View source for Biology:PKM2

{{Short description|Protein-coding gene in the species Homo sapiens}}
{{Infobox_gene}}
'''Pyruvate kinase isozymes M1/M2''' (PKM1/M2), also known as '''pyruvate kinase muscle isozyme''' (PKM), '''pyruvate kinase type K''', '''cytosolic thyroid hormone-binding protein''' (CTHBP),  '''thyroid hormone-binding protein 1''' (THBP1), or '''opa-interacting protein 3''' (OIP3), is an [[Biology:Enzyme|enzyme]] that in humans is encoded by the ''PKM2'' [[Biology:Gene|gene]].<ref name="pmid3818670">{{cite journal | vauthors = Kitagawa S, Obata T, Hasumura S, Pastan I, Cheng SY | title = A cellular 3,3',5-triiodo-L-thyronine binding protein from a human carcinoma cell line. Purification and characterization | journal = The Journal of Biological Chemistry | volume = 262 | issue = 8 | pages = 3903–8 | date = March 1987 | doi = 10.1016/S0021-9258(18)61442-5 | pmid = 3818670 | doi-access = free }}</ref><ref name="pmid2838416">{{cite journal | vauthors = Tsutsumi H, Tani K, Fujii H, Miwa S | title = Expression of L- and M-type pyruvate kinase in human tissues | journal = Genomics | volume = 2 | issue = 1 | pages = 86–9 | date = January 1988 | pmid = 2838416 | doi = 10.1016/0888-7543(88)90112-7 }}</ref><ref name="pmid2854097">{{cite journal | vauthors = Tani K, Yoshida MC, Satoh H, Mitamura K, Noguchi T, Tanaka T, Fujii H, Miwa S | title = Human M2-type pyruvate kinase: cDNA cloning, chromosomal assignment and expression in hepatoma | journal = Gene | volume = 73 | issue = 2 | pages = 509–16 | date = December 1988 | pmid = 2854097 | doi = 10.1016/0378-1119(88)90515-X }}</ref><ref name="pmid2267632">{{cite journal | vauthors = Popescu NC, Cheng SY | title = Chromosomal localization of the gene for a human cytosolic thyroid hormone binding protein homologous to the subunit of pyruvate kinase, subtype M2 | journal = Somatic Cell and Molecular Genetics | volume = 16 | issue = 6 | pages = 593–8 | date = November 1990 | pmid = 2267632 | doi = 10.1007/BF01233100 | s2cid = 8182554 | url = https://zenodo.org/record/1232942 }}</ref>

PKM2 is an isoenzyme of the [[Biology:Glycolysis|glycolytic]] [[Biology:Enzyme|enzyme]] [[Biology:Pyruvate kinase|pyruvate kinase]]. Depending upon the different metabolic functions of the tissues, different isoenzymes of pyruvate kinase are expressed. PKM2 is expressed in some differentiated tissues, such as [[Medicine:Lung|lung]], [[Chemistry:Fat|fat]] tissue, [[Biology:Retina|retina]], and pancreatic islets, as well as in all cells with a high rate of [[Biology:DNA synthesis|nucleic acid synthesis]], such as normal proliferating cells, embryonic cells, and especially tumor cells.<ref name="Corcoran">{{cite journal | vauthors = Corcoran E, Phelan JJ, Fottrell PF | title = Purification and properties of pyruvate kinase from human lung | journal = Biochimica et Biophysica Acta (BBA) - Protein Structure | volume = 446 | issue = 1 | pages = 96–104 | date = September 1976 | pmid = 974119 | doi = 10.1016/0005-2795(76)90101-x }}</ref><ref name="Tolle">{{cite journal | vauthors = Tolle SW, Dyson RD, Newburgh RW, Cardenas JM | title = Pyruvate kinase isozymes in neurons, glia, neuroblastoma, and glioblastoma | journal = Journal of Neurochemistry| volume = 27 | issue = 6 | pages = 1355–1360 | date = December 1976 | pmid = 1003209 | doi = 10.1111/j.1471-4159.1976.tb02615.x | s2cid = 35715586 }}</ref><ref name="Reinacher">{{cite journal | vauthors = Reinacher M, Eigenbrodt E | title = Immunohistological demonstration of the same type of pyruvate kinase isoenzyme (M2-Pk) in tumors of chicken and rat | journal = Virchows Archiv B | volume = 37 | issue = 1 | pages = 79–88 | year = 1981 | pmid = 6116351 | doi = 10.1007/BF02892557 | s2cid = 34155302 }}</ref><ref name="Schering">{{cite journal | vauthors = Schering B, Eigenbrodt E, Linder D, Schoner W | title = Purification and properties of pyruvate kinase type M2 from rat lung | journal = Biochimica et Biophysica Acta (BBA) - General Subjects | volume = 717 | issue = 2 | pages = 337–47 | date = August 1982 | pmid = 7115773 | doi = 10.1016/0304-4165(82)90188-X }}</ref><ref name="Mac Donald">{{cite journal | vauthors = MacDonald MJ, Chang CM | title = Pancreatic islets contain the M2 isoenzyme of pyruvate kinase. Its phosphorylation has no effect on enzyme activity | journal = Molecular and Cellular Biochemistry | volume = 68 | issue = 2 | pages = 115–20 | date = October 1985 | pmid = 3908905 | doi = 10.1007/bf00219375 | s2cid = 6187554 }}</ref><ref name="Brinck">{{cite journal | vauthors = Brinck U, Eigenbrodt E, Oehmke M, Mazurek S, Fischer G | title = L- and M2-pyruvate kinase expression in renal cell carcinomas and their metastases | journal = Virchows Archiv | volume = 424 | issue = 2 | pages = 177–85 | year = 1994 | pmid = 8180780 | doi = 10.1007/BF00193498 | s2cid = 5550950 }}</ref><ref name="Steinberg">{{cite journal | vauthors = Steinberg P, Klingelhöffer A, Schäfer A, Wüst G, Weisse G, Oesch F, Eigenbrodt E | title = Expression of pyruvate kinase M2 in preneoplastic hepatic foci of N-nitrosomorpholine-treated rats | journal = Virchows Archiv | volume = 434 | issue = 3 | pages = 213–20 | date = March 1999 | pmid = 10190300 | doi = 10.1007/s004280050330 | s2cid = 28167108 }}</ref>

