Array ( [0] => {{short description|Series of interconnected biochemical reactions}}{{cs1 config|name-list-style=vanc|display-authors=6}}{{Glycolysis summary}}[[File:Aerobic respiration summary.jpg|thumb|400px|Summary of aerobic respiration]]{{sm|}}'''Glycolysis''' is the [[metabolic pathway]] that converts [[glucose]] ({{chem2|C6H12O6}}) into [[pyruvic acid|pyruvate]] and, in most organisms, occurs in the liquid part of cells (the [[cytosol]]). The [[Thermodynamic free energy|free energy]] released in this process is used to form the high-energy molecules [[adenosine triphosphate]] (ATP) and [[NADH|reduced nicotinamide adenine dinucleotide]] (NADH).{{cite journal | vauthors = Alfarouk KO, Verduzco D, Rauch C, Muddathir AK, Adil HH, Elhassan GO, Ibrahim ME, David Polo Orozco J, Cardone RA, Reshkin SJ, Harguindey S | title = Glycolysis, tumor metabolism, cancer growth and dissemination. A new pH-based etiopathogenic perspective and therapeutic approach to an old cancer question | journal = Oncoscience | volume = 1 | issue = 12 | pages = 777–802 | date = 18 December 2014 | pmid = 25621294 | doi = 10.18632/oncoscience.109 | pmc = 4303887 }} Glycolysis is a sequence of ten reactions catalyzed by [[enzyme]]s. [1] => [[File:Glycolysis Summary.svg|thumb|375x375px|Summary of the 10 reactions of the glycolysis pathway]] [2] => [3] => The wide occurrence of glycolysis in other species indicates that it is an ancient metabolic pathway.{{cite journal | vauthors = Romano AH, Conway T | title = Evolution of carbohydrate metabolic pathways | journal = Research in Microbiology | volume = 147 | issue = 6–7 | pages = 448–455 | year = 1996 | pmid = 9084754 | doi = 10.1016/0923-2508(96)83998-2 | doi-access = free }} Indeed, the reactions that make up glycolysis and its parallel pathway, the [[pentose phosphate pathway]], can occur in the [[Great Oxygenation Event|oxygen-free conditions]] of the [[Archean]] oceans, also in the absence of enzymes, catalyzed by metal ions, meaning this is a plausible prebiotic pathway for [[abiogenesis]].{{cite journal | vauthors = Keller MA, Turchyn AV, Ralser M | title = Non-enzymatic glycolysis and pentose phosphate pathway-like reactions in a plausible Archean ocean | journal = Molecular Systems Biology | volume = 10 | issue = 4 | pages = 725 | date = April 2014 | pmid = 24771084 | pmc = 4023395 | doi = 10.1002/msb.20145228 }} [4] => [5] => The most common type of glycolysis is the ''Embden–Meyerhof–Parnas (EMP) pathway'', which was discovered by [[Gustav Embden]], [[Otto Meyerhof]], and [[Jakub Karol Parnas]]. Glycolysis also refers to other pathways, such as the ''[[Entner–Doudoroff pathway]]'' and various heterofermentative and homofermentative pathways. However, the discussion here will be limited to the Embden–Meyerhof–Parnas pathway.Kim BH, [[Geoffrey Michael Gadd|Gadd GM]]. (2011) Bacterial Physiology and Metabolism, 3rd edition. [6] => [7] => The glycolysis pathway can be separated into two phases:{{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 }} [8] => # Investment phase – wherein ATP is consumed [9] => # Yield phase – wherein more ATP is produced than originally consumed [10] => [11] => [12] => == Overview == [13] => The overall reaction of glycolysis is: [14] =>
[15] => {{Biochem reaction subunit|compound={{sm|d}}-Glucose|link=Glucose|image=D-glucose wpmp.svg}} [16] => {{Biochem reaction subunit|title= |style=background:lightgreen|other_content=+ 2 [NAD]+
+ 2 [ADP]
+ 2 [P]i}} [17] => {{Biochem reaction subunit|title= |enzyme=various}} [18] => {{Biochem reaction subunit|n=2|compound=Pyruvate|image=Pyruvate skeletal.svg}} [19] => {{Biochem reaction subunit|title= |style=background:lightgreen|other_content=+ 2 [NADH]
+ 2 H+
+ 2 [ATP]
+ 2 H2O}}
[20] => [[File:Glycolysis.svg|thumb|445x445px|Glycolysis pathway overview.]] [21] => The use of symbols in this equation makes it appear unbalanced with respect to oxygen atoms, hydrogen atoms, and charges. Atom balance is maintained by the two phosphate (Pi) groups:{{Cite journal| vauthors = Lane AN, Fan TW, Higashi RM | title = Metabolic acidosis and the importance of balanced equations | journal = Metabolomics| volume = 5| issue = 2| pages = 163–165| year = 2009| doi = 10.1007/s11306-008-0142-2 | s2cid = 35500999}} [22] => * Each exists in the form of a [[Phosphoric acid#Orthophosphoric acid chemistry|hydrogen phosphate]] anion ({{chem2|[HPO4](2−)}}), dissociating to contribute {{chem2|2H+}} overall [23] => * Each liberates an oxygen atom when it binds to an [[adenosine diphosphate]] (ADP) molecule, contributing 2{{nbsp}}O overall [24] => [25] => Charges are balanced by the difference between ADP and ATP. In the cellular environment, all three hydroxyl groups of ADP dissociate into −O− and H+, giving ADP3−, and this ion tends to exist in an ionic bond with Mg2+, giving ADPMg−. ATP behaves identically except that it has four hydroxyl groups, giving ATPMg2−. When these differences along with the true charges on the two phosphate groups are considered together, the net charges of −4 on each side are balanced. [26] => [27] => For simple [[fermentation (biochemistry)|fermentations]], the metabolism of one molecule of glucose to two molecules of pyruvate has a net yield of two molecules of ATP. Most cells will then carry out further reactions to "repay" the used NAD+ and produce a final product of [[ethanol]] or [[lactic acid]]. Many bacteria use inorganic compounds as hydrogen acceptors to regenerate the NAD+. [28] => [29] => Cells performing [[aerobic respiration]] synthesize much more ATP, but not as part of glycolysis. These further aerobic reactions use [[pyruvate]], and NADH + H+ from glycolysis. Eukaryotic aerobic respiration produces approximately 34 additional molecules of ATP for each glucose molecule, however most of these are produced by a mechanism vastly different from the [[substrate-level phosphorylation]] in glycolysis. [30] => [31] => The lower-energy production, per glucose, of anaerobic respiration relative to aerobic respiration, results in greater flux through the pathway under hypoxic (low-oxygen) conditions, unless alternative sources of anaerobically oxidizable substrates, such as fatty acids, are found. [32] => [33] => {| class="toccolours collapsible collapsed" width="100%" style="text-align:left" [34] => ! Metabolism of common [[monosaccharide]]s, including glycolysis, [[gluconeogenesis]], [[glycogenesis]] and [[glycogenolysis]] [35] => |- [36] => | [[File:Metabolism of common monosaccharides, and related reactions.png|none|1000px]] [37] => |} [38] => [39] => == History == [40] => The pathway of glycolysis as it is known today took almost 100 years to fully elucidate.{{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 }} The combined results of many smaller experiments were required in order to understand the intricacies of the entire pathway. [41] => [42] => The first steps in understanding glycolysis began in the nineteenth century with the wine industry. For economic reasons, the French wine industry sought to investigate why wine sometimes turned distasteful, instead of fermenting into alcohol. French scientist [[Louis Pasteur]] researched this issue during the 1850s, and the results of his experiments began the long road to elucidating the pathway of glycolysis.{{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 }} His experiments showed that fermentation occurs by the action of living [[microorganism]]s, yeasts, and that yeast's glucose consumption decreased under aerobic conditions of fermentation, in comparison to anaerobic conditions (the [[Pasteur effect]]).{{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 }} [43] => [[File:Eduardbuchner.jpg|left|thumb|Eduard Buchner. Discovered cell-free fermentation.]] [44] => [45] => Insight into the component steps of glycolysis were provided by the non-cellular fermentation experiments of [[Eduard Buchner]] during the 1890s.{{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 }}{{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}} 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.{{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}}{{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.{{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. }} 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.{{rp|151–158}} [46] => [47] => 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). [48] => [49] => [[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+ 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. [50] => [[File:Otto Fritz Meyerhof.jpg|thumb|Otto Meyerhof. One of the main scientists involved in completing the puzzle of glycolysis]] [51] => 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.{{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}}{{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 }} [52] => [53] => 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. [54] => [55] => 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.{{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}} 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. 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. [56] => {{clear}} [57] => [58] => == Sequence of reactions == [59] => ===Summary of reactions=== [60] => {{Glycolysis|navbox=no|style=border: solid 1px #aaa; margin: 0.5em; font-size:90%}} [61] => [62] => ===Preparatory phase=== [63] => [64] => The first five steps of Glycolysis are regarded as the preparatory (or investment) phase, since they consume energy to convert the glucose into two three-carbon sugar phosphates ([[glyceraldehyde 3-phosphate|G3P]]). [65] => [66] => {{Stack|margin=yes|{{Enzymatic Reaction [67] => |forward_enzyme=[[Hexokinase]] [[glucokinase]] ('''HK''')
