RBCC Red Blood Cell Collection

PKM (OIP3, PK2, PK3, PKM2) [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Pyruvate kinase PKM; 2.7.1.40 (Cytosolic thyroid hormone-binding protein; CTHBP; Opa-interacting protein 3; OIP-3; Pyruvate kinase 2/3; Pyruvate kinase muscle isozyme; Thyroid hormone-binding protein 1; THBP1; Tumor M2-PK; p58)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

hRBCD IPI00220644
IPI00220644 Splice isoform M1 or M2 of P14618 Pyruvate kinase, isozymes M1/M2 Splice isoform M1 or M2 of P14618 Pyruvate kinase, isozymes M1/M2 membrane n/a n/a n/a n/a n/a n/a n/a n/a 2 n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a Glycolisis, cytoplasmic splice isoform M1 and M2 found at its expected molecular weight found at molecular weight

UniProt P14618
ID KPYM_HUMAN Reviewed; 531 AA.
AC P14618; A6NFK3; B2R5N8; B3KRY0; B4DFX8; B4DUU6; P14786; Q53GK4;
read moreAC Q96E76; Q9BWB5; Q9UCV6; Q9UPF2;
DT 01-APR-1990, integrated into UniProtKB/Swiss-Prot.
DT 23-JAN-2007, sequence version 4.
DT 22-JAN-2014, entry version 187.
DE RecName: Full=Pyruvate kinase PKM;
DE EC=2.7.1.40;
DE AltName: Full=Cytosolic thyroid hormone-binding protein;
DE Short=CTHBP;
DE AltName: Full=Opa-interacting protein 3;
DE Short=OIP-3;
DE AltName: Full=Pyruvate kinase 2/3;
DE AltName: Full=Pyruvate kinase muscle isozyme;
DE AltName: Full=Thyroid hormone-binding protein 1;
DE Short=THBP1;
DE AltName: Full=Tumor M2-PK;
DE AltName: Full=p58;
GN Name=PKM; Synonyms=OIP3, PK2, PK3, PKM2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM M2).
RC TISSUE=Liver;
RX PubMed=2854097; DOI=10.1016/0378-1119(88)90515-X;
RA Tani K., Yoshida M.C., Satoh H., Mitamura K., Noguchi T., Tanaka T.,
RA Fujii H., Miwa S.;
RT "Human M2-type pyruvate kinase: cDNA cloning, chromosomal assignment
RT and expression in hepatoma.";
RL Gene 73:509-516(1988).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM M2), PROTEIN SEQUENCE OF 70-98,
RP SUBUNIT, AND ENZYME REGULATION.
RX PubMed=2813362; DOI=10.1073/pnas.86.20.7861;
RA Kato H., Fukuda T., Parkison C., McPhie P., Cheng S.-Y.;
RT "Cytosolic thyroid hormone-binding protein is a monomer of pyruvate
RT kinase.";
RL Proc. Natl. Acad. Sci. U.S.A. 86:7861-7865(1989).
RN [3]
RP ERRATUM.
RA Kato H., Fukuda T., Parkison C., McPhie P., Cheng S.-Y.;
RL Proc. Natl. Acad. Sci. U.S.A. 87:1625-1625(1990).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND ALTERNATIVE SPLICING.
RX PubMed=2040271; DOI=10.1111/j.1432-1033.1991.tb15991.x;
RA Takenaka M., Noguchi T., Sadahiro S., Hirai H., Yamada K., Matsuda T.,
RA Imai E., Tanaka T.;
RT "Isolation and characterization of the human pyruvate kinase M gene.";
RL Eur. J. Biochem. 198:101-106(1991).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS M1 AND 3).
RC TISSUE=Astrocyte, and Fetal brain;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM M2).