== Discovery ==
The discovery of PKM2 began with laboratory observations made by [[Biography:Otto Heinrich Warburg|Otto Heinrich Warburg]], a German physiologist and Nobel Laureate in Physiology or Medicine in 1931.<ref>{{Cite journal |last1=Warburg |first1=Otto |last2=Wind |first2=Franz |last3=Negelein |first3=Erwin |date=1927-03-07 |title=The Metabolism of Tumors in the Body |journal=The Journal of General Physiology |volume=8 |issue=6 |pages=519–530 |doi=10.1085/jgp.8.6.519 |issn=0022-1295 |pmc=2140820 |pmid=19872213}}</ref><ref>{{Cite journal |last1=Liberti |first1=Maria V. |last2=Locasale |first2=Jason W. |date=March 2016 |title=The Warburg Effect: How Does it Benefit Cancer Cells? |journal=Trends in Biochemical Sciences |volume=41 |issue=3 |pages=211–218 |doi=10.1016/j.tibs.2015.12.001 |issn=0968-0004 |pmc=4783224 |pmid=26778478}}</ref> Warburg's experiments show that the cells exhibit dependence on glucose and are capable of fermentation, even under aerobic conditions. These observations are known as the Warburg effect. Subsequent research on the metabolic demands of cancer cells, studies have been directed towards the investigation of specific subtypes of pyruvate kinase, notably M1 and M2.

== Structure ==

Two isozymes are encoded by the ''PKM'' gene: PKM1 and PKM2. The M-gene consists of 12 [[Biology:Exon|exon]]s and 11 [[Biology:Intron|intron]]s. PKM1 and PKM2 are different [[Biology:Alternative splicing|splicing]] products of the M-gene (exon 9 for PKM1 and exon 10 for PKM2) and solely differ in 23 amino acids within a 56-amino acid stretch (aa 378–434) at their carboxy terminus.<ref name="Noguchi">{{cite journal | vauthors = Noguchi T, Inoue H, Tanaka T | title = The M1- and M2-type isozymes of rat pyruvate kinase are produced from the same gene by alternative RNA splicing | journal = The Journal of Biological Chemistry | volume = 261 | issue = 29 | pages = 13807–12 | date = October 1986 | doi = 10.1016/S0021-9258(18)67091-7 | pmid = 3020052 | doi-access = free }}</ref><ref name="pmid15996096">{{cite journal | vauthors = Dombrauckas JD, Santarsiero BD, Mesecar AD | title = Structural basis for tumor pyruvate kinase M2 allosteric regulation and catalysis | journal = Biochemistry | volume = 44 | issue = 27 | pages = 9417–29 | date = July 2005 | pmid = 15996096 | doi = 10.1021/bi0474923 | s2cid = 24625677 }}</ref>

== Function ==

[[Biology:Pyruvate kinase|Pyruvate kinase]] catalyzes the last step within [[Biology:Glycolysis|glycolysis]], the de[[Biology:Phosphorylation|phosphorylation]] of phosphoenolpyruvate to pyruvate, and is responsible for net [[Chemistry:Adenosine triphosphate|ATP]] production within the glycolytic sequence. In contrast to [[Biology:Mitochondria|mitochondria]]l [[Biology:Cellular respiration|respiration]], energy regeneration by pyruvate kinase is independent from oxygen supply and allows survival of the organs under [[Chemistry:Tumor hypoxia|hypoxic]] conditions often found in solid tumors.<ref name="pmid15591417">{{cite journal | vauthors = Vaupel P, Harrison L | title = Tumor hypoxia: causative factors, compensatory mechanisms, and cellular response | journal = The Oncologist | volume = 9 | pages = 4–9 | year = 2004 | issue = Suppl 5 | pmid = 15591417 | doi = 10.1634/theoncologist.9-90005-4 | doi-access = free }}</ref>

The involvement of this enzyme in a variety of [[Biology:Signal transduction|pathways]], [[Biology:Protein–protein interaction|protein–protein interaction]]s, and nuclear transport suggests its potential to perform multiple nonglycolytic functions with diverse implications, although multidimensional role of this protein is as yet not fully explored. However, a functional role in [[Biology:Angiogenesis|angiogenesis]] the so-called process of blood vessel formation by interaction and regulation of Jmjd8 has been shown.<ref name="pmid20857498">{{cite journal | vauthors = Gupta V, Bamezai RN | title = Human pyruvate kinase M2: a multifunctional protein | journal = Protein Science | volume = 19 | issue = 11 | pages = 2031–44 | date = November 2010 | pmid = 20857498 | pmc = 3005776 | doi = 10.1002/pro.505 }}</ref><ref name="Boeckel2016">{{cite journal | vauthors = Boeckel JN, Derlet A, Glaser SF, Luczak A, Lucas T, Heumüller AW, Krüger M, Zehendner CM, Kaluza D, Doddaballapur A, Ohtani K, Treguer K, Dimmeler S | title = JMJD8 Regulates Angiogenic Sprouting and Cellular Metabolism by Interacting With Pyruvate Kinase M2 in Endothelial Cells | journal = Arteriosclerosis, Thrombosis, and Vascular Biology | volume = 36 | issue = 7 | pages = 1425–33 | date = July 2016 | pmid = 27199445 | doi = 10.1161/ATVBAHA.116.307695 | doi-access = free }}</ref>