''a [[transferase]]'' [68] => |reverse_enzyme= [69] => |substrate={{sm|d}}-[[Glucose]] ('''Glc''') [70] => |product=α-{{sm|d}}-[[Glucose-6-phosphate]] ('''G6P''') [71] => |reaction_direction_(forward/reversible/reverse)=forward [72] => |minor_forward_substrate(s)=[[Adenosine triphosphate|ATP]] [73] => |minor_forward_product(s)= H+ + [[adenosine diphosphate|ADP]] [74] => |minor_reverse_substrate(s)= [75] => |minor_reverse_product(s)= [76] => |substrate_image=D-glucose wpmp.svg [77] => |product_image=Alpha-D-glucose-6-phosphate wpmp.svg [78] => }}}} [79] => Once glucose enters the cell, the first step is phosphorylation of glucose by a family of enzymes called [[hexokinase]]s to form glucose 6-phosphate (G6P). This reaction consumes ATP, but it acts to keep the glucose concentration inside the cell low, promoting continuous transport of blood glucose into the cell through the plasma membrane transporters. In addition, phosphorylation blocks the glucose from leaking out – the cell lacks transporters for G6P, and free diffusion out of the cell is prevented due to the charged nature of G6P. Glucose may alternatively be formed from the [[phosphorolysis]] or [[hydrolysis]] of intracellular starch or glycogen. [80] => [81] => In [[animal]]s, an [[isozyme]] of hexokinase called [[glucokinase]] is also used in the liver, which has a much lower affinity for glucose (Km in the vicinity of normal glycemia), and differs in regulatory properties. The different substrate affinity and alternate regulation of this enzyme are a reflection of the role of the liver in maintaining blood sugar levels. [82] => [83] => ''Cofactors:'' Mg2+ [84] => {{clear}}{{hr}} [85] => [86] => {{Stack|margin=yes|{{Enzymatic Reaction [87] => |forward_enzyme=[[Phosphoglucoisomerase]] ('''PGI''')
''an [[isomerase]]'' [88] => |reverse_enzyme= [89] => |substrate=α-{{sm|d}}-[[Glucose 6-phosphate]] ('''G6P''') [90] => |product=β-{{sm|d}}-[[Fructose 6-phosphate]] ('''F6P''') [91] => |reaction_direction_(forward/reversible/reverse)=reversible [92] => |minor_forward_substrate(s)= [93] => |minor_forward_product(s)= [94] => |minor_reverse_substrate(s)= [95] => |minor_reverse_product(s)= [96] => |substrate_image=Alpha-D-glucose-6-phosphate wpmp.svg [97] => |product_image=Beta-D-fructose-6-phosphate wpmp.png [98] => }}}} [99] => G6P is then rearranged into [[fructose 6-phosphate]] (F6P) by [[glucose phosphate isomerase]]. [[Fructose]] can also enter the glycolytic pathway by phosphorylation at this point. [100] => [101] => The change in structure is an isomerization, in which the G6P has been converted to F6P. The reaction requires an enzyme, phosphoglucose isomerase, to proceed. This reaction is freely reversible under normal cell conditions. However, it is often driven forward because of a low concentration of F6P, which is constantly consumed during the next step of glycolysis. Under conditions of high F6P concentration, this reaction readily runs in reverse. This phenomenon can be explained through [[Le Chatelier's Principle]]. Isomerization to a keto sugar is necessary for carbanion stabilization in the fourth reaction step (below). [102] => {{clear}}{{hr}} [103] => [104] => {{Stack|margin=yes|{{Enzymatic Reaction [105] => |forward_enzyme=[[Phosphofructokinase 1|Phosphofructokinase]] ('''PFK-1''')
''a [[transferase]]'' [106] => |reverse_enzyme= [107] => |substrate=β-{{sm|d}}-[[Fructose 6-phosphate]] ('''F6P''') [108] => |product=β-{{sm|d}}-[[Fructose 1,6-bisphosphate]] ('''F1,6BP''') [109] => |reaction_direction_(forward/reversible/reverse)=forward [110] => |minor_forward_substrate(s)= ATP [111] => |minor_forward_product(s)= H+ + ADP [112] => |minor_reverse_substrate(s)= [113] => |minor_reverse_product(s)= [114] => |substrate_image=Beta-D-fructose-6-phosphate wpmp.png [115] => |product_image=beta-D-fructose-1,6-bisphosphate_wpmp.svg [116] => }}}} [117] => The energy expenditure of another ATP in this step is justified in 2 ways: The glycolytic process (up to this step) becomes irreversible, and the energy supplied destabilizes the molecule. Because the reaction catalyzed by [[phosphofructokinase 1]] (PFK-1) is coupled to the hydrolysis of ATP (an energetically favorable step) it is, in essence, irreversible, and a different pathway must be used to do the reverse conversion during [[gluconeogenesis]]. This makes the reaction a key regulatory point (see below). [118] => [119] => Furthermore, the second phosphorylation event is necessary to allow the formation of two charged groups (rather than only one) in the subsequent step of glycolysis, ensuring the prevention of free diffusion of substrates out of the cell. [120] => [121] => The same reaction can also be catalyzed by [[PFP (enzyme)|pyrophosphate-dependent phosphofructokinase]] ('''PFP''' or '''PPi-PFK'''), which is found in most plants, some bacteria, archea, and protists, but not in animals. This enzyme uses pyrophosphate (PPi) as a phosphate donor instead of ATP. It is a reversible reaction, increasing the flexibility of glycolytic metabolism.{{cite journal | vauthors = Reeves RE, South DJ, Blytt HJ, Warren LG | title = Pyrophosphate:D-fructose 6-phosphate 1-phosphotransferase. A new enzyme with the glycolytic function of 6-phosphofructokinase | journal = The Journal of Biological Chemistry | volume = 249 | issue = 24 | pages = 7737–7741 | date = December 1974 | pmid = 4372217 | doi = 10.1016/S0021-9258(19)42029-2 | doi-access = free }} A rarer ADP-dependent PFK enzyme variant has been identified in archaean species.{{cite journal | vauthors = Selig M, Xavier KB, Santos H, Schönheit P | title = Comparative analysis of Embden-Meyerhof and Entner-Doudoroff glycolytic pathways in hyperthermophilic archaea and the bacterium Thermotoga | journal = Archives of Microbiology | volume = 167 | issue = 4 | pages = 217–232 | date = April 1997 | pmid = 9075622 | doi = 10.1007/BF03356097 | bibcode = 1997ArMic.167..217S | s2cid = 19489719 }} [122] => [123] => ''Cofactors:'' Mg2+ [124] => {{clear}}{{hr}} [125] => [126] => {{Stack|margin=yes|{{Complex enzymatic reaction [127] => |major_substrate_1=β-{{sm|d}}-[[Fructose 1,6-bisphosphate]] ('''F1,6BP''') [128] => |major_substrate_1_stoichiometric_constant= [129] => |major_substrate_1_image=beta-D-fructose-1,6-bisphosphate_wpmp.svg [130] => |major_substrate_2= [131] => |major_substrate_2_stoichiometric_constant= [132] => |major_substrate_2_image= [133] => |major_product_1={{sm|d}}-[[Glyceraldehyde 3-phosphate]] ('''GADP''') [134] => |major_product_1_stoichiometric_constant= [135] => |major_product_1_image=D-glyceraldehyde-3-phosphate wpmp.png [136] => |major_product_2=[[Dihydroxyacetone phosphate]] ('''DHAP''') [137] => |major_product_2_stoichiometric_constant= [138] => |major_product_2_image=glycerone-phosphate_wpmp.png [139] => |forward_enzyme=[[Fructose-bisphosphate aldolase]] ('''ALDO''')
''a [[lyase]]'' [140] => |reverse_enzyme= [141] => |reaction_direction_(forward/reversible/reverse)=reversible [142] => |minor_forward_substrate(s)= [143] => |minor_forward_product(s) = [144] => |minor_reverse_product(s) = [145] => |minor_reverse_substrate(s)= [146] => }}}} [147] => Destabilizing the molecule in the previous reaction allows the hexose ring to be split by [[Fructose-bisphosphate aldolase|aldolase]] into two triose sugars: [[dihydroxyacetone phosphate]] (a ketose), and [[glyceraldehyde 3-phosphate]] (an aldose). There are two classes of aldolases: class I aldolases, present in animals and plants, and class II aldolases, present in fungi and bacteria; the two classes use different mechanisms in cleaving the ketose ring. [148] => [149] => Electrons delocalized in the carbon-carbon bond cleavage associate with the alcohol group. The resulting carbanion is stabilized by the structure of the carbanion itself via resonance charge distribution and by the presence of a charged ion prosthetic group. [150] => {{clear}}{{hr}} [151] => [152] => {{Stack|margin=yes|{{Enzymatic Reaction [153] => |forward_enzyme=[[Triosephosphate isomerase]] ('''TPI''')
''an isomerase'' [154] => |reverse_enzyme= [155] => |substrate=[[Dihydroxyacetone phosphate]] ('''DHAP''') [156] => |product={{sm|d}}-[[Glyceraldehyde 3-phosphate]] ('''GADP''') [157] => |reaction_direction_(forward/reversible/reverse)=reversible [158] => |minor_forward_substrate(s)= [159] => |minor_forward_product(s) = [160] => |minor_reverse_substrate(s)= [161] => |minor_reverse_product(s) = [162] => |substrate_image=glycerone-phosphate_wpmp.png [163] => |product_image=D-glyceraldehyde-3-phosphate wpmp.png [164] => }}}} [165] => [[Triosephosphate isomerase]] rapidly interconverts dihydroxyacetone phosphate with [[glyceraldehyde 3-phosphate]] ('''GADP''') that proceeds further into glycolysis. This is advantageous, as it directs dihydroxyacetone phosphate down the same pathway as glyceraldehyde 3-phosphate, simplifying regulation. [166] => {{clear}} [167] => [168] => ===Pay-off phase=== [169] => [170] => The second half of glycolysis is known as the pay-off phase, characterised by a net gain of the energy-rich molecules ATP and NADH. Since glucose leads to two triose sugars in the preparatory phase, each reaction in the pay-off phase occurs twice per glucose molecule. This yields 2 NADH molecules and 4 ATP molecules, leading to a net gain of 2 NADH molecules and 2 ATP molecules from the glycolytic pathway per glucose. [171] => [172] => {{Stack|margin=yes|{{Enzymatic Reaction [173] => |forward_enzyme=[[Glyceraldehyde phosphate dehydrogenase]] ('''GAPDH''')
''an [[oxidoreductase]]'' [174] => |reverse_enzyme= [175] => |substrate=[[Glyceraldehyde 3-phosphate]] ('''GADP''') [176] => |product={{sm|d}}-[[1,3-Bisphosphoglycerate]] ('''1,3BPG''') [177] => |reaction_direction_(forward/reversible/reverse)=reversible [178] => |minor_forward_substrate(s)=NAD+ '''+''' Pi [179] => |minor_forward_product(s)=NADH '''+''' H+ [180] => |minor_reverse_substrate(s)=  [181] => |minor_reverse_product(s)=  [182] => |substrate_image=D-glyceraldehyde-3-phosphate wpmp.png [183] => |product_image=1,3-bisphospho-D-glycerate.png [184] => }}}} [185] => The aldehyde groups of the triose sugars are [[oxidised]], and [[inorganic phosphate]] is added to them, forming [[1,3-bisphosphoglycerate]]. [186] => [187] => The hydrogen is used to reduce two molecules of [[NAD+|NAD+]], a hydrogen carrier, to give NADH '''+''' H+ for each triose. [188] => [189] => Hydrogen atom balance and charge balance are both maintained because the phosphate (Pi) group actually exists in the form of a [[Phosphoric acid#Orthophosphoric acid chemistry|hydrogen phosphate]] anion ({{chem2|HPO4(2−)}}), which dissociates to contribute the extra H+ ion and gives a net charge of -3 on both sides. [190] => [191] => Here, [[arsenate]] ({{chem2|[AsO4](3-)}}), an anion akin to inorganic phosphate may replace phosphate as a substrate to form 1-arseno-3-phosphoglycerate. This, however, is unstable and readily hydrolyzes to form [[3-Phosphoglycerate|3-phosphoglycerate]], the intermediate in the next step of the pathway. As a consequence of bypassing this step, the molecule of ATP generated from [[1,3-Bisphosphoglycerate|1-3 bisphosphoglycerate]] in the next reaction will not be made, even though the reaction proceeds. As a result, arsenate is an uncoupler of glycolysis.{{Cite book|title=Biochemistry| vauthors = Garrett RH, Grisham CM |publisher=Cengage Learning | edition = 5th |year=2012|isbn=978-1-133-10629-6}} [192] => {{clear}}{{hr}} [193] => [194] => {{Stack|margin=yes|{{Enzymatic Reaction [195] => |forward_enzyme=[[Phosphoglycerate kinase]] ('''PGK''')