RC TISSUE=Kidney;
RA Suzuki Y., Sugano S., Totoki Y., Toyoda A., Takeda T., Sakaki Y.,
RA Tanaka A., Yokoyama S.;
RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG NIEHS SNPs program;
RL Submitted (JUL-2003) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16572171; DOI=10.1038/nature04601;
RA Zody M.C., Garber M., Sharpe T., Young S.K., Rowen L., O'Neill K.,
RA Whittaker C.A., Kamal M., Chang J.L., Cuomo C.A., Dewar K.,
RA FitzGerald M.G., Kodira C.D., Madan A., Qin S., Yang X., Abbasi N.,
RA Abouelleil A., Arachchi H.M., Baradarani L., Birditt B., Bloom S.,
RA Bloom T., Borowsky M.L., Burke J., Butler J., Cook A., DeArellano K.,
RA DeCaprio D., Dorris L. III, Dors M., Eichler E.E., Engels R.,
RA Fahey J., Fleetwood P., Friedman C., Gearin G., Hall J.L., Hensley G.,
RA Johnson E., Jones C., Kamat A., Kaur A., Locke D.P., Madan A.,
RA Munson G., Jaffe D.B., Lui A., Macdonald P., Mauceli E., Naylor J.W.,
RA Nesbitt R., Nicol R., O'Leary S.B., Ratcliffe A., Rounsley S., She X.,
RA Sneddon K.M.B., Stewart S., Sougnez C., Stone S.M., Topham K.,
RA Vincent D., Wang S., Zimmer A.R., Birren B.W., Hood L., Lander E.S.,
RA Nusbaum C.;
RT "Analysis of the DNA sequence and duplication history of human
RT chromosome 15.";
RL Nature 440:671-675(2006).
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM M2), AND VARIANT
RP VAL-204.
RC TISSUE=Kidney, Lung carcinoma, Ovary, Retina, and Rhabdomyosarcoma;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [11]
RP PROTEIN SEQUENCE OF 2-43; 57-73; 93-115; 126-135; 167-186; 231-246;
RP 271-311; 401-422; 448-455 AND 490-498, CLEAVAGE OF INITIATOR
RP METHIONINE, ACETYLATION AT SER-2, AND MASS SPECTROMETRY.
RC TISSUE=B-cell lymphoma;
RA Bienvenut W.V.;
RL Submitted (JUL-2005) to UniProtKB.
RN [12]
RP PROTEIN SEQUENCE OF 2-18, CATALYTIC ACTIVITY, ENZYME REGULATION,
RP BIOPHYSICOCHEMICAL PROPERTIES, SUBUNIT, AND INTERACTION WITH THYROID
RP HORMONE.
RX PubMed=1854723; DOI=10.1021/bi00243a010;
RA Ashizawa K., McPhie P., Lin K.-H., Cheng S.-Y.;
RT "An in vitro novel mechanism of regulating the activity of pyruvate
RT kinase M2 by thyroid hormone and fructose 1, 6-bisphosphate.";
RL Biochemistry 30:7105-7111(1991).
RN [13]
RP PROTEIN SEQUENCE OF 2-32.
RC TISSUE=Platelet;
RX PubMed=12665801; DOI=10.1038/nbt810;
RA Gevaert K., Goethals M., Martens L., Van Damme J., Staes A.,
RA Thomas G.R., Vandekerckhove J.;
RT "Exploring proteomes and analyzing protein processing by mass
RT spectrometric identification of sorted N-terminal peptides.";
RL Nat. Biotechnol. 21:566-569(2003).
RN [14]
RP PROTEIN SEQUENCE OF 74-89, AND MASS SPECTROMETRY.
RC TISSUE=Brain, and Cajal-Retzius cell;
RA Lubec G., Vishwanath V.;
RL Submitted (MAR-2007) to UniProtKB.
RN [15]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 368-531 (ISOFORM M2).
RX PubMed=9466265; DOI=10.1046/j.1365-2958.1998.00670.x;
RA Williams J.M., Chen G.-C., Zhu L., Rest R.F.;
RT "Using the yeast two-hybrid system to identify human epithelial cell
RT proteins that bind gonococcal Opa proteins: intracellular gonococci
RT bind pyruvate kinase via their Opa proteins and require host pyruvate
RT for growth.";
RL Mol. Microbiol. 27:171-186(1998).
RN [16]
RP INTERACTION WITH HERC1.