== Localization ==

=== Tissue ===

The PKM1 isozyme is expressed in organs that are strongly dependent upon a high rate of energy regeneration, such as [[Biology:Muscle|muscle]] and [[Biology:Brain|brain]].<ref name="Eigenbrodt1980">{{cite journal | vauthors = Eigenbrodt E, Glossmann H | title = Glycolysis – one of the keys to cancer|journal = Trends Pharmacol. Sci. | year = 1980 | volume = 1 | issue = 2 | pages = 240–245| doi = 10.1016/0165-6147(80)90009-7 }}</ref><ref name="Eigenbrodt1992">{{cite journal | vauthors = Eigenbrodt E, Reinacher M, Scheefers-Borchel U, Scheefers H, Friis R | title = Double role for pyruvate kinase type M2 in the expansion of phosphometabolite pools found in tumor cells | journal = Critical Reviews in Oncogenesis | volume = 3 | issue = 1–2 | pages = 91–115 | year = 1992 | pmid = 1532331 }}</ref><ref name="Mazurek2005">{{cite journal | vauthors = Mazurek S, Boschek CB, Hugo F, Eigenbrodt E | title = Pyruvate kinase type M2 and its role in tumor growth and spreading | journal = Seminars in Cancer Biology | volume = 15 | issue = 4 | pages = 300–8 | date = August 2005 | pmid = 15908230 | doi = 10.1016/j.semcancer.2005.04.009 }}</ref>

=== Cellular ===
PKM2 is enzyme pyruvate kinase M2 (PKM2) and a transcriptional coactivator of [[Biology:STAT1|STAT1]] responsible for the induction of the protein [[Biology:PD-L1|PDL-1]] expression and its regulation in tumor and immune cells.<ref name="Palsson-McDermott"/> In the lactate production, the upregulated PKM2 is required and it leads to its contribution in inflammatory response, organ injury and septic death <ref>{{cite journal | vauthors = Palsson-McDermott EM, Curtis AM, Goel G, Lauterbach MA, Sheedy FJ, Gleeson LE, van den Bosch MW, Quinn SR, Domingo-Fernandez R, Johnston DG, Jiang JK, Jiang JK, Israelsen WJ, Keane J, Thomas C, Clish C, Vander Heiden M, Vanden Heiden M, Xavier RJ, O'Neill LA | title = Pyruvate kinase M2 regulates Hif-1α activity and IL-1β induction and is a critical determinant of the warburg effect in LPS-activated macrophages | journal = Cell Metabolism | volume = 21 | issue = 1 | pages = 65–80 | date = January 2015 | pmid = 25565206 | pmc = 5198835 | doi = 10.1016/j.cmet.2014.12.005 }}</ref><ref>{{cite journal | vauthors = Zhang Z, Deng W, Kang R, Xie M, Billiar T, Wang H, Cao L, Tang D | title = Plumbagin Protects Mice from Lethal Sepsis by Modulating Immunometabolism Upstream of PKM2 | journal = Molecular Medicine | volume = 22 | pages = 162–172 | date = September 2016 | pmid = 26982513 | pmc = 5004715 | doi = 10.2119/molmed.2015.00250 }}</ref><ref>{{cite journal | vauthors = Yang L, Xie M, Yang M, Yu Y, Zhu S, Hou W, Kang R, Lotze MT, Billiar TR, Wang H, Cao L, Tang D | title = PKM2 regulates the Warburg effect and promotes HMGB1 release in sepsis | journal = Nature Communications | volume = 5 | issue = 1 | pages = 4436 | date = July 2014 | pmid = 25019241 | doi = 10.1038/ncomms5436 | pmc = 4104986 | bibcode = 2014NatCo...5.4436Y }}</ref> As a consequence, the removal of PKM2 in myeloid cells, administration of anti-PD-L1 or supplementation with recombinant interleukin -1 (IL-7)  eases the microbial clearance, inhibits T cell apoptosis, reduce multiple organ dysfunction and reduce septic death in Bmal1-deficient mice.<ref>{{cite journal | vauthors = Deng W, Zhu S, Zeng L, Liu J, Kang R, Yang M, Cao L, Wang H, Billiar TR, Jiang J, Xie M, Tang D | title = The Circadian Clock Controls Immune Checkpoint Pathway in Sepsis | journal = Cell Reports | volume = 24 | issue = 2 | pages = 366–378 | date = July 2018 | pmid = 29996098 | pmc = 6094382 | doi = 10.1016/j.celrep.2018.06.026 }}</ref>

