PKM2

PKM2 (alias pyruvate kinase type M2, alias M2-PK) also termed pyruvate kinase type K, type K4 or type III is an isoenzyme of the glycolytic enzyme pyruvate kinase.

Depending upon the different metabolic functions of the tissues different isoenzymes of pyruvate kinase are expressed.

The pyruvate kinase isoenzyme type M2 is expressed in some differentiated tissues, such as lung, fat tissue, retina and pancreatic islets as well as in all cells with a high rate of nucleic acid synthesis, such as normal proliferating cells, embryonic cells and especially tumor cells.Corcoran>cite journal|author = Corcoran E, Phelan JJ, Fottrell PF|title = Purification and properties of pyruvate kinase from human lung. |journal = Biochim. Biophys. Acta |year = 1976|volume = 446|pages = 96–104|pmid = 974119] Tolle>cite journal|author = Tolle SW, Dyson RD, Newburgh RW, Cardenas JM|title = Pyruvate kinase isozymes in neurons, glia, neuroblastoma and glioblastoma. |journal = J. Neurochem. |year = 1976|volume = 27|pages = 1355–1360|pmid = 1003209|doi = 10.1111/j.1471-4159.1976.tb02615.x] Reinacher>cite journal|author = 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 Arch. B Cell Pathol. Incl. Mol. Pathol. |year = 1981|volume = 37|pages = 79–88|pmid = 6116351|doi = 10.1007/BF02892557] Schering>cite journal|author = Schering B, Eigenbrodt E, Linder D, Schoner W.|title = Purification and properties of pyruvate kinase type M2 from rat lung. |journal = Biochim. Biophys. Acta |year = 1982|volume = 717|pages = 337–347|pmid = 7115773] Mac Donald>cite journal|author = Mac Donald MJ, Chang CM|title = Pancreatic islets contain the M2 isoenzyme of pyruvate kinase. |journal = Mol. Cell Biochem. |year = 1985|volume = 68|pages = 115–120|pmid = 3908905] Brinck>cite journal|author = 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 Arch. |year = 1994|volume = 424|pages = 177–185|pmid = 8180780|doi = 10.1007/BF00193498] Steinberg>cite journal|author = 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 Arch. |year = 1999|volume = 434|pages = 213–220|pmid = 10190300|doi = 10.1007/s004280050330] Eigenbrodt1980>cite journal|author = Eigenbrodt E, Glossmann H|title = Glycolysis – one of the keys to cancer.|journal = Trends Pharmacol. Sci. |year = 1980|volume = 1|pages = 240–245] Eigenbrodt1992>cite journal|author = 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 = Crit. Rev. Oncog. |year = 1992|volume = 3|pages = 91–115|pmid = 1532331] Mazurek2005>cite journal | author = Mazurek S, Boschek CB, Hugo F, Eigenbrodt E | title = Pyruvate kinase type M2 and its role in tumor growth and spreading | journal = Semin. Cancer Biol. | volume = 15 | issue = 4 | pages = 300–8 | year = 2005 | pmid = 15908230 | doi = 10.1016/j.semcancer.2005.04.009 | issn = ]

M2-PK is encoded by the gene gene|PKM2 which does also encode for the pyruvate kinase isoenzyme type M1 (PKM1 or M1-PK). The M-gene consists of 12 exons and 11 introns. PKM1 and PKM2 are different 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.Noguchi>cite journal|author = 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 splicing. |journal = J. Biol. Chem. |year = 1986|volume = 261|pages = 13807–13812|pmid = 3020052] cite journal | author = 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 | year = 2005 | pmid = 15996096 | doi = 10.1021/bi0474923 | issn = ]

PKM1 (M1-PK) is expressed in organs which are strongly dependent upon a high rate of energy regeneration, such as muscle and brain.