RX PubMed=12650930; DOI=10.1016/S0014-5793(03)00205-9;
RA Garcia-Gonzalo F.R., Cruz C., Munoz P., Mazurek S., Eigenbrodt E.,
RA Ventura F., Bartrons R., Rosa J.L.;
RT "Interaction between HERC1 and M2-type pyruvate kinase.";
RL FEBS Lett. 539:78-84(2003).
RN [17]
RP ISGYLATION.
RX PubMed=16139798; DOI=10.1016/j.bbrc.2005.08.132;
RA Giannakopoulos N.V., Luo J.K., Papov V., Zou W., Lenschow D.J.,
RA Jacobs B.S., Borden E.C., Li J., Virgin H.W., Zhang D.E.;
RT "Proteomic identification of proteins conjugated to ISG15 in mouse and
RT human cells.";
RL Biochem. Biophys. Res. Commun. 336:496-506(2005).
RN [18]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-105, AND MASS
RP SPECTROMETRY.
RX PubMed=15592455; DOI=10.1038/nbt1046;
RA Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H.,
RA Zha X.-M., Polakiewicz R.D., Comb M.J.;
RT "Immunoaffinity profiling of tyrosine phosphorylation in cancer
RT cells.";
RL Nat. Biotechnol. 23:94-101(2005).
RN [19]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-37, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [20]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-37, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=16964243; DOI=10.1038/nbt1240;
RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.;
RT "A probability-based approach for high-throughput protein
RT phosphorylation analysis and site localization.";
RL Nat. Biotechnol. 24:1285-1292(2006).
RN [21]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=17308100; DOI=10.1158/0008-5472.CAN-06-2870;
RA Stetak A., Veress R., Ovadi J., Csermely P., Keri G., Ullrich A.;
RT "Nuclear translocation of the tumor marker pyruvate kinase M2 induces
RT programmed cell death.";
RL Cancer Res. 67:1602-1608(2007).
RN [22]
RP INTERACTION WITH PML, ENZYME REGULATION, SUBUNIT, AND SUBCELLULAR
RP LOCATION.
RX PubMed=18298799; DOI=10.1111/j.1365-2443.2008.01165.x;
RA Shimada N., Shinagawa T., Ishii S.;
RT "Modulation of M2-type pyruvate kinase activity by the cytoplasmic PML
RT tumor suppressor protein.";
RL Genes Cells 13:245-254(2008).
RN [23]
RP INTERACTION WITH POU5F1, IDENTIFICATION BY MASS SPECTROMETRY,
RP FUNCTION, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=18191611; DOI=10.1016/j.biocel.2007.11.009;
RA Lee J., Kim H.K., Han Y.-M., Kim J.;
RT "Pyruvate kinase isozyme type M2 (PKM2) interacts and cooperates with
RT Oct-4 in regulating transcription.";
RL Int. J. Biochem. Cell Biol. 40:1043-1054(2008).
RN [24]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-37, AND MASS
RP SPECTROMETRY.
RC TISSUE=Platelet;
RX PubMed=18088087; DOI=10.1021/pr0704130;
RA Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J.,
RA Schuetz C., Walter U., Gambaryan S., Sickmann A.;
RT "Phosphoproteome of resting human platelets.";
RL J. Proteome Res. 7:526-534(2008).
RN [25]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-37, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [26]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-37, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [27]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, AND MASS SPECTROMETRY.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [28]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-37; TYR-175 AND THR-195,
RP AND MASS SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [29]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-62; LYS-89; LYS-166; LYS-266
RP AND LYS-433, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [30]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-37, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [31]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [32]
RP INTERACTION WITH EGLN3 AND HIF1A, SUBCELLULAR LOCATION, INDUCTION,
RP FUNCTION, MASS SPECTROMETRY, HYDROXYLATION AT PRO-403 AND PRO-408, AND
RP MUTAGENESIS OF PRO-403 AND PRO-408.