=== Subcellular ===

PKM2 is a [[Biology:Cytosol|cytosol]]ic enzyme that is associated with other glycolytic enzymes, i.e., [[Biology:Hexokinase|hexokinase]], [[Biology:Glyceraldehyde 3-phosphate dehydrogenase|glyceraldehyde 3-P dehydrogenase]], [[Biology:Phosphoglycerate kinase|phosphoglycerate kinase]], phosphoglyceromutase, [[Biology:Enolase|enolase]], and [[Biology:Lactate dehydrogenase|lactate dehydrogenase]] within a so-called glycolytic enzyme complex.<ref name="Mazurek2005"/><ref name="Zwerschke">{{cite journal | vauthors = Zwerschke W, Mazurek S, Massimi P, Banks L, Eigenbrodt E, Jansen-Dürr P | title = Modulation of type M2 pyruvate kinase activity by the human papillomavirus type 16 E7 oncoprotein | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 96 | issue = 4 | pages = 1291–6 | date = February 1999 | pmid = 9990017 | pmc = 15456 | doi = 10.1073/pnas.96.4.1291 | bibcode = 1999PNAS...96.1291Z | doi-access = free }}</ref><ref name="Mazurek2001">{{cite journal | vauthors = Mazurek S, Zwerschke W, Jansen-Dürr P, Eigenbrodt E | title = Metabolic cooperation between different oncogenes during cell transformation: interaction between activated ras and HPV-16 E7 | journal = Oncogene | volume = 20 | issue = 47 | pages = 6891–8 | date = October 2001 | pmid = 11687968 | doi = 10.1038/sj.onc.1204792 | s2cid = 24269991 | doi-access =  }}</ref><ref name="christofk2008]">{{cite journal | vauthors = Christofk HR, Vander Heiden MG, Wu N, Asara JM, Cantley LC | title = Pyruvate kinase M2 is a phosphotyrosine-binding protein | journal = Nature | volume = 452 | issue = 7184 | pages = 181–6 | date = March 2008 | pmid = 18337815 | doi = 10.1038/nature06667 | bibcode = 2008Natur.452..181C | s2cid = 4346405 }}</ref>

However, PKM2 contains an inducible nuclear localization signal in its C-terminal domain. The role of PKM2 within the [[Biology:Cell nucleus|nucleus]] is complex, since pro-proliferative but also pro-apoptotic stimuli have been described.  On the one hand, nuclear PKM2 was found to participate in the phosphorylation of [[Biology:Histone|histone]] 1 by direct phosphate transfer from PEP to histone 1. On the other hand, nuclear translocation of PKM2 induced by a [[Biology:Somatostatin|somatostatin]] analogue, H<sub>2</sub>O<sub>2</sub>, or UV light has been linked with [[Biology:Caspase|caspase]]-independent programmed cell death.<ref name="Ignacak">{{cite journal | vauthors = Ignacak J, Stachurska MB | title = The dual activity of pyruvate kinase type M2 from chromatin extracts of neoplastic cells | journal = Comparative Biochemistry and Physiology. Part B, Biochemistry & Molecular Biology | volume = 134 | issue = 3 | pages = 425–33 | date = March 2003 | pmid = 12628374 | doi = 10.1016/S1096-4959(02)00283-X }}</ref><ref name="Hoshino">{{cite journal | vauthors = Hoshino A, Hirst JA, Fujii H | title = Regulation of cell proliferation by interleukin-3-induced nuclear translocation of pyruvate kinase | journal = The Journal of Biological Chemistry | volume = 282 | issue = 24 | pages = 17706–11 | date = June 2007 | pmid = 17446165 | doi = 10.1074/jbc.M700094200 | doi-access = free }}</ref><ref name="Stetak">{{cite journal | vauthors = Steták A, Veress R, Ovádi J, Csermely P, Kéri G, Ullrich A | title = Nuclear translocation of the tumor marker pyruvate kinase M2 induces programmed cell death | journal = Cancer Research | volume = 67 | issue = 4 | pages = 1602–8 | date = February 2007 | pmid = 17308100 | doi = 10.1158/0008-5472.CAN-06-2870 | doi-access = free }}</ref>

== Clinical significance ==

=== Bi-functional role within tumors ===

PKM2 is expressed in most human tumors.<ref name="Reinacher"/><ref name="Brinck"/><ref name="Steinberg"/> Initially, a switch from PKM1 to PKM2 expression during tumorigenesis was discussed.<ref name="Christofk2008b">{{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> These conclusions, however, were the result of misinterpretation of [[Biology:Western blot|western blot]]s that had used PKM1-expressing mouse muscle as the sole non-cancer tissue. In clinical cancer samples, solely an up-regulation of PKM2, but no cancer specificity, could be confirmed.<ref name="pmid21789790">{{cite journal | vauthors = Bluemlein K, Grüning NM, Feichtinger RG, Lehrach H, Kofler B, Ralser M | title = No evidence for a shift in pyruvate kinase PKM1 to PKM2 expression during tumorigenesis | journal = Oncotarget | volume = 2 | issue = 5 | pages = 393–400 | date = May 2011 | pmid = 21789790 | pmc = 3248187 | doi = 10.18632/oncotarget.278 }}</ref>

In contrast to the closely homologous PKM1, which always occurs in a highly active tetrameric form and which is not allosterically regulated, PKM2 may occur in a tetrameric form but also in a [[Biology:Protein dimer|dimer]]ic form.  The '''tetrameric form of PKM2''' has a high affinity to its substrate phosphoenolpyruvate (PEP), and is highly active at physiological PEP concentrations. When PKM2 is mainly in the highly active tetrameric form, which is the case in differentiated tissues and most normal proliferating cells, glucose is converted to pyruvate under the production of energy. Meanwhile, the '''dimeric form of PKM2''' is characterized by a low affinity to its substrate PEP and is nearly inactive at physiological PEP concentrations. Dimeric PKM2 produces little to no ATP in the conversion of PEP to pyruvate, making the net yield of ATP zero for glycolysis.<ref>{{cite journal | vauthors = Zahra K, Dey T, Mishra SP, Pandey U | title = Pyruvate Kinase M2 and Cancer: The Role of PKM2 in Promoting Tumorigenesis | journal = Frontiers in Oncology | volume = 10 | pages = 159 | date = 2020-03-02 | pmid = 32195169 | pmc = 7061896 | doi = 10.3389/fonc.2020.00159 | doi-access = free }}</ref> When PKM2 is mainly in the less active dimeric form, which is the case in tumor cells, all glycolytic intermediates above pyruvate kinase accumulate and are channelled into synthetic processes, which branch off from glycolytic intermediates such as nucleic acid-, phospholipid-, and amino acid synthesis.<ref name="Eigenbrodt1980"/><ref name="Eigenbrodt1992"/><ref name="Mazurek2005"/> Nucleic acids, phospholipids, and amino acids are important cell building-blocks, which are greatly needed by highly proliferating cells, such as tumor cells.

