Editing Pyruvate kinase (section)

=== Applications of pyruvate kinase inhibition ===

==== Reactive Oxygen Species (ROS) Inhibition ====
[[Reactive oxygen species]] (ROS) are chemically reactive forms of oxygen. In human lung cells, ROS has been shown to inhibit the M2 isozyme of pyruvate kinase (PKM2). ROS achieves this inhibition by oxidizing Cys358 and inactivating PKM2. As a result of PKM2 inactivation, glucose flux is no longer converted into pyruvate, but is instead utilized in the pentose phosphate pathway, resulting in the reduction and detoxification of ROS. In this manner, the harmful effects of ROS are increased and cause greater oxidative stress on the lung cells, leading to potential tumor formation. This inhibitory mechanism is important because it may suggest that the regulatory mechanisms in PKM2 are responsible for aiding cancer cell resistance to oxidative stress and enhanced tumorigenesis.<ref>{{cite journal | vauthors = Anastasiou D, Poulogiannis G, Asara JM, Boxer MB, Jiang JK, Shen M, Bellinger G, Sasaki AT, Locasale JW, Auld DS, Thomas CJ, Vander Heiden MG, Cantley LC | title = Inhibition of pyruvate kinase M2 by reactive oxygen species contributes to cellular antioxidant responses | journal = Science | volume = 334 | issue = 6060 | pages = 1278–83 | date = December 2011 | pmid = 22052977 | pmc = 3471535 | doi = 10.1126/science.1211485 | bibcode = 2011Sci...334.1278A }}</ref><ref>{{cite journal | vauthors = Christofk HR, Vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R, Fleming MD, Schreiber SL, Cantley LC | title = The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth | journal = Nature | volume = 452 | issue = 7184 | pages = 230–3 | date = March 2008 | pmid = 18337823 | doi = 10.1038/nature06734 | bibcode = 2008Natur.452..230C | s2cid = 16111842 }}</ref>

==== Phenylalanine inhibition ====
Phenylalanine is found to function as a competitive inhibitor of pyruvate kinase in the brain. Although the degree of phenylalanine inhibitory activity is similar in both fetal and adult cells, the enzymes in the fetal brain cells are significantly more vulnerable to inhibition than those in adult brain cells. A study of PKM2 in babies with the genetic brain disease [[Phenylketonuria|phenylketonurics]] (PKU), showed elevated levels of phenylalanine and decreased effectiveness of PKM2. This inhibitory mechanism provides insight into the role of pyruvate kinase in brain cell damage.<ref>{{cite journal | vauthors = Miller AL, Hawkins RA, Veech RL | title = Phenylketonuria: phenylalanine inhibits brain pyruvate kinase in vivo | journal = Science | volume = 179 | issue = 4076 | pages = 904–6 | date = March 1973 | pmid = 4734564 | doi = 10.1126/science.179.4076.904 | bibcode = 1973Sci...179..904M | s2cid = 12776382 }}</ref><ref>{{cite journal | vauthors = Weber G | title = Inhibition of human brain pyruvate kinase and hexokinase by phenylalanine and phenylpyruvate: possible relevance to phenylketonuric brain damage | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 63 | issue = 4 | pages = 1365–9 | date = August 1969 | pmid = 5260939 | pmc = 223473 | doi = 10.1073/pnas.63.4.1365 | bibcode = 1969PNAS...63.1365W | doi-access = free }}</ref>