Editing Glycolysis (section)

== History ==
The modern understanding of the pathway of glycolysis took almost 100 years to fully learn.<ref name="pmid12722184">{{cite journal | vauthors = Barnett JA | title = A history of research on yeasts 5: the fermentation pathway | journal = Yeast | volume = 20 | issue = 6 | pages = 509–543 | date = April 2003 | pmid = 12722184 | doi = 10.1002/yea.986 | s2cid = 26805351 | doi-access = free }}</ref> The combined results of many smaller experiments were required to understand the entire pathway.

The first steps in understanding glycolysis began in the 19th century. For economic reasons, the French wine industry sought to investigate why wine sometimes turned distasteful, instead of fermenting into alcohol. The French scientist [[Louis Pasteur]] researched this issue during the 1850s.<ref>{{cite web |title=Louis Pasteur and Alcoholic Fermentation |url=http://www.pasteurbrewing.com/articles/beer-wine-fermentation.html |website=www.pasteurbrewing.com |access-date=2016-02-23 |archive-url=https://web.archive.org/web/20110113030412/http://www.pasteurbrewing.com/articles/beer-wine-fermentation.html |archive-date=2011-01-13 |url-status=dead }}</ref> His experiments showed that alcohol fermentation occurs by the action of living [[microorganism]]s, yeasts, and that glucose consumption decreased under aerobic conditions (the [[Pasteur effect]]).<ref>{{cite journal | vauthors = Alba-Lois L, Segal-Kischinevzky C | title = Yeast fermentation and the making of beer and wine. | journal = Nature Education | date = January 2010 | volume = 3 | issue = 9 | pages = 17 | url = http://www.nature.com/scitable/topicpage/yeast-fermentation-and-the-making-of-beer-14372813 }}</ref>
[[File:Eduardbuchner.jpg|left|thumb|Eduard Buchner discovered cell-free fermentation.]]

The component steps of glycolysis were first analysed by the non-cellular fermentation experiments of [[Eduard Buchner]] during the 1890s.<ref>{{cite journal | vauthors = Kohler R | title = The background to Eduard Buchner's discovery of cell-free fermentation | journal = Journal of the History of Biology | volume = 4 | issue = 1 | pages = 35–61 | date = 1971-03-01 | pmid = 11609437 | doi = 10.1007/BF00356976 | s2cid = 46573308 }}</ref><ref>{{cite web |title=Eduard Buchner - Biographical |url=https://www.nobelprize.org/nobel_prizes/chemistry/laureates/1907/buchner-bio.html |website=www.nobelprize.org |access-date=2016-02-23}}</ref> Buchner demonstrated that the conversion of glucose to ethanol was possible using a non-living extract of yeast, due to the action of [[enzyme]]s in the extract.<ref name = "Cornish-Bowden_1997">{{cite book |publisher=Publicacions de la Universitat de València |title=New Beer in an Old Bottle: Eduard Buchner and the Growth of Biochemical Knowledge | editor-first = Athel | editor-last = Cornish-Bawden |year=1997 |location=Valencia, Spain |chapter=Harden and Young's Discovery of Fructose 1,6-Bisphosphate}}</ref>{{rp|135–148}} This experiment not only revolutionized biochemistry, but also allowed later scientists to analyze this pathway in a more controlled laboratory setting. In a series of experiments (1905–1911), scientists [[Arthur Harden]] and [[William John Young (biochemist)|William Young]] discovered more pieces of glycolysis.<ref name=":1">{{Cite book|title=Bios 302| vauthors = Palmer G |url=http://www.bioc.rice.edu/~graham/Bios302/chapters/Chapter_3.pdf | archive-url = https://web.archive.org/web/20171118060851/http://www.bioc.rice.edu/~graham/Bios302/chapters/Chapter_3.pdf | archive-date = 18 November 2017 |chapter=Chapter 3: The History of Glycolysis: An Example of a Linear Metabolic Pathway. }}</ref> They discovered the regulatory effects of ATP on glucose consumption during alcohol fermentation. They also shed light on the role of one compound as a glycolysis intermediate: fructose 1,6-bisphosphate.<ref name = "Cornish-Bowden_1997" />{{rp|151–158}}