''a [[transferase]]'' [196] => |reverse_enzyme=[[Phosphoglycerate kinase]] ('''PGK''') [197] => |substrate=[[1,3-Bisphosphoglycerate]] ('''1,3BPG''') [198] => |product=[[3-Phosphoglycerate]] ('''3PG''') [199] => |reaction_direction_(forward/reversible/reverse)=reversible [200] => |minor_forward_substrate(s)=ADP [201] => |minor_forward_product(s)=ATP [202] => |minor_reverse_substrate(s)=  [203] => |minor_reverse_product(s)=  [204] => |substrate_image=1,3-bisphospho-D-glycerate.png [205] => |product_image=3-phospho-D-glycerate wpmp.png [206] => }}}} [207] => [208] => This step is the enzymatic transfer of a phosphate group from [[1,3-bisphosphoglycerate]] to ADP by [[phosphoglycerate kinase]], forming ATP and [[3-phosphoglycerate]]. At this step, glycolysis has reached the break-even point: 2 molecules of ATP were consumed, and 2 new molecules have now been synthesized. This step, one of the two [[substrate-level phosphorylation]] steps, requires ADP; thus, when the cell has plenty of ATP (and little ADP), this reaction does not occur. Because ATP decays relatively quickly when it is not metabolized, this is an important regulatory point in the glycolytic pathway. [209] => [210] => ADP actually exists as ADPMg−, and ATP as ATPMg2−, balancing the charges at −5 both sides. [211] => [212] => ''Cofactors:'' Mg2+ [213] => {{clear}}{{hr}} [214] => [215] => {{Stack|margin=yes|{{Enzymatic Reaction [216] => |forward_enzyme=[[Phosphoglycerate mutase]] ('''PGM''')
''a [[mutase]]'' [217] => |reverse_enzyme= [218] => |substrate=[[3-Phosphoglycerate]] ('''3PG''') [219] => |product=[[2-Phosphoglycerate]] ('''2PG''') [220] => |reaction_direction_(forward/reversible/reverse)=reversible [221] => |minor_forward_substrate(s)= [222] => |minor_forward_product(s)= [223] => |minor_reverse_substrate(s)= [224] => |minor_reverse_product(s)= [225] => |substrate_image=3-phospho-D-glycerate wpmp.png [226] => |product_image=2-phospho-D-glycerate_wpmp.png [227] => }}}} [228] => [[Phosphoglycerate mutase]] isomerises [[3-phosphoglycerate]] into [[2-phosphoglycerate]]. [229] => {{clear}}{{hr}} [230] => [231] => {{Stack|margin=yes|{{Enzymatic Reaction [232] => |forward_enzyme=[[Enolase]] ('''ENO''')
''a [[lyase]]'' [233] => |reverse_enzyme=[[Enolase]] ('''ENO''') [234] => |substrate=[[2-Phosphoglycerate]] ('''2PG''') [235] => |product=[[Phosphoenolpyruvate]] ('''PEP''') [236] => |reaction_direction_(forward/reversible/reverse)=reversible [237] => |minor_forward_substrate(s)= [238] => |minor_forward_product(s)= H2O [239] => |minor_reverse_substrate(s)=   [240] => |minor_reverse_product(s)= [241] => |substrate_image=2-phospho-D-glycerate_wpmp.png [242] => |product_image=phosphoenolpyruvate_wpmp.png [243] => }}}} [244] => [[Enolase]] next converts [[2-phosphoglycerate]] to [[phosphoenolpyruvate]]. This reaction is an elimination reaction involving an [[E1cB-elimination reaction|E1cB]] mechanism. [245] => [246] => ''Cofactors:'' 2 Mg2+, one "conformational" ion to coordinate with the carboxylate group of the substrate, and one "catalytic" ion that participates in the dehydration. [247] => {{clear}}{{hr}} [248] => [249] => {{Stack|margin=yes|{{Enzymatic Reaction [250] => |forward_enzyme=[[Pyruvate kinase]] ('''PK''')
''a [[transferase]]'' [251] => |reverse_enzyme= [252] => |substrate=[[Phosphoenolpyruvate]] ('''PEP''') [253] => |product=[[Pyruvate]] ('''Pyr''') [254] => |reaction_direction_(forward/reversible/reverse)=forward [255] => |minor_forward_substrate(s)=ADP + H+ [256] => |minor_forward_product(s)=ATP [257] => |minor_reverse_substrate(s)= [258] => |minor_reverse_product(s)= [259] => |substrate_image=phosphoenolpyruvate_wpmp.png [260] => |product_image=pyruvate_wpmp.png [261] => }}}} [262] => [263] => A final [[substrate-level phosphorylation]] now forms a molecule of [[pyruvate]] and a molecule of ATP by means of the enzyme [[pyruvate kinase]]. This serves as an additional regulatory step, similar to the phosphoglycerate kinase step. [264] => [265] => ''Cofactors:'' Mg2+ [266] => {{clear}} [267] => [268] => === Biochemical logic === [269] => The existence of more than one point of regulation indicates that intermediates between those points enter and leave the glycolysis pathway by other processes. For example, in the first regulated step, [[hexokinase]] converts glucose into glucose-6-phosphate. Instead of continuing through the glycolysis pathway, this intermediate can be converted into glucose storage molecules, such as [[glycogen]] or [[starch]]. The reverse reaction, breaking down, e.g., glycogen, produces mainly glucose-6-phosphate; very little free glucose is formed in the reaction. The glucose-6-phosphate so produced can enter glycolysis ''after'' the first control point. [270] => [271] => In the second regulated step (the third step of glycolysis), [[phosphofructokinase]] converts fructose-6-phosphate into fructose-1,6-bisphosphate, which then is converted into glyceraldehyde-3-phosphate and dihydroxyacetone phosphate. The dihydroxyacetone phosphate can be removed from glycolysis by conversion into glycerol-3-phosphate, which can be used to form triglycerides.{{Cite book | vauthors = Berg JM, Tymoczko JL, Stryer L | title = Biochemistry | place = New York | publisher = Freeman | year = 2007 | edition = 6th | page = 622 | isbn = 978-0-7167-8724-2 }} Conversely, [[triglyceride]]s can be broken down into fatty acids and glycerol; the latter, in turn, can be [[Glycerol#Metabolism|converted]] into dihydroxyacetone phosphate, which can enter glycolysis ''after'' the second control point. [272] => [273] => === Free energy changes === [274] => {| align="right" class="wikitable" [275] => |+ Concentrations of metabolites in [[Red blood cell|erythrocytes]]{{Cite book | vauthors = Garrett R, Grisham CM | title = Biochemistry | place = Belmont, CA | publisher = Thomson Brooks/Cole | year = 2005 | edition = 3rd | page = 584 | isbn = 978-0-534-49033-1 }}{{rp|584}} [276] => ! Compound [277] => ! Concentration / mM [278] => |- [279] => |Glucose [280] => |5.0 [281] => |- [282] => |Glucose-6-phosphate [283] => |0.083 [284] => |- [285] => |Fructose-6-phosphate [286] => |0.014 [287] => |- [288] => |Fructose-1,6-bisphosphate [289] => |0.031 [290] => |- [291] => |Dihydroxyacetone phosphate [292] => |0.14 [293] => |- [294] => |Glyceraldehyde-3-phosphate [295] => |0.019 [296] => |- [297] => |1,3-Bisphosphoglycerate [298] => |0.001 [299] => |- [300] => |2,3-Bisphosphoglycerate [301] => |4.0 [302] => |- [303] => |3-Phosphoglycerate [304] => |0.12 [305] => |- [306] => |2-Phosphoglycerate [307] => |0.03 [308] => |- [309] => |Phosphoenolpyruvate [310] => |0.023 [311] => |- [312] => |Pyruvate [313] => |0.051 [314] => |- [315] => |ATP [316] => |1.85 [317] => |- [318] => |ADP [319] => |0.14 [320] => |- [321] => |Pi [322] => |1.0 [323] => |} [324] => [325] => The change in free energy, Δ''G'', for each step in the glycolysis pathway can be calculated using Δ''G'' = Δ''G''°′ + ''RT''ln ''Q'', where ''Q'' is the [[reaction quotient]]. This requires knowing the concentrations of the [[Metabolomics|metabolites]]. All of these values are available for [[Red blood cell|erythrocytes]], with the exception of the concentrations of NAD+ and NADH. The ratio of [[NADH|NAD+ to NADH]] in the cytoplasm is approximately 1000, which makes the oxidation of glyceraldehyde-3-phosphate (step 6) more favourable. [326] => [327] => Using the measured concentrations of each step, and the standard free energy changes, the actual free energy change can be calculated. (Neglecting this is very common - the delta G of ATP hydrolysis in cells is not the standard free energy change of ATP hydrolysis quoted in textbooks). [328] => [329] => {| class="wikitable" [330] => |+ Change in free energy for each step of glycolysis{{rp|582–583}} [331] => ! Step [332] => ! Reaction [333] => ! colspan=2|Δ''G''°′
(kJ/mol) [334] => ! colspan=2|Δ''G''
(kJ/mol) [335] => |- [336] => | 1 [337] => | Glucose + ATP4− → Glucose-6-phosphate2− + ADP3− + H+ [338] => | {{decimal cell|−16.7}} [339] => | {{decimal cell|−34}} [340] => |- [341] => | 2 [342] => | Glucose-6-phosphate2− → Fructose-6-phosphate2− [343] => | {{decimal cell|1.67}} [344] => | {{decimal cell|−2.9}} [345] => |- [346] => | 3 [347] => | Fructose-6-phosphate2− + ATP4− → Fructose-1,6-bisphosphate4− + ADP3− + H+ [348] => | {{decimal cell|−14.2}} [349] => | {{decimal cell|−19}} [350] => |- [351] => | 4 [352] => | Fructose-1,6-bisphosphate4− → Dihydroxyacetone phosphate2− + Glyceraldehyde-3-phosphate2− [353] => | {{decimal cell|23.9}} [354] => | {{decimal cell|−0.23}} [355] => |- [356] => | 5 [357] => | Dihydroxyacetone phosphate2− → Glyceraldehyde-3-phosphate2− [358] => | {{decimal cell|7.56}} [359] => | {{decimal cell|2.4}} [360] => |- [361] => | 6 [362] => | Glyceraldehyde-3-phosphate2− + Pi2− + NAD+ → 1,3-Bisphosphoglycerate4− + NADH + H+ [363] => | {{decimal cell|6.30}} [364] => | {{decimal cell|−1.29}} [365] => |- [366] => | 7 [367] => | 1,3-Bisphosphoglycerate4− + ADP3− → 3-Phosphoglycerate3− + ATP4− [368] => | {{decimal cell|−18.9}} [369] => | {{decimal cell|0.09}} [370] => |- [371] => | 8 [372] => | 3-Phosphoglycerate3− → 2-Phosphoglycerate3− [373] => | {{decimal cell|4.4}} [374] => | {{decimal cell|0.83}} [375] => |- [376] => | 9 [377] => | 2-Phosphoglycerate3− → Phosphoenolpyruvate3− + H2O [378] => | {{decimal cell|1.8}} [379] => | {{decimal cell|1.1}} [380] => |- [381] => | 10 [382] => | Phosphoenolpyruvate3− + ADP3− + H+ → Pyruvate− + ATP4− [383] => | {{decimal cell|−31.7}} [384] => | {{decimal cell|−23.0}} [385] => |} [386] => [387] => From measuring the physiological concentrations of metabolites in an erythrocyte it seems that about seven of the steps in glycolysis are in equilibrium for that cell type. Three of the steps — the ones with large negative free energy changes — are not in equilibrium and are referred to as ''irreversible''; such steps are often subject to regulation. [388] => [389] => Step 5 in the figure is shown behind the other steps, because that step is a side-reaction that can decrease or increase the concentration of the intermediate glyceraldehyde-3-phosphate. That compound is converted to dihydroxyacetone phosphate by the enzyme triose phosphate isomerase, which is a [[kinetic perfection|catalytically perfect]] enzyme; its rate is so fast that the reaction can be assumed to be in equilibrium. The fact that Δ''G'' is not zero indicates that the actual concentrations in the erythrocyte are not accurately known. [390] => [391] => == Regulation == [392] => The enzymes that catalyse glycolysis are regulated via a range of biological mechanisms in order to control overall [[Flux (metabolism)|flux]] though the pathway. This is vital for both [[Homeostasis|homeostatsis]] in a static environment, and [[metabolic adaptation]] to a changing environment or need.