Due to the key position of pyruvate kinase within glycolysis, the tetramer:dimer ratio of PKM2 determines whether glucose carbons are converted to pyruvate and lactate under the production of energy (tetrameric form) or channelled into synthetic processes (dimeric form).<ref name="Eigenbrodt1980"/><ref name="Eigenbrodt1992"/><ref name="Mazurek2005"/> However, even if PKM2 activity is low leading to the diversion of upstream intermediates to synthetic processes, pyruvate and lactate will still be made using carbon atoms from glucose and other metabolites through 86 pathways bypassing [[Biology:Pyruvate kinase|pyruvate kinase]].<ref>Christos Chinopoulos (2020), From Glucose to Lactate and Transiting Intermediates Through Mitochondria, Bypassing Pyruvate Kinase: Considerations for Cells Exhibiting Dimeric PKM2 or Otherwise Inhibited Kinase Activity, https://www.frontiersin.org/articles/10.3389/fphys.2020.543564/full</ref> These pyruvate kinase bypassing pathways are different from those participating in [[Biology:Gluconeogenesis|gluconeogenesis]]. Interestingly, many of the pyruvate kinase bypassing pathways use metabolites that transit through [[Biology:Mitochondria|mitochondria]], highlighting the importance of mitochondria in cancer metabolism irrespective of [[Biology:Oxidative phosphorylation|oxidative phosphorylation]].

In tumor cells, PKM2 is mainly in the dimeric form and has, therefore, been termed [[Biology:Tumor M2-PK|Tumor M2-PK]]. The quantification of Tumor M2-PK in plasma and stool is a tool for early detection of tumors and follow-up studies during therapy. The dimerization of PKM2 in tumor cells is induced by direct interaction of PKM2 with different oncoproteins (pp60v-src, HPV-16 E7, and A-Raf).<ref name="Zwerschke"/><ref name="Mazurek2001"/><ref name="Oude Weernink">{{cite journal | vauthors = Oude Weernink PA, Rijksen G, Staal GE | title = Phosphorylation of pyruvate kinase and glycolytic metabolism in three human glioma cell lines | journal = Tumour Biology | volume = 12 | issue = 6 | pages = 339–52 | year = 1991 | pmid = 1798909 | doi = 10.1159/000217735 }}</ref><ref name="Eigenbrodt1998">{{cite book |vauthors=Eigenbrodt E, Mazurek S, Friis RR | title = Cell Growth and Oncogenesis | chapter = Double role of pyruvate kinase type M2 in the regulation of phosphometabolite pools | series = Molecular and Cell Biology Updates | year = 1998 | publisher = Birkhäuser Verlag | location = Basel/Switzerland | pages = 15–30 | isbn = 3-7643-5727-4 | doi=10.1007/978-3-0348-8950-6_2}}</ref><ref name="Mazurek2007">{{cite journal | vauthors = Mazurek S, Drexler HC, Troppmair J, Eigenbrodt E, Rapp UR | title = Regulation of pyruvate kinase type M2 by A-Raf: a possible glycolytic stop or go mechanism | journal = Anticancer Research | volume = 27 | issue = 6B | pages = 3963–71 | year = 2007 | pmid = 18225557 }}</ref>  The physiological function of the interaction between PKM2 and HERC1 as well as between PKM2 and PKCdelta is unknown).<ref name="Garcia">{{cite journal | vauthors = Garcia-Gonzalo FR, Cruz C, Muñoz P, Mazurek S, Eigenbrodt E, Ventura F, Bartrons R, Rosa JL | title = Interaction between HERC1 and M2-type pyruvate kinase | journal = FEBS Letters | volume = 539 | issue = 1–3 | pages = 78–84 | date = March 2003 | pmid = 12650930 | doi = 10.1016/S0014-5793(03)00205-9 | s2cid = 32809019 }}</ref><ref name="Siwko">{{cite journal | vauthors = Siwko S, Mochly-Rosen D | title = Use of a novel method to find substrates of protein kinase C delta identifies M2 pyruvate kinase | journal = The International Journal of Biochemistry & Cell Biology | volume = 39 | issue = 5 | pages = 978–87 | year = 2007 | pmid = 17337233 | pmc = 1931518 | doi = 10.1016/j.biocel.2007.01.018 }}</ref> Due to the essential role of PKM2 in aerobic glycolysis (The Warburg effect) which is a dominant metabolic pathway used by cancer cells.<ref name="Palsson-McDermott">{{cite journal | vauthors = Palsson-McDermott EM, Dyck L, Zasłona Z, Menon D, McGettrick AF, Mills KH, O'Neill LA | title = Pyruvate Kinase M2 Is Required for the Expression of the Immune Checkpoint PD-L1 in Immune Cells and Tumors | journal = Frontiers in Immunology | volume = 8 | pages = 1300 | date = 2017-10-13 | pmid = 29081778 | pmc = 5646285 | doi = 10.3389/fimmu.2017.01300 | doi-access = free }}</ref> Its overcome in this pathway in macrophages may lead to better outcome in experimental sepsis.<ref>{{cite journal | vauthors = Zhang Z, Deng W, Kang R, Xie M, Billiar T, Wang H, Cao L, Tang D | display-authors = 6 | title = Plumbagin Protects Mice from Lethal Sepsis by Modulating Immunometabolism Upstream of PKM2 | journal = Molecular Medicine | volume = 22 | pages = 162–172 | date = September 2016 | pmid = 26982513 | pmc = 5004715 | doi = 10.2119/molmed.2015.00250 }}</ref><ref>{{cite journal | vauthors = Yang L, Xie M, Yang M, Yu Y, Zhu S, Hou W, Kang R, Lotze MT, Billiar TR, Wang H, Cao L, Tang D | display-authors = 6 | title = PKM2 regulates the Warburg effect and promotes HMGB1 release in sepsis | journal = Nature Communications | volume = 5 | pages = 4436 | date = July 2014 | pmid = 25019241 | pmc = 4104986 | doi = 10.1038/ncomms5436 | first8 = Shan | first9 = Yan | bibcode = 2014NatCo...5.4436Y | first7 = Wen }}</ref><ref>{{cite journal | vauthors = Huang J, Liu K, Zhu S, Xie M, Kang R, Cao L, Tang D | title = AMPK regulates immunometabolism in sepsis | journal = Brain, Behavior, and Immunity | volume = 72 | pages = 89–100 | date = August 2018 | pmid = 29109024 | doi = 10.1016/j.bbi.2017.11.003 | s2cid = 38415440 }}</ref> Thus, PKM2 is a regulator of LPS- and tumor-induced [[Biology:PD-L1|PD-L1]] expression on [[Biology:Macrophage|macrophage]]s and [[Biology:Dendritic cell|dendritic cell]]s as well as tumor cells.<ref name="Palsson-McDermott"/>