RX PubMed=21620138; DOI=10.1016/j.cell.2011.03.054;
RA Luo W., Hu H., Chang R., Zhong J., Knabel M., O'Meally R., Cole R.N.,
RA Pandey A., Semenza G.L.;
RT "Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-
RT inducible factor 1.";
RL Cell 145:732-744(2011).
RN [33]
RP INTERACTION WITH EGLN3.
RX PubMed=21483450; DOI=10.1038/cr.2011.66;
RA Chen N., Rinner O., Czernik D., Nytko K.J., Zheng D., Stiehl D.P.,
RA Zamboni N., Gstaiger M., Frei C.;
RT "The oxygen sensor PHD3 limits glycolysis under hypoxia via direct
RT binding to pyruvate kinase.";
RL Cell Res. 21:983-986(2011).
RN [34]
RP ACETYLATION AT LYS-305.
RX PubMed=21700219; DOI=10.1016/j.molcel.2011.04.025;
RA Lv L., Li D., Zhao D., Lin R., Chu Y., Zhang H., Zha Z., Liu Y.,
RA Li Z., Xu Y., Wang G., Huang Y., Xiong Y., Guan K.L., Lei Q.Y.;
RT "Acetylation targets the M2 isoform of pyruvate kinase for degradation
RT through chaperone-mediated autophagy and promotes tumor growth.";
RL Mol. Cell 42:719-730(2011).
RN [35]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-37, AND MASS
RP SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [36]
RP X-RAY CRYSTALLOGRAPHY (2.82 ANGSTROMS) OF ISOFORM M2 IN COMPLEX WITH
RP OXALATE AND FBP, CATALYTIC ACTIVITY, SUBUNIT, ENZYME MECHANISM, ENZYME
RP REGULATION, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=15996096; DOI=10.1021/bi0474923;
RA Dombrauckas J.D., Santarsiero B.D., Mesecar A.D.;
RT "Structural basis for tumor pyruvate kinase M2 allosteric regulation
RT and catalysis.";
RL Biochemistry 44:9417-9429(2005).
RN [37]
RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS).
RG Structural genomics consortium (SGC);
RT "Structure of human muscle pyruvate kinase (PKM2).";
RL Submitted (MAY-2005) to the PDB data bank.
RN [38]
RP X-RAY CRYSTALLOGRAPHY (2.03 ANGSTROMS) OF 14-531 ALONE AND IN COMPLEX
RP WITH FBP, AND ENZYME REGULATION.
RX PubMed=18337815; DOI=10.1038/nature06667;
RA Christofk H.R., Vander Heiden M.G., Wu N., Asara J.M., Cantley L.C.;
RT "Pyruvate kinase M2 is a phosphotyrosine-binding protein.";
RL Nature 452:181-186(2008).
RN [39]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 2-531, ENZYME REGULATION BY
RP SERINE, MAGNESIUM-BINDING SITES, SUBUNIT, AND MUTAGENESIS OF SER-437
RP AND HIS-464.
RX PubMed=23064226; DOI=10.1038/nature11540;
RA Chaneton B., Hillmann P., Zheng L., Martin A.C., Maddocks O.D.,
RA Chokkathukalam A., Coyle J.E., Jankevics A., Holding F.P.,
RA Vousden K.H., Frezza C., O'Reilly M., Gottlieb E.;
RT "Serine is a natural ligand and allosteric activator of pyruvate
RT kinase M2.";
RL Nature 491:458-462(2012).
CC -!- FUNCTION: Glycolytic enzyme that catalyzes the transfer of a
CC phosphoryl group from phosphoenolpyruvate (PEP) to ADP, generating
CC ATP. Stimulates POU5F1-mediated transcriptional activation. Plays
CC a general role in caspase independent cell death of tumor cells.
CC The ratio betwween the highly active tetrameric form and nearly
CC inactive dimeric form determines whether glucose carbons are
CC channeled to biosynthetic processes or used for glycolytic ATP
CC production. The transition between the 2 forms contributes to the
CC control of glycolysis and is important for tumor cell
CC proliferation and survival.
CC -!- CATALYTIC ACTIVITY: ATP + pyruvate = ADP + phosphoenolpyruvate.
CC -!- COFACTOR: Magnesium.