{{cite journal | vauthors = Shimizu K, Matsuoka Y | title = Regulation of glycolytic flux and overflow metabolism depending on the source of energy generation for energy demand | journal = Biotechnology Advances | volume = 37 | issue = 2 | pages = 284–305 | date = March 2019 | pmid = 30576718 | doi = 10.1016/j.biotechadv.2018.12.007 | s2cid = 58591361 }} The details of regulation for some enzymes are highly conserved between species, whereas others vary widely.{{cite journal | vauthors = Chubukov V, Gerosa L, Kochanowski K, Sauer U | title = Coordination of microbial metabolism | journal = Nature Reviews. Microbiology | volume = 12 | issue = 5 | pages = 327–340 | date = May 2014 | pmid = 24658329 | doi = 10.1038/nrmicro3238 | s2cid = 28413431 }}{{cite book | vauthors = Hochachka PW | title = Hypoxia | chapter = Cross-Species Studies of Glycolytic Function | series = Advances in Experimental Medicine and Biology | volume = 474 | pages = 219–229 | date = 1999 | pmid = 10635004 | doi = 10.1007/978-1-4615-4711-2_18 | publisher = Springer US | isbn = 978-1-4613-7134-2 | veditors = Roach RC, Wagner PD, Hackett PH | place = Boston, MA }} [393] => [394] => # Gene Expression: Firstly, the cellular concentrations of glycolytic enzymes are modulated via [[regulation of gene expression]] via [[transcription factors]],{{cite journal | vauthors = Lemaigre FP, Rousseau GG | title = Transcriptional control of genes that regulate glycolysis and gluconeogenesis in adult liver | journal = The Biochemical Journal | volume = 303 | issue = 1 | pages = 1–14 | date = October 1994 | pmid = 7945228 | pmc = 1137548 | doi = 10.1042/bj3030001 }} with several glycolysis enzymes themselves acting as [[Protein kinase|regulatory protein kinases]] in the nucleus.{{cite journal | vauthors = Bian X, Jiang H, Meng Y, Li YP, Fang J, Lu Z | title = Regulation of gene expression by glycolytic and gluconeogenic enzymes | journal = Trends in Cell Biology | pages = 786–799 | date = March 2022 | volume = 32 | issue = 9 | pmid = 35300892 | doi = 10.1016/j.tcb.2022.02.003 | s2cid = 247459973 }} [395] => # [[Allosteric inhibition]] and activation by metabolites: In particular [[end-product inhibition]] of regulated enzymes by metabolites such as ATP serves as negative feedback regulation of the pathway.{{cite journal | vauthors = Gerosa L, Sauer U | title = Regulation and control of metabolic fluxes in microbes | journal = Current Opinion in Biotechnology | volume = 22 | issue = 4 | pages = 566–575 | date = August 2011 | pmid = 21600757 | doi = 10.1016/j.copbio.2011.04.016 }} [396] => # Allosteric inhibition and activation by [[Protein–protein interaction|Protein-protein interactions]] (PPI).{{cite journal | vauthors = Chowdhury S, Hepper S, Lodi MK, Saier MH, Uetz P | title = The Protein Interactome of Glycolysis in ''Escherichia coli'' | journal = Proteomes | volume = 9 | issue = 2 | pages = 16 | date = April 2021 | pmid = 33917325 | pmc = 8167557 | doi = 10.3390/proteomes9020016 | doi-access = free }} Indeed, some proteins interact with and regulate multiple glycolytic enzymes.{{cite journal | vauthors = Rodionova IA, Zhang Z, Mehla J, Goodacre N, Babu M, Emili A, Uetz P, Saier MH | title = The phosphocarrier protein HPr of the bacterial phosphotransferase system globally regulates energy metabolism by directly interacting with multiple enzymes in ''Escherichia coli'' | journal = The Journal of Biological Chemistry | volume = 292 | issue = 34 | pages = 14250–14257 | date = August 2017 | pmid = 28634232 | pmc = 5572926 | doi = 10.1074/jbc.M117.795294 | doi-access = free }} [397] => # [[post-translational modification|Post-translational modification (PTM)]].{{cite journal | vauthors = Pisithkul T, Patel NM, Amador-Noguez D | title = Post-translational modifications as key regulators of bacterial metabolic fluxes | journal = Current Opinion in Microbiology | volume = 24 | pages = 29–37 | date = April 2015 | pmid = 25597444 | doi = 10.1016/j.mib.2014.12.006 }} In particular, phosphorylation and dephosphorylation is a key mechanism of regulation of pyruvate kinase in the liver. [398] => # [[Subcellular localization|Localization]] [399] => [400] => === Regulation by insulin in animals === [401] => [402] => In animals, regulation of blood glucose levels by the pancreas in conjunction with the liver is a vital part of [[homeostasis]]. The [[beta cells]] in the [[pancreatic islets]] are sensitive to the blood glucose concentration.{{cite journal | vauthors = Koeslag JH, Saunders PT, Terblanche E | title = A reappraisal of the blood glucose homeostat which comprehensively explains the type 2 diabetes mellitus-syndrome X complex | journal = The Journal of Physiology | volume = 549 | issue = Pt 2 | pages = 333–346 | date = June 2003 | pmid = 12717005 | pmc = 2342944 | doi = 10.1113/jphysiol.2002.037895 | publication-date = 2003 }} A rise in the blood glucose concentration causes them to release [[insulin]] into the blood, which has an effect particularly on the liver, but also on [[adipocyte|fat]] and [[muscle]] cells, causing these tissues to remove glucose from the blood. When the blood sugar falls the pancreatic beta cells cease insulin production, but, instead, stimulate the neighboring pancreatic [[Alpha|alpha cells]] to release [[glucagon]] into the blood. This, in turn, causes the liver to release glucose into the blood by breaking down stored [[glycogen]], and by means of gluconeogenesis. If the fall in the blood glucose level is particularly rapid or severe, other glucose sensors cause the release of [[epinephrine]] from the [[adrenal glands]] into the blood. This has the same action as glucagon on glucose metabolism, but its effect is more pronounced. In the liver glucagon and epinephrine cause the [[phosphorylation]] of the key, regulated enzymes of glycolysis, [[Fatty acid metabolism#Fatty acid Synthesis|fatty acid synthesis]], [[Cholesterol|cholesterol synthesis]], gluconeogenesis, and glycogenolysis. Insulin has the opposite effect on these enzymes.{{cite book | vauthors = Stryer L | title = Biochemistry. |chapter= Glycolysis. |edition= Fourth |location= New York |publisher= W.H. Freeman and Company|date= 1995 |pages= 483–508 |isbn= 0-7167-2009-4 }} The phosphorylation and dephosphorylation of these enzymes (ultimately in response to the glucose level in the blood) is the dominant manner by which these pathways are controlled in the liver, fat, and muscle cells. Thus the phosphorylation of [[phosphofructokinase]] inhibits glycolysis, whereas its dephosphorylation through the action of insulin stimulates glycolysis. [403] => [404] => === Regulated Enzymes in Glycolysis === [405] => The three [[enzymes#Control of activity|regulatory enzymes]] are [[hexokinase]] (or [[glucokinase]] in the liver), [[phosphofructokinase 1|phosphofructokinase]], and [[pyruvate kinase]]. The [[flux (biochemistry)|flux]] through the glycolytic pathway is adjusted in response to conditions both inside and outside the cell. The internal factors that regulate glycolysis do so primarily to provide [[adenosine triphosphate|ATP]] in adequate quantities for the cell's needs. The external factors act primarily on the [[liver]], [[Adipose tissue|fat tissue]], and [[muscle]]s, which can remove large quantities of glucose from the blood after meals (thus preventing [[hyperglycemia]] by storing the excess glucose as fat or glycogen, depending on the tissue type). The liver is also capable of releasing glucose into the blood between meals, during fasting, and exercise thus preventing [[hypoglycemia]] by means of [[glycogenolysis]] and [[gluconeogenesis]]. These latter reactions coincide with the halting of glycolysis in the liver. [406] => [407] => In addition hexokinase and [[glucokinase]] act independently of the hormonal effects as controls at the entry points of glucose into the cells of different tissues. Hexokinase responds to the [[glucose-6-phosphate]] (G6P) level in the cell, or, in the case of glucokinase, to the blood sugar level in the blood to impart entirely intracellular controls of the glycolytic pathway in different tissues (see [[#Hexokinase and glucokinase|below]]). [408] => [409] => When glucose has been converted into G6P by hexokinase or glucokinase, it can either be converted to [[glucose-1-phosphate]] (G1P) for conversion to [[glycogen]], or it is alternatively converted by glycolysis to [[Pyruvic acid|pyruvate]], which enters the [[mitochondrion]] where it is converted into [[acetyl-CoA]] and then into [[citrate]]. Excess [[citrate]] is exported from the mitochondrion back into the cytosol, where [[ATP citrate lyase]] regenerates [[acetyl-CoA]] and [[oxaloacetic acid|oxaloacetate]] (OAA). The acetyl-CoA is then used for [[fatty acid synthesis]] and [[Cholesterol|cholesterol synthesis]], two important ways of utilizing excess glucose when its concentration is high in blood. The regulated enzymes catalyzing these reactions perform these functions when they have been dephosphorylated through the action of insulin on the liver cells. Between meals, during [[fasting]], [[Physical exercise|exercise]] or hypoglycemia, glucagon and epinephrine are released into the blood. This causes liver glycogen to be converted back to G6P, and then converted to glucose by the liver-specific enzyme [[glucose 6-phosphatase]] and released into the blood. Glucagon and epinephrine also stimulate gluconeogenesis, which converts non-carbohydrate substrates into G6P, which joins the G6P derived from glycogen, or substitutes for it when the liver glycogen store have been depleted. This is critical for brain function, since the brain utilizes glucose as an energy source under most conditions.