Studies involving the use of PKM2 activators have looked at promoting the conversion of dimeric PKM2 to its tetrameric form, hindering the growth of cancer cells.<ref>{{Cite journal |last1=Zahra |first1=Kulsoom |last2=Dey |first2=Tulika |last3=Ashish |last4=Mishra |first4=Surendra Pratap |last5=Pandey |first5=Uma |date=2020 |title=Pyruvate Kinase M2 and Cancer: The Role of PKM2 in Promoting Tumorigenesis |journal=Frontiers in Oncology |volume=10 |page=159 |doi=10.3389/fonc.2020.00159 |pmid=32195169 |pmc=7061896 |issn=2234-943X |doi-access=free }}</ref> Furthermore, concurrent research is centered on targeting the tetrameric form of PKM2 with small-molecule activators, such as TEPP-46 and DASA-58, to increase its resistance to inhibition.<ref>{{Cite journal |last1=Puckett |first1=Dexter L. |last2=Alquraishi |first2=Mohammed |last3=Chowanadisai |first3=Winyoo |last4=Bettaieb |first4=Ahmed |date=January 2021 |title=The Role of PKM2 in Metabolic Reprogramming: Insights into the Regulatory Roles of Non-Coding RNAs |journal=International Journal of Molecular Sciences |language=en |volume=22 |issue=3 |pages=1171 |doi=10.3390/ijms22031171 |pmid=33503959 |pmc=7865720 |issn=1422-0067 |doi-access=free }}</ref>

However, the tetramer:dimer ratio of PKM2 is not stationary value. High levels of the glycolytic intermediate [[Chemistry:Fructose 1,6-bisphosphate|fructose 1,6-bisphosphate]] induce the re-association of the dimeric form of PKM2 to the tetrameric form. As a consequence, glucose is converted to pyruvate and [[Chemistry:Lactic acid|lactate]] with the production of energy until fructose 1,6-bisphosphate levels drop below a critical value to allow dissociation to the dimeric form. This regulation is termed ''metabolic budget system''.<ref name="Eigenbrodt1992"/><ref name ="Mazurek2005"/><ref name="Ashizawa">{{cite journal | vauthors = Ashizawa K, Willingham MC, Liang CM, Cheng SY | title = In vivo regulation of monomer-tetramer conversion of pyruvate kinase subtype M2 by glucose is mediated via fructose 1,6-bisphosphate | journal = The Journal of Biological Chemistry | volume = 266 | issue = 25 | pages = 16842–6 | date = September 1991 | doi = 10.1016/S0021-9258(18)55378-3 | pmid = 1885610 | doi-access = free }}</ref> Another activator of PKM2 is the amino acid [[Chemistry:Serine|serine]].<ref name="Eigenbrodt1992"/> The thyroid hormone 3,3´,5-triiodi-L-thyronine ([[Chemistry:Triiodothyronine|T3]]) binds to the [[Chemistry:Monomer|monomer]]ic form of PKM2 and prevents its association to the tetrameric form.<ref name="Kato">{{cite journal | vauthors = Kato H, Fukuda T, Parkison C, McPhie P, Cheng SY | title = Cytosolic thyroid hormone-binding protein is a monomer of pyruvate kinase | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 86 | issue = 20 | pages = 7861–5 | date = October 1989 | pmid = 2813362 | pmc = 298171 | doi = 10.1073/pnas.86.20.7861 | bibcode = 1989PNAS...86.7861K | doi-access = free }}</ref>