CC -!- COFACTOR: Potassium.
CC -!- ENZYME REGULATION: Isoform M2 is allosterically activated by D-
CC fructose 1,6-bisphosphate (FBP). Inhibited by oxalate and 3,3',5-
CC triiodo-L-thyronine (T3). The activity of the tetrameric form is
CC inhibited by PML. Selective binding to tyrosine-phosphorylated
CC peptides releases the allosteric activator FBP, leading to
CC inhibition of PKM enzymatic activity, this diverts glucose
CC metabolites from energy production to anabolic processes when
CC cells are stimulated by certain growth factors. Glycolytic flux
CC are highly dependent on de novo biosynthesis of serine and
CC glycine, and serine is a natural ligand and allosteric activator
CC of isoform M2.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=2.7 mM for phosphoenolpyruvate (at 32 degrees Celsius, pH
CC 8.0);
CC KM=0.17 mM for phosphoenolpyruvate (in the presence of 2 mM FBP,
CC at 32 degrees Celsius, pH 8.0);
CC KM=0.34 mM for ADP (at 32 degrees Celsius, pH 8.0);
CC KM=0.24 mM for ADP (in the presence of 2 mM FBP, at 32 degrees
CC Celsius, pH 8.0);
CC KM=0.13 mM for phosphoenolpyruvate (in the presence of 2 mM FBP,
CC at 25 degrees Celsius);
CC KM=0.63 mM for ADP (in the presence of 2 mM FBP, at 25 degrees
CC Celsius);
CC pH dependence:
CC Optimum pH for T3 binding is 6.0-6.5. Increase in pH causes T3
CC binding to drop, does not bind T3 above pH 9.0 or below pH 5.0;
CC -!- PATHWAY: Carbohydrate degradation; glycolysis; pyruvate from D-
CC glyceraldehyde 3-phosphate: step 5/5.
CC -!- SUBUNIT: Monomer and homotetramer. Exists as a monomer in the
CC absence of FBP, and reversibly associates to form a homotetramer
CC in the presence of FBP. The monomeric form binds T3. Tetramer
CC formation induces pyruvate kinase activity. The tetrameric form
CC has high affinity for the substrate and is associated within the
CC glycolytic enzyme complex. Exists in a nearly inactive dimeric
CC form in tumor cells and the dimeric form has less affinity for the
CC substrate. Binding to certain oncoproteins such as HPV-16 E7
CC oncoprotein can trigger dimerization. FBP stimulates the formation
CC of tetramers from dimers. Interacts with HERC1, POU5F1 and PML.
CC Interacts (isoform M2) with EGLN3; the interaction hydroxylates
CC PKM under hypoxia and enhances binding to HIF1A. Interacts
CC (isoform M2) with HIF1A; the interaction is enhanced by binding of
CC EGLN3, promoting enhanced transcription activity under hypoxia.
CC -!- INTERACTION:
CC Q9WMX2:- (xeno); NbExp=4; IntAct=EBI-353408, EBI-710918;
CC P49407:ARRB1; NbExp=3; IntAct=EBI-353408, EBI-743313;
CC P32121:ARRB2; NbExp=4; IntAct=EBI-353408, EBI-714559;
CC P53355:DAPK1; NbExp=3; IntAct=EBI-353408, EBI-358616;
CC Q9H6Z9:EGLN3; NbExp=2; IntAct=EBI-4304679, EBI-1175354;
CC Q16665:HIF1A; NbExp=7; IntAct=EBI-4304679, EBI-447269;
CC P04049:RAF1; NbExp=3; IntAct=EBI-353408, EBI-365996;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Note=Translocates to the
CC nucleus in response to different apoptotic stimuli. Nuclear
CC translocation is sufficient to induce cell death that is caspase
CC independent, isoform-specific and independent of its enzymatic
CC activity.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=M2; Synonyms=M2-PK, PKM2;
CC IsoId=P14618-1; Sequence=Displayed;
CC Name=M1; Synonyms=M1-PK, PKM1;
CC IsoId=P14618-2, P14786-1;
CC Sequence=VSP_011101;
CC Name=3;
CC IsoId=P14618-3; Sequence=VSP_043370;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Specifically expressed in proliferating cells,
CC such as embryonic stem cells, embryonic carcinoma cells, as well
CC as cancer cells.