{{cite book | vauthors = Stryer L | title=Biochemistry. |edition= Fourth |location= New York |publisher= W.H. Freeman and Company|date= 1995 |pages= 773|isbn= 0-7167-2009-4 }} The simultaneously phosphorylation of, particularly, [[phosphofructokinase]], but also, to a certain extent pyruvate kinase, prevents glycolysis occurring at the same time as gluconeogenesis and glycogenolysis. [410] => [411] => ====Hexokinase and glucokinase==== [412] => [[File:Hexokinase B 1IG8 wpmp.png|thumb|right|[[Yeast]] [[hexokinase]] B ({{PDB|1IG8}})]] [413] => All cells contain the enzyme [[hexokinase]], which catalyzes the conversion of glucose that has entered the cell into [[glucose-6-phosphate]] (G6P). Since the cell membrane is impervious to G6P, hexokinase essentially acts to transport glucose into the cells from which it can then no longer escape. Hexokinase is inhibited by high levels of G6P in the cell. Thus the rate of entry of glucose into cells partially depends on how fast G6P can be disposed of by glycolysis, and by [[Glycogenesis|glycogen synthesis]] (in the cells which store glycogen, namely liver and muscles).{{cite book | vauthors = Voet D, Voet JG, Pratt CW |title=Fundamentals of Biochemistry | edition = 2nd |publisher=John Wiley and Sons, Inc. |year=2006 |pages=[https://archive.org/details/fundamentalsofbi00voet_0/page/547 547, 556] |isbn=978-0-471-21495-3 |url=https://archive.org/details/fundamentalsofbi00voet_0/page/547 }} [414] => [415] => [[Glucokinase]], unlike [[hexokinase]], is not inhibited by G6P. It occurs in liver cells, and will only phosphorylate the glucose entering the cell to form [[glucose-6-phosphate]] (G6P), when the glucose in the blood is abundant. This being the first step in the glycolytic pathway in the liver, it therefore imparts an additional layer of control of the glycolytic pathway in this organ. [416] => [417] => ==== Phosphofructokinase ==== [418] => [[File:Phosphofructokinase 6PFK wpmp.png|thumb|left|[[Bacillus stearothermophilus]] [[phosphofructokinase]] ({{PDB|6PFK}})]] [419] => [[Phosphofructokinase 1|Phosphofructokinase]] is an important control point in the glycolytic pathway, since it is one of the irreversible steps and has key allosteric effectors, [[Adenosine monophosphate|AMP]] and [[fructose 2,6-bisphosphate]] (F2,6BP). [420] => [421] => [[Fructose 2,6-bisphosphate]] (F2,6BP) is a very potent activator of phosphofructokinase (PFK-1) that is synthesized when F6P is phosphorylated by a second phosphofructokinase ([[PFK2]]). In the liver, when blood sugar is low and [[glucagon]] elevates cAMP, [[PFK2]] is phosphorylated by [[protein kinase A]]. The phosphorylation inactivates [[PFK2]], and another domain on this protein becomes active as [[fructose bisphosphatase-2]], which converts F2,6BP back to F6P. Both [[glucagon]] and [[epinephrine]] cause high levels of cAMP in the liver. The result of lower levels of liver fructose-2,6-bisphosphate is a decrease in activity of [[phosphofructokinase]] and an increase in activity of [[fructose 1,6-bisphosphatase]], so that gluconeogenesis (in essence, "glycolysis in reverse") is favored. This is consistent with the role of the liver in such situations, since the response of the liver to these hormones is to release glucose to the blood. [422] => [423] => [[Adenosine triphosphate|ATP]] competes with [[Adenosine monophosphate|AMP]] for the allosteric effector site on the PFK enzyme. ATP concentrations in cells are much higher than those of AMP, typically 100-fold higher,{{cite journal | vauthors = Beis I, Newsholme EA | title = The contents of adenine nucleotides, phosphagens and some glycolytic intermediates in resting muscles from vertebrates and invertebrates | journal = The Biochemical Journal | volume = 152 | issue = 1 | pages = 23–32 | date = October 1975 | pmid = 1212224 | pmc = 1172435 | doi = 10.1042/bj1520023 }} but the concentration of ATP does not change more than about 10% under physiological conditions, whereas a 10% drop in ATP results in a 6-fold increase in AMP.{{cite book | vauthors = Voet D, Voet JG | date = 2004 | title = Biochemistry | edition = 3rd | location = New York | publisher = John Wiley & Sons, Inc. }} Thus, the relevance of ATP as an allosteric effector is questionable. An increase in AMP is a consequence of a decrease in [[energy charge]] in the cell. [424] => [425] => [[Citrate]] inhibits phosphofructokinase when tested ''in vitro'' by enhancing the inhibitory effect of ATP. However, it is doubtful that this is a meaningful effect ''in vivo'', because citrate in the cytosol is utilized mainly for conversion to [[acetyl-CoA]] for [[fatty acid]] and [[cholesterol]] synthesis. [426] => [427] => [[TP53-inducible glycolysis and apoptosis regulator|TIGAR]], a p53 induced enzyme, is responsible for the regulation of [[phosphofructokinase 1|phosphofructokinase]] and acts to protect against oxidative stress.{{Cite book|title=TIGAR| vauthors = Lackie J |publisher=Oxford University Press|year=2010|isbn=978-0-19-954935-1|location=Oxford Reference Online}} TIGAR is a single enzyme with dual function that regulates F2,6BP. It can behave as a phosphatase (fructuose-2,6-bisphosphatase) which cleaves the phosphate at carbon-2 producing F6P. It can also behave as a kinase (PFK2) adding a phosphate onto carbon-2 of F6P which produces F2,6BP. In humans, the TIGAR protein is encoded by ''C12orf5'' gene. The TIGAR enzyme will hinder the forward progression of glycolysis, by creating a build up of fructose-6-phosphate (F6P) which is isomerized into glucose-6-phosphate (G6P). The accumulation of G6P will shunt carbons into the pentose phosphate pathway.{{cite journal | vauthors = Bensaad K, Tsuruta A, Selak MA, Vidal MN, Nakano K, Bartrons R, Gottlieb E, Vousden KH | title = TIGAR, a p53-inducible regulator of glycolysis and apoptosis | journal = Cell | volume = 126 | issue = 1 | pages = 107–120 | date = July 2006 | pmid = 16839880 | doi = 10.1016/j.cell.2006.05.036 | s2cid = 15006256 | doi-access = free }}{{Cite web|url=https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=57103|title=TIGAR TP53 induced glycolysis regulatory phosphatase [Homo sapiens (human)] - Gene - NCBI|website=www.ncbi.nlm.nih.gov|access-date=2018-05-17}} [428] => [429] => ==== Pyruvate kinase ==== [430] => [[File:Pyruvate Kinase 1A3W wpmp.png|thumb|right|[[Yeast]] [[pyruvate kinase]] ({{PDB|1A3W}})]] [431] => {{Main|Pyruvate kinase}} [432] => The final step of glycolysis is catalysed by pyruvate kinase to form pyruvate and another ATP. It is regulated by a range of different transcriptional, covalent and non-covalent regulation mechanisms, which can vary widely in different tissues.{{cite journal | vauthors = Carbonell J, Felíu JE, Marco R, Sols A | title = Pyruvate kinase. Classes of regulatory isoenzymes in mammalian tissues | journal = European Journal of Biochemistry | volume = 37 | issue = 1 | pages = 148–156 | date = August 1973 | pmid = 4729424 | doi = 10.1111/j.1432-1033.1973.tb02969.x | hdl = 10261/78345 | hdl-access = free }}{{cite journal | vauthors = Valentini G, Chiarelli L, Fortin R, Speranza ML, Galizzi A, Mattevi A | title = The allosteric regulation of pyruvate kinase | journal = The Journal of Biological Chemistry | volume = 275 | issue = 24 | pages = 18145–18152 | date = June 2000 | pmid = 10751408 | doi = 10.1074/jbc.m001870200 | doi-access = free }}{{cite journal | vauthors = Israelsen WJ, Vander Heiden MG | title = Pyruvate kinase: Function, regulation and role in cancer | journal = Seminars in Cell & Developmental Biology | volume = 43 | pages = 43–51 | date = July 2015 | pmid = 26277545 | pmc = 4662905 | doi = 10.1016/j.semcdb.2015.08.004 }} For example, in the liver, pyruvate kinase is regulated based on glucose availability. During fasting (no glucose available), [[glucagon]] activates [[protein kinase A]] which phosphorylates pyruvate kinase to inhibit it.{{cite journal | vauthors = Engström L | title = The regulation of liver pyruvate kinase by phosphorylation--dephosphorylation | journal = Current Topics in Cellular Regulation | volume = 13 | pages = 28–51 | date = 1978 | pmid = 208818 | doi = 10.1016/b978-0-12-152813-3.50006-9 | publisher = Elsevier | isbn = 978-0-12-152813-3 }} An increase in blood sugar leads to secretion of [[insulin]], which activates [[protein phosphatase 1]], leading to dephosphorylation and re-activation of pyruvate kinase. These controls prevent pyruvate kinase from being active at the same time as the enzymes that catalyze the reverse reaction ([[pyruvate carboxylase]] and [[phosphoenolpyruvate carboxykinase]]), preventing a [[futile cycle]]. Conversely, the isoform of pyruvate kinasein found in muscle is not affected by [[protein kinase A]] (which is activated by adrenaline in that tissue), so that glycolysis remains active in muscles even during fasting. [433] => [434] => == Post-glycolysis processes == [435] => The overall process of glycolysis is: [436] => [437] => :Glucose + 2 NAD+ + 2 ADP + 2 Pi → 2 Pyruvate + 2 NADH + 2 H+ + 2 ATP + 2 H2O [438] => [439] => If glycolysis were to continue indefinitely, all of the NAD+ would be used up, and glycolysis would stop. To allow glycolysis to continue, organisms must be able to oxidize NADH back to NAD+. How this is performed depends on which external electron acceptor is available. [440] => [441] => ===Anoxic regeneration of NAD+=== [442] => {{Unreferenced section|date=June 2022}} [443] => One method of doing this is to simply have the pyruvate do the oxidation; in this process, pyruvate is converted to [[lactic acid|lactate]] (the [[conjugate base]] of lactic acid) in a process called [[lactic acid fermentation]]: [444] => [445] => :Pyruvate + NADH + H+ → Lactate + NAD+ [446] => [447] => This process occurs in the [[bacterium|bacteria]] involved in making [[yogurt]] (the lactic acid causes the milk to curdle). This process also occurs in animals under hypoxic (or partially anaerobic) conditions, found, for example, in overworked muscles that are starved of oxygen. In many tissues, this is a cellular last resort for energy; most animal tissue cannot tolerate anaerobic conditions for an extended period of time. [448] => [449] => Some organisms, such as yeast, convert NADH back to NAD+ in a process called [[ethanol fermentation]]. In this process, the pyruvate is converted first to acetaldehyde and carbon dioxide, and then to ethanol. [450] => [451] => [[Lactic acid fermentation]] and [[ethanol fermentation]] can occur in the absence of oxygen. This anaerobic fermentation allows many single-cell organisms to use glycolysis as their only energy source. [452] => [453] => Anoxic regeneration of NAD+ is only an effective means of energy production during short, intense exercise in vertebrates, for a period ranging from 10 seconds to 2 minutes during a maximal effort in humans. (At lower exercise intensities it can sustain muscle activity in [[Mammalian diving reflex|diving animals]], such as seals, whales and other aquatic vertebrates, for very much longer periods of time.) Under these conditions NAD+ is replenished by NADH donating its electrons to pyruvate to form lactate. This produces 2 ATP molecules per glucose molecule, or about 5% of glucose's energy potential (38 ATP molecules in bacteria). But the speed at which ATP is produced in this manner is about 100 times that of oxidative phosphorylation. The pH in the cytoplasm quickly drops when hydrogen ions accumulate in the muscle, eventually inhibiting the enzymes involved in glycolysis. [454] => [455] => The burning sensation in muscles during hard exercise can be attributed to the release of hydrogen ions during the shift to glucose fermentation from glucose oxidation to carbon dioxide and water, when aerobic metabolism can no longer keep pace with the energy demands of the muscles. These hydrogen ions form a part of lactic acid. The body falls back on this less efficient but faster method of producing ATP under low oxygen conditions. This is thought to have been the primary means of energy production in earlier organisms before oxygen reached high concentrations in the atmosphere between 2000 and 2500 million years ago, and thus would represent a more ancient form of energy production than the aerobic replenishment of NAD+ in cells. [456] => [457] => The liver in mammals gets rid of this excess lactate by transforming it back into pyruvate under aerobic conditions; see [[Cori cycle]]. [458] => [459] => Fermentation of pyruvate to lactate is sometimes also called "anaerobic glycolysis", however, glycolysis ends with the production of pyruvate regardless of the presence or absence of oxygen. [460] => [461] => In the above two examples of fermentation, NADH is oxidized by transferring two electrons to pyruvate. However, anaerobic bacteria use a wide variety of compounds as the terminal electron acceptors in [[cellular respiration]]: nitrogenous compounds, such as nitrates and nitrites; sulfur compounds, such as sulfates, sulfites, sulfur dioxide, and elemental sulfur; carbon dioxide; iron compounds; manganese compounds; cobalt compounds; and uranium compounds. [462] => [463] => ===Aerobic regeneration of NAD+ and further catabolism of pyruvate=== [464] => In [[aerobic organism|aerobic]] [[eukaryote]]s, a complex mechanism has developed to use the oxygen in air as the final electron acceptor, in a process called [[oxidative phosphorylation]]. [[aerobic organism|Aerobic]] [[prokaryotes]], which lack mitochondria, use a variety of [[Oxidative phosphorylation#Prokaryotic electron transport chains|simpler mechanisms]]. [465] => * Firstly, the [[Nicotinamide adenine dinucleotide|NADH + H+]] generated by glycolysis has to be transferred to the mitochondrion to be oxidized, and thus to regenerate the NAD+ necessary for glycolysis to continue. However the inner mitochondrial membrane is impermeable to NADH and NAD+.{{cite book | vauthors = Stryer L | title = Biochemistry |chapter= Oxidative phosphorylation. |edition= Fourth |location= New York |publisher= W.H. Freeman and Company|date= 1995 |pages= 537–549 |isbn= 0-7167-2009-4 }} Use is therefore made of two “shuttles” to transport the electrons from NADH across the mitochondrial membrane. They are the [[malate-aspartate shuttle]] and the [[glycerol phosphate shuttle]]. In the former the electrons from NADH are transferred to cytosolic [[Oxaloacetic acid|oxaloacetate]] to form [[Malic acid|malate]]. The malate then traverses the inner mitochondrial membrane into the mitochondrial matrix, where it is reoxidized by NAD+ forming intra-mitochondrial oxaloacetate and NADH. The oxaloacetate is then re-cycled to the cytosol via its conversion to aspartate which is readily transported out of the mitochondrion. In the glycerol phosphate shuttle electrons from cytosolic NADH are transferred to [[dihydroxyacetone]] to form [[glycerol-3-phosphate]] which readily traverses the outer mitochondrial membrane. Glycerol-3-phosphate is then reoxidized to dihydroxyacetone, donating its electrons to [[Flavin adenine dinucleotide|FAD]] instead of NAD+. This reaction takes place on the inner mitochondrial membrane, allowing FADH2 to donate its electrons directly to coenzyme Q ([[ubiquinone]]) which is part of the [[electron transport chain]] which ultimately transfers electrons to molecular oxygen {{chem2|O2}}, with the formation of water, and the release of energy eventually captured in the form of [[Adenosine triphosphate|ATP]]. [466] => * The glycolytic end-product, pyruvate (plus NAD+) is converted to [[acetyl-CoA]], {{chem2|CO2}} and NADH + H+ within the [[mitochondria]] in a process called [[pyruvate decarboxylation]]. [467] => * The resulting acetyl-CoA enters the [[citric acid cycle]] (or Krebs Cycle), where the acetyl group of the acetyl-CoA is converted into carbon dioxide by two decarboxylation reactions with the formation of yet more intra-mitochondrial NADH + H+. [468] => * The intra-mitochondrial NADH + H+ is oxidized to NAD+ by the [[electron transport chain]], using oxygen as the final electron acceptor to form water. The energy released during this process is used to create a hydrogen ion (or proton) gradient across the [[inner membrane of the mitochondrion]]. [469] => * Finally, the proton gradient is used to produce about 2.5 [[Adenosine triphosphate|ATP]] for every NADH + H+ oxidized in a process called [[oxidative phosphorylation]]. [470] => [471] => ===Conversion of carbohydrates into fatty acids and cholesterol=== [472] => The pyruvate produced by glycolysis is an important intermediary in the conversion of carbohydrates into [[fatty acids]] and [[cholesterol]].{{cite book | vauthors = Stryer L | title = Biochemistry |chapter= Fatty acid metabolism. |edition= Fourth |location= New York |publisher= W.H. Freeman and Company|date= 1995 |pages= 603–628 |isbn= 0-7167-2009-4 }} This occurs via the conversion of pyruvate into [[acetyl-CoA]] in the [[mitochondrion]]. However, this acetyl CoA needs to be transported into cytosol where the synthesis of fatty acids and cholesterol occurs. This cannot occur directly. To obtain cytosolic acetyl-CoA, [[Citric acid|citrate]] (produced by the condensation of acetyl CoA with [[Oxaloacetic acid|oxaloacetate]]) is removed from the [[citric acid cycle]] and carried across the inner mitochondrial membrane into the [[cytosol]]. There it is cleaved by [[ATP citrate lyase]] into acetyl-CoA and oxaloacetate. The oxaloacetate is returned to mitochondrion as malate (and then back into oxaloacetate to transfer more acetyl-CoA out of the mitochondrion). The cytosolic acetyl-CoA can be carboxylated by [[acetyl-CoA carboxylase]] into [[Malonyl-CoA|malonyl CoA]], the first committed step in the [[Fatty acid synthesis|synthesis of fatty acids]], or it can be combined with [[acetoacetyl-CoA]] to form 3-hydroxy-3-methylglutaryl-CoA ([[HMG-CoA]]) which is the rate limiting step controlling the [[Mevalonate pathway|synthesis of cholesterol]].{{cite book | vauthors = Stryer L | title = Biochemistry |chapter= Biosynthesis of membrane lipids and steroids. |edition= Fourth |location= New York |publisher= W.H. Freeman and Company|date= 1995 |pages= 691–707 |isbn= 0-7167-2009-4 }} Cholesterol can be used as is, as a structural component of cellular membranes, or it can be used to synthesize the [[Steroid#Steroidogenesis|steroid hormones]], [[Bile acids|bile salts]], and [[vitamin D]]. [473] => [474] => ===Conversion of pyruvate into oxaloacetate for the citric acid cycle=== [475] => Pyruvate molecules produced by glycolysis are [[active transport|actively transported]] across the inner [[Mitochondrion|mitochondrial]] membrane, and into the matrix where they can either be [[Redox|oxidized]] and combined with [[coenzyme A]] to form {{chem2|CO2}}, acetyl-CoA, and NADH, or they can be [[carboxylated]] (by [[pyruvate carboxylase]]) to form [[oxaloacetate]]. This latter reaction "fills up" the amount of oxaloacetate in the citric acid cycle, and is therefore an [[anaplerotic reaction]] (from the Greek meaning to "fill up"), increasing the cycle's capacity to metabolize acetyl-CoA when the tissue's energy needs (e.g. in [[Cardiac muscle|heart]] and [[Skeletal striated muscle|skeletal muscle]]) are suddenly increased by activity.