Editing Glycolysis (section)

==== Phosphofructokinase ====
[[File:Phosphofructokinase 6PFK wpmp.png|thumb|left|[[Bacillus stearothermophilus]] [[phosphofructokinase]] ({{PDB|6PFK}})]]
[[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).

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 F2,6BP 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.

[[Adenosine triphosphate|ATP]] competes with 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,<ref>{{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 }}</ref> 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.<ref>{{cite book | vauthors = Voet D, Voet JG | date = 2004 | title = Biochemistry | edition = 3rd | location = New York | publisher = John Wiley & Sons, Inc. }}</ref> 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.

[[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.

[[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>