The pyruvate kinase reaction

Pyruvate kinase catalyzes the last step within glycolysis, the dephosphorylation of phosphoenolpyruvate to pyruvate and is responsible for net ATP production within the glycolytic sequence. In contrast to mitochondrial respiration energy regeneration by pyruvate kinase is independent from oxygen supply and allows survival of the organs under hypoxic conditions often found in solid tumors.cite journal | author = Vaupel P, Harrison L | title = Tumor hypoxia: causative factors, compensatory mechanisms, and cellular response | journal = Oncologist | volume = 9 Suppl 5 | issue = | pages = 4–9 | year = 2004 | pmid = 15591417 | doi = 10.1634/theoncologist.9-90005-4 | issn = ]

Cellular localization

M2-PK is a cytosolic enzyme which is associated with other glycolytic enzymes i.e. hexokinase, glyceraldehyde 3-P dehydrogenase, phosphoglycerate kinase, phosphoglyceromutase, enolase and lactate dehydrogenase within a so called glycolytic enzyme complex.Mazurek2005/>Zwerschke>cite journal | author = 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 = Proc. Natl. Acad. Sci. U.S.A. | volume = 96 | issue = 4 | pages = 1291–6 | year = 1999 | pmid = 9990017 | doi = 10.1073/pnas.96.4.1291 | issn = ] Mazurek2001>cite journal | author = 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 | year = 2001 | pmid = 11687968 | doi = 10.1038/sj.onc.1204792 | issn = ] christofk2008>cite journal | author = 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 | year = 2008 | pmid = 18337815 | doi = 10.1038/nature06667 | issn = ]

However, PKM2 contains an inducible nuclear translocation signal in its C-domain. The role of M2-PK within the 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 histone 1 by direct phosphate transfer from PEP to histone 1. On the other hand nuclear translocation of M2-PK induced by a somatostatin analogue, H₂O₂ or UV light has been linked with caspase-independent programmed cell death.Ignacak>cite journal | author = Ignacak J, Stachurska MB | title = The dual activity of pyruvate kinase type M2 from chromatin extracts of neoplastic cells | journal = Comp. Biochem. Physiol. B, Biochem. Mol. Biol. | volume = 134 | issue = 3 | pages = 425–33 | year = 2003 | pmid = 12628374 | doi = 10.1016/S1096-4959(02)00283-X | issn = ] Hoshino>cite journal | author = Hoshino A, Hirst JA, Fujii H | title = Regulation of cell proliferation by interleukin-3-induced nuclear translocation of pyruvate kinase | journal = J. Biol. Chem. | volume = 282 | issue = 24 | pages = 17706–11 | year = 2007 | pmid = 17446165 | doi = 10.1074/jbc.M700094200 | issn = ] Stetak>cite journal | author = 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 Res. | volume = 67 | issue = 4 | pages = 1602–8 | year = 2007 | pmid = 17308100 | doi = 10.1158/0008-5472.CAN-06-2870 | issn = ]

Bi-functional role of PKM2 within tumor metabolism

During tumor formation a shift in the isoenzyme equipment of pyruvate kinase takes place. The tissue specific isoenzymes (type M1, type L and type R) disappear and M2-PK is expressed.Reinacher/>Brinck/>Steinberg/> In contrast to the closely homologous pyruvate kinase isoenzyme type M1, 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 dimeric form.

The tetrameric form of M2-PK has a high affinity to its substrate phosphoenolpyruvate (PEP), and is highly active at physiological PEP concentrations. When M2-PK 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.

The dimeric form of M2-PK is characterized by a low affinity to its substrate PEP and is nearly inactive at physiological PEP concentrations. When M2-PK 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.Eigenbrodt1980/>Eigenbrodt1992/>Mazurek2005/>
Nucleic acids, phospholipids and amino acids are important cell building blocks which are badly 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).Eigenbrodt1980/>Eigenbrodt1992/>Mazurek2005/>