{{cite book | vauthors = Stryer L | title = Biochemistry |chapter= Citric acid cycle. |edition= Fourth |location= New York |publisher= W.H. Freeman and Company|date= 1995 |pages= 509–527, 569–579, 614–616, 638–641, 732–735, 739–748, 770–773 |isbn= 0-7167-2009-4 }} [476] => In the [[citric acid cycle]] all the intermediates (e.g. citrate, iso-citrate, alpha-ketoglutarate, succinate, fumarate, malate and oxaloacetate) are regenerated during each turn of the cycle. Adding more of any of these intermediates to the mitochondrion therefore means that that additional amount is retained within the cycle, increasing all the other intermediates as one is converted into the other. Hence the addition of oxaloacetate greatly increases the amounts of all the citric acid intermediates, thereby increasing the cycle's capacity to metabolize acetyl CoA, converting its acetate component into {{chem2|CO2}} and water, with the release of enough energy to form 11 [[Adenosine triphosphate|ATP]] and 1 [[Guanosine triphosphate|GTP]] molecule for each additional molecule of acetyl CoA that combines with oxaloacetate in the cycle. [477] => [478] => To cataplerotically remove oxaloacetate from the citric cycle, [[malate]] can be transported from the mitochondrion into the cytoplasm, decreasing the amount of oxaloacetate that can be regenerated. Furthermore, citric acid intermediates are [[Citric acid cycle#Citric acid cycle intermediates serve as substrates for biosynthetic processes|constantly used to form a variety of substances such as the purines, pyrimidines and porphyrins]]. [479] => [480] => == Intermediates for other pathways == [481] => This article concentrates on the [[catabolic]] role of glycolysis with regard to converting potential chemical energy to usable chemical energy during the oxidation of glucose to pyruvate. Many of the metabolites in the glycolytic pathway are also used by [[anabolic]] pathways, and, as a consequence, flux through the pathway is critical to maintain a supply of carbon skeletons for biosynthesis.{{Cite journal |last1=Judge |first1=Ayesha |last2=Dodd |first2=Michael S. |date=2020-10-08 |title=Metabolism |url=https://portlandpress.com/essaysbiochem/article/64/4/607/226177/Metabolism |journal=Essays in Biochemistry |language=en |volume=64 |issue=4 |pages=607–647 |doi=10.1042/EBC20190041 |issn=0071-1365 |pmc=7545035 |pmid=32830223}} [482] => [483] => The following metabolic pathways are all strongly reliant on glycolysis as a source of metabolites: and many more. [484] => * [[Pentose phosphate pathway]], which begins with the dehydrogenation of [[glucose-6-phosphate]], the first intermediate to be produced by glycolysis, produces various pentose sugars, and [[Nicotinamide adenine dinucleotide phosphate|NADPH]] for the synthesis of [[fatty acid]]s and [[cholesterol]]. [485] => * [[Glycogenesis|Glycogen synthesis]] also starts with glucose-6-phosphate at the beginning of the glycolytic pathway. [486] => * [[Glycerol]], for the formation of [[triglyceride]]s and [[phospholipid]]s, is produced from the glycolytic intermediate [[glyceraldehyde-3-phosphate]]. [487] => * Various post-glycolytic pathways: [488] => :* [[Fatty acid metabolism#Fatty acid Synthesis|Fatty acid synthesis]] [489] => :* [[Cholesterol#Biosynthesis|Cholesterol synthesis]] [490] => :* The [[citric acid cycle]] which in turn leads to: [491] => ::*[[Amino acid synthesis]] [492] => ::*[[Nucleotide#Synthesis|Nucleotide synthesis]] [493] => ::*[[Porphyrin#Biosynthesis|Tetrapyrrole synthesis]] [494] => [495] => Although [[gluconeogenesis]] and glycolysis share many intermediates the one is not functionally a branch or tributary of the other. There are two regulatory steps in both pathways which, when active in the one pathway, are automatically inactive in the other. The two processes can therefore not be simultaneously active.{{cite book | vauthors = Stryer L | title=Biochemistry. |edition= Fourth |location= New York |publisher= W.H. Freeman and Company|date= 1995 |pages= 559–565, 574–576, 614–623|isbn= 0-7167-2009-4 }} Indeed, if both sets of reactions were highly active at the same time the net result would be the hydrolysis of four high energy phosphate bonds (two ATP and two GTP) per reaction cycle. [496] => [497] => [[Nicotinamide adenine dinucleotide|NAD+]] is the oxidizing agent in glycolysis, as it is in most other energy yielding metabolic reactions (e.g. [[beta-oxidation]] of fatty acids, and during the [[citric acid cycle]]). The NADH thus produced is primarily used to ultimately transfer electrons to {{chem2|O2}} to produce water, or, when {{chem2|O2}} is not available, to produce compounds such as [[Lactic acid|lactate]] or [[ethanol]] (see ''Anoxic regeneration of NAD+'' above). NADH is rarely used for synthetic processes, the notable exception being [[gluconeogenesis]]. During [[Fatty acid metabolism#Fatty acid Synthesis|fatty acid]] and [[Cholesterol#Biosyntesis|cholesterol synthesis]] the reducing agent is [[Nicotinamide adenine dinucleotide phosphate|NADPH]]. This difference exemplifies a general principle that NADPH is consumed during biosynthetic reactions, whereas NADH is generated in energy-yielding reactions. The source of the NADPH is two-fold. When [[Malic acid|malate]] is oxidatively decarboxylated by “NADP+-linked malic enzyme" [[Pyruvic acid|pyruvate]], {{chem2|CO2}} and NADPH are formed. NADPH is also formed by the [[pentose phosphate pathway]] which converts glucose into ribose, which can be used in synthesis of [[nucleotides]] and [[nucleic acids]], or it can be catabolized to pyruvate. [498] => [499] => == Glycolysis in disease == [500] => [501] => === Diabetes === [502] => Cellular uptake of glucose occurs in response to insulin signals, and glucose is subsequently broken down through glycolysis, lowering blood sugar levels. However, the low insulin levels seen in diabetes result in hyperglycemia, where glucose levels in the blood rise and glucose is not properly taken up by cells. Hepatocytes further contribute to this hyperglycemia through [[gluconeogenesis]]. Glycolysis in hepatocytes controls hepatic glucose production, and when glucose is overproduced by the liver without having a means of being broken down by the body, hyperglycemia results.{{Cite journal|date=2012-08-01|title=Glycolysis in the control of blood glucose homeostasis|journal=Acta Pharmaceutica Sinica B|language=en|volume=2|issue=4|pages=358–367|doi=10.1016/j.apsb.2012.06.002|issn=2211-3835| vauthors = Guo X, Li H, Xu H, Woo S, Dong H, Lu F, Lange AJ, Wu C |doi-access=free}} [503] => [504] => === Genetic diseases === [505] => Glycolytic mutations are generally rare due to importance of the metabolic pathway; the majority of occurring mutations result in an inability of the cell to respire, and therefore cause the death of the cell at an early stage. However, some mutations ([[glycogen storage disease]]s and other [[inborn errors of carbohydrate metabolism]]) are seen with one notable example being [[pyruvate kinase deficiency]], leading to chronic hemolytic anemia.{{cn|date=May 2023}} [506] => [507] => === Cancer === [508] => Malignant tumor cells perform glycolysis at a rate that is ten times faster than their noncancerous tissue counterparts.{{cite journal | vauthors = Alfarouk KO, Verduzco D, Rauch C, Muddathir AK, Adil HH, Elhassan GO, Ibrahim ME, David Polo Orozco J, Cardone RA, Reshkin SJ, Harguindey S | title = Glycolysis, tumor metabolism, cancer growth and dissemination. A new pH-based etiopathogenic perspective and therapeutic approach to an old cancer question | journal = Oncoscience | volume = 1 | issue = 12 | pages = 777–802 | date = 2014 | pmid = 25621294 | pmc = 4303887 | doi = 10.18632/oncoscience.109 }} During their genesis, limited capillary support often results in hypoxia (decreased O2 supply) within the tumor cells. Thus, these cells rely on anaerobic metabolic processes such as glycolysis for ATP (adenosine triphosphate). Some tumor cells overexpress specific glycolytic enzymes which result in higher rates of glycolysis.{{cite journal | vauthors = Alfarouk KO, Shayoub ME, Muddathir AK, Elhassan GO, Bashir AH | title = Evolution of Tumor Metabolism might Reflect Carcinogenesis as a Reverse Evolution process (Dismantling of Multicellularity) | journal = Cancers | volume = 3 | issue = 3 | pages = 3002–3017 | date = July 2011 | pmid = 24310356 | pmc = 3759183 | doi = 10.3390/cancers3033002 | doi-access = free }} Often these enzymes are Isoenzymes, of traditional glycolysis enzymes, that vary in their susceptibility to traditional feedback inhibition. The increase in glycolytic activity ultimately counteracts the effects of hypoxia by generating sufficient ATP from this anaerobic pathway.{{cite book | vauthors = Nelson DL, Cox MM |title=Lehninger principles of biochemistry |date=2005 |publisher=W.H. Freeman |location=New York |isbn=978-0-7167-4339-2 |edition=4th |url=https://archive.org/details/lehningerprincip00lehn_0}} This phenomenon was first described in 1930 by [[Otto Heinrich Warburg|Otto Warburg]] and is referred to as the [[Warburg effect (oncology)|Warburg effect]]. The [[Warburg hypothesis]] claims that cancer is primarily caused by dysfunctionality in mitochondrial metabolism, rather than because of the uncontrolled growth of cells. [509] => A number of theories have been advanced to explain the Warburg effect. One such theory suggests that the increased glycolysis is a normal protective process of the body and that malignant change could be primarily caused by energy metabolism.{{cite web |title=What is Cancer? |url=http://thepathogenesisofcancer.com/ |access-date=September 8, 2012 |date=October 2011 | vauthors = Gold J |archive-url=https://web.archive.org/web/20180519194539/http://thepathogenesisofcancer.com/ |archive-date=May 19, 2018 |url-status=dead}} [510] => [511] => This high glycolysis rate has important medical applications, as high [[Aerobic_fermentation | aerobic glycolysis]] by malignant tumors is utilized clinically to diagnose and monitor treatment responses of [[cancer]]s by [[Chemical imaging|imaging]] uptake of [[Fluorodeoxyglucose|2-18F-2-deoxyglucose]] (FDG) (a [[radioactive]] modified hexokinase [[substrate (biochemistry)|substrate]]) with [[positron emission tomography]] (PET).{{cite journal | vauthors = Pauwels EK, Sturm EJ, Bombardieri E, Cleton FJ, Stokkel MP | title = Positron-emission tomography with [18F]fluorodeoxyglucose. Part I. Biochemical uptake mechanism and its implication for clinical studies | journal = Journal of Cancer Research and Clinical Oncology | volume = 126 | issue = 10 | pages = 549–59 | date = October 2000 | pmid = 11043392 | doi = 10.1007/pl00008465 | s2cid = 2725555 }}{{cite web | title=PET Scan: PET Scan Info Reveals ... | url=http://www.petscaninfo.com/ | access-date=December 5, 2005 }} [512] => [513] => There is ongoing research to affect mitochondrial metabolism and treat cancer by reducing glycolysis and thus starving cancerous cells in various new ways, including a [[ketogenic diet]].