluconeogenesis is 18%, 35%, and 36%, respectively.<ref name="pmid9725823" /> The remaining glucose production comes from protein breakdown,<ref name="pmid9725823" /> muscle glycogen,<ref name="pmid9725823" /> and [[glycerol]] from [[lipolysis]].<ref name="pmid16848698">{{cite journal | vauthors = Cahill GF | title = Fuel metabolism in starvation | journal = Annual Review of Nutrition | volume = 26 | pages = 1–22 | year = 2006 | pmid = 16848698 | doi = 10.1146/annurev.nutr.26.061505.111258 }}</ref>

The drug [[metformin]] can cause lactic acidosis in patients with [[kidney failure]] because metformin inhibits the hepatic gluconeogenesis of the Cori cycle, particularly the mitochondrial respiratory chain complex 1.<ref name="pmid24283301">{{cite journal | vauthors = Vecchio S, Giampreti A, Petrolini VM, Lonati D, Protti A, Papa P, Rognoni C, Valli A, Rocchi L, Rolandi L, Manzo L, Locatelli CA | display-authors = 6 | title = Metformin accumulation: lactic acidosis and high plasmatic metformin levels in a retrospective case series of 66 patients on chronic therapy | journal = Clinical Toxicology | volume = 52 | issue = 2 | pages = 129–35 | date = February 2014 | pmid = 24283301 | doi = 10.3109/15563650.2013.860985 | s2cid = 23259898 }}</ref> The buildup of lactate and its substrates for lactate production, pyruvate and alanine, lead to excess lactate.<ref name="pmid7862618">{{cite journal | vauthors = Sirtori CR, Pasik C | title = Re-evaluation of a biguanide, metformin: mechanism of action and tolerability | journal = Pharmacological Research | volume = 30 | issue = 3 | pages = 187–228 | date = 1994 | pmid = 7862618 | doi = 10.1016/1043-6618(94)80104-5 }}</ref> Normally, the excess acid that is the result of the inhibition of the mitochondrial chain complex would be cleared by the kidneys, but in patients with kidney failure, the kidneys cannot handle the excess acid. 
A common misconception posits that lactate is the agent responsible for the acidosis, but lactate is a [[Organic acid|conjugate base]], being mostly ionised at physiologic pH, and serves as a marker of associated acid production rather than being its cause.<ref>{{Cite web|url=http://www.emedsa.org.au/MedicalPBL/LacticAcidosisMyth.html|title = The myth of lactic acidosis}}</ref><ref>{{Cite web|url=https://emcrit.org/ibcc/metformin/|title = Metformin toxicity}}</ref>

== See also ==
*[[Alanine cycle]]
*[[Citric acid cycle]]

== References ==
{{reflist}}

== Further reading ==
{{refbegin}}
* {{cite book | veditors = Smith AD, Datta SP, Smith GH, Campbell PN, Bentley R | date = 1997 | title = Oxford Dictionary of Biochemistry and Molecular Biology | location = New York | publisher = Oxford University Press | isbn = 978-0-19-854768-6 }}
{{refend}}

{{Glycolysis enzymes}}

{{DEFAULTSORT:Cori Cycle}}
[[Category:Biochemical reactions]]
[[Category:Carbohydrate metabolism]]
[[Category:Exercise biochemistry]]
[[Category:Metabolic pathways]]
[[Category:1929 in science]]