CC -!- PTM: ISGylated.
CC -!- PTM: Under hypoxia, hydroxylated by EGLN3.
CC -!- PTM: Acetylation at Lys-305 is stimulated by high glucose
CC concentration, it decreases enzyme activity and promotes its
CC lysosomal-dependent degradation via chaperone-mediated autophagy.
CC -!- MISCELLANEOUS: There are 4 isozymes of pyruvate kinase in mammals
CC (L, R, M1, M2) encoded by 2 different genes: PKLR and PKM. The L
CC and R isozymes are generated from the PKLR by differential
CC splicing of RNA; the M1 and M2 forms are produced from the PKM
CC gene by differential splicing. L type is major isozyme in the
CC liver, R is found in red cells, M1 is the main form in muscle,
CC heart and brain, and M2 is found in early fetal tissues as well as
CC in most cancer cells.
CC -!- SIMILARITY: Belongs to the pyruvate kinase family.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAG57589.1; Type=Erroneous initiation; Note=Translation N-terminally shortened;
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/pkm2/";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Pyruvate kinase entry;
CC URL="http://en.wikipedia.org/wiki/Pyruvate_kinase";
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/PKM2ID41728ch15q22.html";
CC -----------------------------------------------------------------------
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DR EMBL; M23725; AAA36449.1; -; mRNA.
DR EMBL; M26252; AAA36672.1; -; mRNA.
DR EMBL; X56494; CAA39849.1; -; Genomic_DNA.
DR EMBL; AK092369; BAG52542.1; -; mRNA.
DR EMBL; AK222927; BAD96647.1; -; mRNA.
DR EMBL; AK294315; BAG57589.1; ALT_INIT; mRNA.
DR EMBL; AK300800; BAG62458.1; -; mRNA.
DR EMBL; AK312253; BAG35185.1; -; mRNA.
DR EMBL; AY352517; AAQ15274.1; -; Genomic_DNA.
DR EMBL; AC020779; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471082; EAW77884.1; -; Genomic_DNA.
DR EMBL; CH471082; EAW77888.1; -; Genomic_DNA.
DR EMBL; BC000481; AAH00481.3; -; mRNA.
DR EMBL; BC007640; AAH07640.1; -; mRNA.
DR EMBL; BC007952; AAH07952.3; -; mRNA.
DR EMBL; BC012811; AAH12811.3; -; mRNA.
DR EMBL; BC035198; AAH35198.1; -; mRNA.
DR EMBL; AF025439; AAC39559.1; -; mRNA.
DR PIR; S30038; S30038.
DR PIR; S64635; S64635.
DR RefSeq; NP_001193725.1; NM_001206796.1.
DR RefSeq; NP_001193726.1; NM_001206797.1.
DR RefSeq; NP_001193727.1; NM_001206798.1.
DR RefSeq; NP_001193728.1; NM_001206799.1.
DR RefSeq; NP_002645.3; NM_002654.4.
DR RefSeq; NP_872270.1; NM_182470.2.
DR RefSeq; NP_872271.1; NM_182471.2.
DR RefSeq; XP_005254502.1; XM_005254445.1.
DR UniGene; Hs.534770; -.
DR PDB; 1T5A; X-ray; 2.80 A; A/B/C/D=1-531.
DR PDB; 1ZJH; X-ray; 2.20 A; A=3-530.
DR PDB; 3BJF; X-ray; 2.03 A; A/B/C/D=14-531.
DR PDB; 3BJT; X-ray; 2.50 A; A/B/C/D=2-531.
DR PDB; 3G2G; X-ray; 2.00 A; A/B/C/D=1-531.
DR PDB; 3GQY; X-ray; 1.85 A; A/B/C/D=1-531.
DR PDB; 3GR4; X-ray; 1.60 A; A/B/C/D=1-531.