{{cite journal | vauthors = Schwartz L, Seyfried T, Alfarouk KO, Da Veiga Moreira J, Fais S | title = Out of Warburg effect: An effective cancer treatment targeting the tumor specific metabolism and dysregulated pH | journal = Seminars in Cancer Biology | volume = 43 | pages = 134–138 | date = April 2017 | pmid = 28122260 | doi = 10.1016/j.semcancer.2017.01.005 }}{{cite journal | vauthors = Schwartz L, Supuran CT, Alfarouk KO | title = The Warburg Effect and the Hallmarks of Cancer | journal = Anti-Cancer Agents in Medicinal Chemistry | volume = 17 | issue = 2 | pages = 164–170 | date = 2017 | pmid = 27804847 | doi = 10.2174/1871520616666161031143301 }}{{cite journal | vauthors = Maroon J, Bost J, Amos A, Zuccoli G | title = Restricted calorie ketogenic diet for the treatment of glioblastoma multiforme | journal = Journal of Child Neurology | volume = 28 | issue = 8 | pages = 1002–1008 | date = August 2013 | pmid = 23670248 | doi = 10.1177/0883073813488670 | s2cid = 1994087 }} [514] => [515] => ==Interactive pathway map== [516] => The diagram below shows human protein names. Names in other organisms may be different and the number of [[isozyme]]s (such as HK1, HK2, ...) is likely to be different too. [517] => [518] => {{GlycolysisGluconeogenesis_WP534}} [519] => [520] => == Alternative nomenclature == [521] => Some of the metabolites in glycolysis have alternative names and nomenclature. In part, this is because some of them are common to other pathways, such as the [[Calvin cycle]]. [522] => [523] => {| class="wikitable" [524] => ! [525] => !colspan="2"|This article [526] => !colspan="2"|Alternative [527] => |- [528] => |1 [529] => |[[Glucose]] [530] => |Glc [531] => |Dextrose [532] => | [533] => |- [534] => |2 [535] => |[[Glucose-6-phosphate]] [536] => |G6P [537] => | [538] => | [539] => |- [540] => |3 [541] => |[[Fructose-6-phosphate]] [542] => |F6P [543] => | [544] => | [545] => |- [546] => |4 [547] => | [[Fructose-1,6-bisphosphate]] [548] => |F1,6BP [549] => |Fructose 1,6-diphosphate [550] => |FBP; FDP; F1,6DP [551] => |- [552] => |5 [553] => |[[Dihydroxyacetone phosphate]] [554] => |DHAP [555] => |Glycerone phosphate [556] => | [557] => |- [558] => |6 [559] => |[[Glyceraldehyde-3-phosphate]] [560] => |GADP [561] => |3-Phosphoglyceraldehyde [562] => |PGAL; G3P; GALP; GAP; TP [563] => |- [564] => |7 [565] => | [[1,3-Bisphosphoglycerate]] [566] => |1,3BPG [567] => |Glycerate-1,3-bisphosphate,
glycerate-1,3-diphosphate,
1,3-diphosphoglycerate [568] => |PGAP; BPG; DPG [569] => |- [570] => |8 [571] => |[[3-Phosphoglycerate]] [572] => |3PG [573] => |Glycerate-3-phosphate [574] => |PGA; GP [575] => |- [576] => |9 [577] => | [[2-Phosphoglycerate]] [578] => |2PG [579] => |Glycerate-2-phosphate [580] => | [581] => |- [582] => |10 [583] => |[[Phosphoenolpyruvate]] [584] => |PEP [585] => | [586] => | [587] => |- [588] => |11 [589] => | [[Pyruvate]] [590] => |Pyr [591] => |Pyruvic acid conjugate base [592] => | [593] => |} [594] => [595] => == Structure of glycolysis components in Fischer projections and polygonal model == [596] => [597] => The intermediates of glycolysis depicted in Fischer projections show the chemical changing step by step. Such image can be compared to polygonal model representation.{{cite journal | vauthors = Bonafe CF, Bispo JA, de Jesus MB | title = The polygonal model: A simple representation of biomolecules as a tool for teaching metabolism | journal = Biochemistry and Molecular Biology Education | volume = 46 | issue = 1 | pages = 66–75 | date = January 2018 | pmid = 29131491 | doi = 10.1002/bmb.21093 | s2cid = 31317102 | doi-access = free }} Another comparation of Fischer projections and Poligonal Model in glycolysis is shown in a video.{{cite web| vauthors = Bonafe C |url=https://www.youtube.com/watch?v=PaX9NOb8oX4&list=UUF-2nRkGkKY-O-st3tMzQ8Q&index=19.htm| archive-url=https://ghostarchive.org/varchive/youtube/20211104/PaX9NOb8oX4| archive-date=2021-11-04 | url-status=live|title=Introduction to Polygonal Model - PART 1. Glycolysis and Structure of the Participant Molecules.|date=23 September 2019|work=YouTube}}{{cbignore}} Video animations in the same channel in YouTube can be seen for another metabolic pathway (Krebs Cycle) and the representation and applying of Polygonal Model in Organic Chemistry {{cite web|title=Metabolism Animation and Polygonal Model|url=https://www.youtube.com/channel/UCF-2nRkGkKY-O-st3tMzQ8Q?view_as=subscriber|work=YouTube|access-date=2019-12-11|language=en}} [598] => [599] => {{wide image|Glycolysis--F-PM.png|1430px|Glycolysis - Structure of anaerobic glycolysis components showed using Fischer projections, left, and polygonal model, right. The compounds correspond to glucose (GLU), glucose 6-phosphate (G6P), fructose 6-phosphate (F6P), fructose 1,6-bisphosphate ( F16BP), dihydroxyacetone phosphate (DHAP), glyceraldehyde 3-phosphate(GA3P), 1,3-bisphosphoglycerate (13BPG), 3-phosphoglycerate (3PG), 2-phosphoglycerate (2PG), phosphoenolpyruvate (PEP), pyruvate (PIR), and lactate (LAC). The enzymes which participate of this pathway are indicated by underlined numbers, and correspond to hexokinase (1), glucose-6-phosphate isomerase (2), phosphofructokinase-1 (3), fructose-bisphosphate aldolase (4), triosephosphate isomerase (5), glyceraldehyde-3-phosphate dehydrogenase (5), phosphoglycerate kinase (7), phosphoglycerate mutase (8), phosphopyruvate hydratase (enolase) (9), pyruvate kinase (10), and lactate dehydrogenase (11). The participant coenzymes (NAD+, NADH + H+, ATP and ADP), inorganic phosphate, {{chem2|H2O}} and {{chem2|CO2}} were omitted in these representations. The phosphorylation reactions from ATP, as well the ADP phosphorylation reactions in later steps of glycolysis are shown as ~P respectively entering or going out the pathway. The oxireduction reactions using NAD+ or NADH are observed as hydrogens “2H” going out or entering the pathway.}} [600] => [601] => == See also == [602] => {{Portal|Biology}} [603] => {{commons category|Glycolysis}} [604] => * [[Carbohydrate catabolism]] [605] => * [[Citric acid cycle]] [606] => * [[Cori cycle]] [607] => * [[Fermentation (biochemistry)]] [608] => * [[Gluconeogenesis]] [609] => * [[Glycolytic oscillation]] [610] => * [[Glycogen storage disease|Glycogenoses (glycogen storage diseases)]] [611] => * [[Inborn errors of carbohydrate metabolism]] [612] => * [[Pentose phosphate pathway]] [613] => * [[Pyruvate decarboxylation]] [614] => * [[Triose kinase]] [615] => [616] => == References == [617] => {{reflist}} [618] => [619] => == External links == [620] => * [http://www.iubmb-nicholson.org/swf/glycolysis.swf A Detailed Glycolysis Animation provided] by [[IUBMB]] ([http://get.adobe.com/flashplayer/ Adobe Flash] Required) [621] => * [https://web.archive.org/web/20051221131713/http://nist.rcsb.org/pdb/molecules/pdb50_1.html The Glycolytic enzymes in Glycolysis] at RCSB PDB [622] => * [http://www.wdv.com/CellWorld/Biochemistry/Glycolytic Glycolytic cycle with animations] at wdv.com [623] => * [http://biochemweb.fenteany.com/metabolism.shtml Metabolism, Cellular Respiration and Photosynthesis - The Virtual Library of Biochemistry, Molecular Biology and Cell Biology] [624] => * [https://web.archive.org/web/20051016004951/http://www2.ufp.pt/~pedros/bq/glycolysis.htm The chemical logic behind glycolysis] at ufp.pt [625] => * [http://www.expasy.org/tools/pathways/boehringer_legends.html Expasy biochemical pathways poster] at [[ExPASy]] [626] => * {{MedicalMnemonics|317|5468}} [627] => * [http://www.metpath.teithe.gr/?lang=en&part=glycolysis ''metpath'': Interactive representation of glycolysis] [628] => {{Library resources box [629] => |by=no [630] => |onlinebooks=no [631] => |others=no [632] => |about=yes [633] => |label=Glycolysis}} [634] => [635] => {{Carbohydrate metabolism}} [636] => {{MetabolismMap}} [637] => {{Glycolysis enzymes}} [638] => [639] => {{Authority control}} [640] => [641] => [[Category:Glycolysis| ]] [642] => [[Category:Biochemistry]] [643] => [[Category:Carbohydrates]] [644] => [[Category:Cellular respiration]] [645] => [[Category:Metabolic pathways]] [] => )
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Glycolysis

Glycolysis is the metabolic pathway that converts glucose, a six-carbon sugar, into two molecules of pyruvate, a three-carbon compound. It is the first step in cellular respiration, a process that provides energy to cells by breaking down glucose.

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It is the first step in cellular respiration, a process that provides energy to cells by breaking down glucose. The glycolytic pathway consists of a series of ten enzymatic reactions, each catalyzed by a specific enzyme. These reactions occur in the cytoplasm of cells and do not require the presence of oxygen, making glycolysis an anaerobic process. However, the end products of glycolysis, such as pyruvate, can enter other metabolic pathways if oxygen is present, leading to further energy production through aerobic respiration. Glycolysis begins with the phosphorylation of glucose, which primes the molecule for subsequent reactions. Through a series of rearrangements, phosphorylations, and dephosphorylations, glucose is eventually converted into two molecules of pyruvate. Along the way, the pathway generates a small amount of ATP (adenosine triphosphate), the primary energy currency of cells, and NADH (nicotinamide adenine dinucleotide), a molecule that carries high-energy electrons to the electron transport chain. Glycolysis has a critical role in energy metabolism, particularly during situations where oxygen is limited, such as intense exercise or low-oxygen environments. It enables cells to generate ATP quickly and efficiently, providing an immediate source of energy. Abnormal glycolysis has been implicated in various diseases, including cancer. Cancer cells often exhibit increased glycolytic activity even in the presence of oxygen, a phenomenon known as the Warburg effect. This metabolic shift allows cancer cells to meet their energy requirements and promotes tumor growth and survival. Overall, glycolysis is a fundamental metabolic pathway that plays a central role in energy production and cellular function. Understanding its mechanisms and regulation is crucial for advancing our knowledge of metabolism and developing potential therapeutic interventions for various diseases.

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