In tumor cells PKM2 is mainly in the dimeric form and has therefore been termed 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).Zwerschke/>Mazurek2001/>Oude Weernink>cite journal|author = Oude Weernink PA, Rijksen G, Staal GEJ|title = Phosphorylation of pyruvate kinase type and glycolytic metabolism in three human glioma cell lines. |journal = Tumour Biol. |year = 1991|volume = 12|pages = 339–352|pmid = 1798909] Eigenbrodt1998>cite book | author = Eigenbrodt E, Mazurek S, Friis RR | title = Double role of pyruvate kinase type M2 in the regulation of phosphometabolite pools. In: Bannasch P, Kanduc D, Papa S, Tager JM (eds) | journal = Cell growth and Oncogenesis | year = 1998 | publisher = Birkhäuser Verlag | location = Basel/Switzerland | volume = | pages = 15-30 | isbn = 3-7643-5727-4 ] Mazurek2007>cite journal|author = 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 metabolism|journal = Anticancer Res. |year = 2007|volume = 27|pages = 3963–3971|pmid = 18225557] The physiological function of the interaction between PKM2 and HERC1 as well as between PKM2 and PKCdelta is unknown).Garcia>cite journal | author = 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 Lett. | volume = 539 | issue = 1-3 | pages = 78–84 | year = 2003 | pmid = 12650930 | doi = 10.1016/S0014-5793(03)00205-9 | issn = ] Siwko>cite journal | author = Siwko S, Mochly-Rosen D | title = Use of a novel method to find substrates of protein kinase C delta identifies M2 pyruvate kinase | journal = Int. J. Biochem. Cell Biol. | volume = 39 | issue = 5 | pages = 978–87 | year = 2007 | pmid = 17337233 | doi = 10.1016/j.biocel.2007.01.018 | issn = ]

However, the tetramer : dimer ratio of PKM2 is not stationary value. High levels of the glycolytic intermediate fructose 1,6-P2 induce the re-association of the dimeric form of M2-PK to the tetrameric form. Consequently, glucose is converted to pyruvate and lactate with the production of energy until fructtose 1,6-P2 levels drop below a critical value to allow the dissociation the the dimeric form. This regulation is termed "metabolic budget system".Eigenbrodt1992/>Ashizawa>cite journal|author = 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-P2. |journal = J. Biol. Chem. |year = 1991|volume = 266|pages = 16842–16846|pmid = 1885610] Mazurek2005/> Another activator of M2-PK is the amino acid serine.Eigenbrodt1992/> The thyroid hormone 3,3´,5-triiodi-L-tyhronine (T3) binds to the monomeric form of M2-PK and prevents its association to the tetrameric form.Kato>cite journal|author = Kato H, Fukuda T, Parkinson C, McPhie P, Cheng SY|title = Cytosolic thyroid hormone-binding protein is a monomer of pyruvate kinase.|journal = Proc. Natl. Acad. Sci. USA |year = 1989|volume = 86|pages = 7861–7865|pmid = 2813362|doi = 10.1073/pnas.86.20.7861]

In tumor cells the increased rate of lactate production in the presence of oxygen is termed the 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.Christofk2008b>cite journal | author = 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 | year = 2008 | pmid = 18337823 | doi = 10.1038/nature06734 | issn = ] Accordingly, cotransfection of NIH 3T3 cells with gag-A-Raf and a kinase dead mutant of M2-PK reduced colony whereas cotransfection with gag-A-Raf and wild type M2-PK led to a doubling of focus formation.LeMellay>cite journal | author = 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 = Adv. Enzyme Regul. | volume = 42 | issue = | pages = 317–32 | year = 2002 | pmid = 12123723 | doi = 10.1016/S0065-2571(01)00036-X | issn = ]

Role of PKM2 in bacterial pathogenesis

With the yeast two hybrid system gonococcal Opa proteins where found to interact with M2-PK. 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.williams>cite journal | author = 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 = Mol. Microbiol. | volume = 27 | issue = 1 | pages = 171–86 | year = 1998 | pmid = 9466265 | doi = 10.1046/j.1365-2958.1998.00670.x ]

ee also

* Pyruvate kinase
* Tumor M2-PK

External links

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References

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