The elucidation of fructose 1,6-bisphosphate was accomplished by measuring {{chem2|CO2}} levels when yeast juice was incubated with glucose. {{chem2|CO2}} production increased rapidly then slowed down. Harden and Young noted that this process would restart if an inorganic phosphate (Pi) was added to the mixture. Harden and Young deduced that this process produced organic phosphate esters, and further experiments allowed them to extract fructose diphosphate (F-1,6-DP).

[[Arthur Harden]] and [[William John Young (biochemist)|William Young]] along with Nick Sheppard determined, in a second experiment, that a heat-sensitive high-molecular-weight subcellular fraction (the enzymes) and a heat-insensitive low-molecular-weight cytoplasm fraction (ADP, ATP and NAD<sup>+</sup> and other [[Cofactor (biochemistry)|cofactors]]) are required together for fermentation to proceed. This experiment begun by observing that dialyzed (purified) yeast juice could not ferment or even create a sugar phosphate. This mixture was rescued with the addition of undialyzed yeast extract that had been boiled. Boiling the yeast extract renders all proteins inactive (as it denatures them). The ability of boiled extract plus dialyzed juice to complete fermentation suggests that the cofactors were non-protein in character.<ref name=":1" />
[[File:Otto Fritz Meyerhof.jpg|thumb|Otto Meyerhof, one of the main scientists involved in completing the puzzle of glycolysis]]
In the 1920s [[Otto Fritz Meyerhof|Otto Meyerhof]] was able to link together some of the many individual pieces of glycolysis discovered by Buchner, Harden, and Young. Meyerhof and his team were able to extract different glycolytic enzymes from [[muscle tissue]], and combine them to artificially create the pathway from glycogen to lactic acid.<ref>{{cite web |title=Otto Meyerhof - Biographical |url=https://www.nobelprize.org/nobel_prizes/medicine/laureates/1922/meyerhof-bio.html |website=www.nobelprize.org |access-date=2016-02-23}}</ref><ref name=":0">{{cite journal | vauthors = Kresge N, Simoni RD, Hill RL | title = Otto Fritz Meyerhof and the elucidation of the glycolytic pathway | journal = The Journal of Biological Chemistry | volume = 280 | issue = 4 | pages = e3 | date = January 2005 | pmid = 15665335 | doi = 10.1016/S0021-9258(20)76366-0 | doi-access = free }}</ref>

In one paper, Meyerhof and scientist Renate Junowicz-Kockolaty investigated the reaction that splits fructose 1,6-diphosphate into the two triose phosphates. Previous work proposed that the split occurred via 1,3-diphosphoglyceraldehyde plus an oxidizing enzyme and cozymase. Meyerhoff and Junowicz found that the equilibrium constant for the isomerase and aldoses reaction were not affected by inorganic phosphates or any other cozymase or oxidizing enzymes. They further removed diphosphoglyceraldehyde as a possible intermediate in glycolysis.<ref name=":0" />

With all of these pieces available by the 1930s, [[Gustav Embden]] proposed a detailed, step-by-step outline of that pathway we now know as glycolysis.<ref>{{cite web |title=Embden, Gustav – Dictionary definition of Embden, Gustav {{!}} Encyclopedia.com: FREE online dictionary |url=http://www.encyclopedia.com/doc/1G2-2830901312.html |website=www.encyclopedia.com |access-date=2016-02-23}}</ref> The biggest difficulties in determining the intricacies of the pathway were due to the very short lifetime and low steady-state concentrations of the intermediates of the fast glycolytic reactions. By the 1940s, Meyerhof, Embden and many other biochemists had finally completed the puzzle of glycolysis.<ref name=":0" /> The understanding of the isolated pathway has been expanded in the subsequent decades, to include further details of its regulation and integration with other metabolic pathways.
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