Glycolysis: Difference between revisions

The wide occurrence of glycolysis in other species indicates that it is an ancient metabolic pathway.<ref>{{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 }}</ref> 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]].<ref>{{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 }}</ref>

The overall reaction of glycolysis is:

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.{{citation needed|date=September 2024}}

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>

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<ref name="glycolysis_animation"/> ([[glyceraldehyde 3-phosphate|G3P]]).

In [[animal]]s, an [[isozyme]] of hexokinase called [[glucokinase]] is also used in the liver, which has a much lower affinity for glucose (K_m 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.

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).

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.

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.

Hydrogen atom balance and charge balance are both maintained because the phosphate (P_i) group actually exists in the form of a [[Phosphoric acid#Orthophosphoric acid chemistry|hydrogen phosphate]] anion ({{chem2|HPO4(2−)}}),<ref name="ImportanceBalance" /> which dissociates to contribute the extra H⁺ ion and gives a net charge of −3 on both sides.

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.<ref>{{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 }}</ref> The details of regulation for some enzymes are highly conserved between species, whereas others vary widely.<ref name=":3">{{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 }}</ref><ref>{{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 }}</ref>

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]]).<ref name="stryer" />

[[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.<ref>{{Cite book|title=TIGAR| vauthors = Lackie J |publisher=Oxford University Press|year=2010|isbn=978-0-19-954935-1|location=Oxford Reference Online}}</ref> 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.<ref>{{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 }}</ref><ref>{{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}}</ref>

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.<ref>{{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 }}</ref><ref>{{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 }}</ref><ref>{{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 }}</ref> 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.<ref name=":4">{{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 }}</ref> An increase in blood sugar leads to secretion of [[insulin]], which activates [[protein phosphatase 1]], leading to dephosphorylation and re-activation of pyruvate kinase.<ref name=":4" /> 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]].<ref name=":4" /> 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.<ref name=":4" />

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.{{citation needed|date=May 2023}}

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.

* [http://www.expasy.org/tools/pathways/boehringer_legends.html Expasy biochemical pathways poster] at [[ExPASy]]

* [http://www.metpath.teithe.gr/?lang=en&part=glycolysis ''metpath'': Interactive representation of glycolysis]