In tumor cells, the increased rate of lactate production in the presence of oxygen is termed the [[Medicine:Warburg effect (oncology)|Warburg effect]]. Genetic manipulation of cancer cells so that they produce adult PKM1 instead of PKM2 reverses the Warburg effect and reduces the growth rate of these modified cancer cells.<ref name="Christofk2008b" /> Accordingly, cotransfection of NIH 3T3 cells with gag-A-Raf and a kinase dead mutant of PKM2 reduced colony whereas cotransfection with gag-A-Raf and [[Biology:Wild type|wild type]] PKM2 led to a doubling of focus formation.<ref name="LeMellay">{{cite journal | vauthors = Le Mellay V, Houben R, Troppmair J, Hagemann C, Mazurek S, Frey U, Beigel J, Weber C, Benz R, Eigenbrodt E, Rapp UR | title = Regulation of glycolysis by Raf protein serine/threonine kinases | journal = Advances in Enzyme Regulation | volume = 42 | pages = 317–32 | year = 2002 | pmid = 12123723 | doi = 10.1016/S0065-2571(01)00036-X }}</ref>

The dimeric form of PKM2 has been observed to have protein kinase activity in tumor cells. It is able to bind to and phosphorylate the histone H3 of chromatin in cancer cells, thereby having a role in the regulation of gene expression.<ref name=":02">{{cite journal | vauthors = Yang W, Xia Y, Hawke D, Li X, Liang J, Xing D, Aldape K, Hunter T, Alfred Yung WK, Lu Z | title = PKM2 phosphorylates histone H3 and promotes gene transcription and tumorigenesis | journal = Cell | volume = 150 | issue = 4 | pages = 685–96 | date = August 2012 | pmid = 22901803 | doi = 10.1016/j.cell.2012.07.018 | pmc=3431020}}</ref> This modification of histone H3 and the resulting involvement in gene expression regulation can be a cause of tumor cell proliferation.<ref name=":02" />

The pyruvate kinase activity of PKM2 can be promoted by SAICAR (succinylaminoimidazolecarboxamide ribose-5′-phosphate), an intermediate in purine biosynthesis. In cancer cells, glucose starvation leads to a rise in SAICAR levels and the subsequent stimulation of pyruvate kinase activity of PKM2. This allows for the completion of the glycolytic pathway to produce pyruvate and, therefore, survival under glucose deprivation.<ref name=":0">{{cite journal | vauthors = Keller KE, Tan IS, Lee YS | title = SAICAR stimulates pyruvate kinase isoform M2 and promotes cancer cell survival in glucose-limited conditions | journal = Science | volume = 338 | issue = 6110 | pages = 1069–72 | date = November 2012 | pmid = 23086999 | pmc = 3527123 | doi = 10.1126/science.1224409 | bibcode = 2012Sci...338.1069K }}</ref> In addition, an abundance of SAICAR can modify glucose absorption and lactate production in cancer cells.<ref name=":0" /> However, it has been shown that SAICAR binding also sufficiently stimulates the protein kinase activity of PKM2 in tumor cells.<ref name=":1">{{cite journal | vauthors = Keller KE, Doctor ZM, Dwyer ZW, Lee YS | title = SAICAR induces protein kinase activity of PKM2 that is necessary for sustained proliferative signaling of cancer cells | language = en | journal = Molecular Cell | volume = 53 | issue = 5 | pages = 700–9 | date = March 2014 | pmid = 24606918 | doi = 10.1016/j.molcel.2014.02.015 | pmc=4000728}}</ref> In turn, the SAICAR-PKM2 complex can potentially phosphorylate a number of other protein kinases using PEP as the phosphate donor. Many of these proteins contribute to the regulation of cancer cell proliferation. Specifically, PKM2 can be a component in mitogen-activated protein kinase (MAPK) signaling, which is associated with increased cell proliferation if functioning improperly. This provides a potential link between SAICAR-activated PKM2 and cancer cell growth.<ref name=":1" />

=== Natural mutations and carcinogenesis===

Two [[Biology:Missense mutation|missense mutation]]s, H391Y and K422R, of PKM2 were found in cells from [[Medicine:Bloom syndrome|Bloom syndrome]] patients prone to developing cancer. Results show that, despite the presence of mutations in the inter-subunit contact domain, the K422R and H391Y mutant proteins maintained their homotetrameric structure, similar to the wild-type protein, but showed a loss of activity of 75 and 20%, respectively. H391Y showed a 6-fold increase in affinity for its substrate phosphoenolpyruvate and behaved like a non-allosteric protein with compromised [[Biology:Cooperative binding|cooperative binding]]. However, the affinity for phosphoenolpyruvate was lost significantly in K422R. Unlike K422R, H391Y showed enhanced thermal stability, stability over a range of [[Chemistry:PH|pH]] values, a lesser effect of the allosteric inhibitor Phe, and resistance toward structural alteration upon binding of the activator (fructose 1,6-bisphosphate) and inhibitor (Phe). Both mutants showed a slight shift in the pH optimum from 7.4 to 7.0.<ref name="pmid19265196">{{cite journal | vauthors = Akhtar K, Gupta V, Koul A, Alam N, Bhat R, Bamezai RN | title = Differential behavior of missense mutations in the intersubunit contact domain of the human pyruvate kinase M2 isozyme | journal = The Journal of Biological Chemistry | volume = 284 | issue = 18 | pages = 11971–81 | date = May 2009 | pmid = 19265196 | pmc = 2673266 | doi = 10.1074/jbc.M808761200 | doi-access = free }}</ref> The co-expression of homotetrameric wild type and mutant PKM2 in the cellular milieu resulting in the interaction between the two at the monomer level was substantiated further by in vitro experiments. The cross-monomer interaction significantly altered the oligomeric state of PKM2 by favoring dimerisation and heterotetramerization. In silico study provided an added support in showing that hetero-oligomerization was energetically favorable. The hetero-oligomeric populations of PKM2 showed altered activity and affinity, and their expression resulted in an increased growth rate of Escherichia coli as well as mammalian cells, along with an increased rate of [[Biology:Polyploidy|polyploidy]]. These features are known to be essential to tumor progression.<ref name="pmid20304929">{{cite journal | vauthors = Gupta V, Kalaiarasan P, Faheem M, Singh N, Iqbal MA, Bamezai RN | title = Dominant negative mutations affect oligomerization of human pyruvate kinase M2 isozyme and promote cellular growth and polyploidy | journal = The Journal of Biological Chemistry | volume = 285 | issue = 22 | pages = 16864–73 | date = May 2010 | pmid = 20304929 | pmc = 2878009 | doi = 10.1074/jbc.M109.065029 | doi-access = free }}</ref>

Further, cells stably expressing exogenous wild- or mutant-PKM2 (K422R or H391Y) or co-expressing both wild and mutant (PKM2-K422R or PKM2-H391Y), were assessed for cancer metabolism and tumorigenic potential. Cells co-expressing PKM2 and mutant (K422R or H391Y) showed significantly aggressive cancer metabolism, compared to cells expressing either wild or mutant PKM2 independently. A similar trend was observed for oxidative endurance, tumorigenic potential, cellular proliferation and tumor growth. These observations signify the dominant negative nature of these mutations. Remarkably, PKM2-H391Y co-expressed cells showed a maximal effect on all the studied parameters. Such a dominant negative impaired function of PKM2 in tumor development is not known; also evidencing for the first time the possible predisposition of BS patients with impaired PKM2 activity to cancer, and the importance of studying genetic variations in PKM2 in future to understand their relevance in cancer in general.<ref>{{cite journal | vauthors = Iqbal MA, Siddiqui FA, Chaman N, Gupta V, Kumar B, Gopinath P, Bamezai RN | title = Missense mutations in pyruvate kinase M2 promote cancer metabolism, oxidative endurance, anchorage independence, and tumor growth in a dominant negative manner | journal = The Journal of Biological Chemistry | volume = 289 | issue = 12 | pages = 8098–105 | date = March 2014 | pmid = 24492614 | pmc = 3961641 | doi = 10.1074/jbc.M113.515742 | doi-access = free }}</ref>

=== Regulatory circuits ===

Cancer cells are characterized by a reprogramming of energy metabolism. Over the last decade, understanding of the metabolic changes that occur in cancer has increased dramatically, and there is great interest in targeting metabolism for cancer therapy. PKM2 plays a key role in modulating glucose metabolism to support cell proliferation. PKM2, like other PK isoforms, catalyzes the last energy-generating step in glycolysis, but is unique in its capacity to be regulated. PKM2 is regulated on several cellular levels, including gene expression, alternative splicing and [[Biology:Post-translational modification|post-translational modification]]. In addition, PKM2 is regulated by key metabolic intermediates and interacts with more than twenty different proteins. Hence, this isoenzyme is an important regulator of glycolysis and additional functions in other novel roles that have recently emerged. Recent evidence indicates that intervening in the complex regulatory network of PKM2 has severe consequences on tumor cell proliferation, indicating the potential of this enzyme as a target for tumor therapy.<ref>{{cite journal | vauthors = Gupta V, Wellen KE, Mazurek S, Bamezai RN | title = Pyruvate kinase M2: regulatory circuits and potential for therapeutic intervention | journal = Current Pharmaceutical Design | volume = 20 | issue = 15 | pages = 2595–606 | year = 2013 | pmid = 23859618 | doi = 10.2174/13816128113199990484 }}</ref>

=== Bacterial pathogenesis ===

With the yeast two-hybrid system, gonococcal Opa proteins were found to interact with PKM2. The results suggest that direct molecular interaction with the host metabolic enzyme PKM2 is required for the acquisition of pyruvate and for gonococcal growth and survival.<ref name="williams">{{cite journal | vauthors = Williams JM, Chen GC, Zhu L, Rest RF | title = Using the yeast two-hybrid system to identify human epithelial cell proteins that bind gonococcal Opa proteins: intracellular gonococci bind pyruvate kinase via their Opa proteins and require host pyruvate for growth | journal = Molecular Microbiology | volume = 27 | issue = 1 | pages = 171–86 | date = January 1998 | pmid = 9466265 | doi = 10.1046/j.1365-2958.1998.00670.x | doi-access = free }}</ref>

== Interactive pathway map ==

== See also ==
* [[Biology:Pyruvate kinase|Pyruvate kinase]]
* [[Biology:Tumor M2-PK|Tumor M2-PK]]
* [[Medicine:Bloom syndrome|Bloom syndrome]]

== References ==
{{reflist}}

== External links ==
* {{MeshName|Pyruvate+kinase}}
* {{cite web | url = http://www.metabolic-database.com/html/m2-pk.html | title = Pyruvate kinase isoenzyme type M2 (M2-PK) | access-date = 2008-03-22 | author =  Erich Eigenbrodt |author2=Sybille Mazurek  | work = Tumor metabolome database }}
* {{PDBe-KB2|P14618|Pyruvate kinase PKM}}

{{PDB_Gallery|geneid=5315}}
{{Glycolysis enzymes}}

[[Category:Metabolism]]
[[Category:Enzymes]]

{{Sourceattribution|PKM2}}