DR PDB; 3H6O; X-ray; 2.00 A; A/B/C/D=1-531.
DR PDB; 3ME3; X-ray; 1.95 A; A/B/C/D=1-531.
DR PDB; 3SRD; X-ray; 2.90 A; A/B/C/D=1-531.
DR PDB; 3SRF; X-ray; 2.84 A; A/B/C/D/E/F/G/H=1-531.
DR PDB; 3SRH; X-ray; 2.60 A; A/B/C/D=1-531.
DR PDB; 3U2Z; X-ray; 2.10 A; A/B/C/D=1-531.
DR PDB; 4B2D; X-ray; 2.30 A; A/B/C/D=2-531.
DR PDB; 4FXF; X-ray; 2.55 A; A/B/C/D=1-531.
DR PDB; 4FXJ; X-ray; 2.90 A; A/B/C/D=1-531.
DR PDB; 4G1N; X-ray; 2.30 A; A/B/C/D=14-531.
DR PDB; 4JPG; X-ray; 2.33 A; A/B/C/D=1-531.
DR PDBsum; 1T5A; -.
DR PDBsum; 1ZJH; -.
DR PDBsum; 3BJF; -.
DR PDBsum; 3BJT; -.
DR PDBsum; 3G2G; -.
DR PDBsum; 3GQY; -.
DR PDBsum; 3GR4; -.
DR PDBsum; 3H6O; -.
DR PDBsum; 3ME3; -.
DR PDBsum; 3SRD; -.
DR PDBsum; 3SRF; -.
DR PDBsum; 3SRH; -.
DR PDBsum; 3U2Z; -.
DR PDBsum; 4B2D; -.
DR PDBsum; 4FXF; -.
DR PDBsum; 4FXJ; -.
DR PDBsum; 4G1N; -.
DR PDBsum; 4JPG; -.
DR ProteinModelPortal; P14618; -.
DR SMR; P14618; 13-531.
DR DIP; DIP-31273N; -.
DR IntAct; P14618; 82.
DR MINT; MINT-4998892; -.
DR BindingDB; P14618; -.
DR ChEMBL; CHEMBL1075189; -.
DR DrugBank; DB00119; Pyruvic acid.
DR PhosphoSite; P14618; -.
DR DMDM; 20178296; -.
DR DOSAC-COBS-2DPAGE; P14618; -.
DR OGP; P14618; -.
DR REPRODUCTION-2DPAGE; IPI00220644; -.
DR REPRODUCTION-2DPAGE; IPI00479186; -.
DR UCD-2DPAGE; P14618; -.
DR PaxDb; P14618; -.
DR PRIDE; P14618; -.
DR DNASU; 5315; -.
DR Ensembl; ENST00000319622; ENSP00000320171; ENSG00000067225.
DR Ensembl; ENST00000335181; ENSP00000334983; ENSG00000067225.
DR Ensembl; ENST00000389093; ENSP00000373745; ENSG00000067225.
DR Ensembl; ENST00000449901; ENSP00000403365; ENSG00000067225.
DR Ensembl; ENST00000565154; ENSP00000455901; ENSG00000067225.
DR Ensembl; ENST00000565184; ENSP00000455736; ENSG00000067225.
DR Ensembl; ENST00000568459; ENSP00000456970; ENSG00000067225.
DR GeneID; 5315; -.
DR KEGG; hsa:5315; -.
DR UCSC; uc002aty.2; human.
DR CTD; 5315; -.
DR GeneCards; GC15M072492; -.
DR HGNC; HGNC:9021; PKM.
DR HPA; CAB019421; -.
DR HPA; HPA029501; -.
DR MIM; 179050; gene.
DR neXtProt; NX_P14618; -.
DR PharmGKB; PA33353; -.
DR eggNOG; COG0469; -.
DR HOGENOM; HOG000021559; -.
DR HOVERGEN; HBG000941; -.
DR InParanoid; P14618; -.
DR KO; K00873; -.
DR OMA; HGTRIAN; -.
DR OrthoDB; EOG78M01Q; -.
DR BioCyc; MetaCyc:HS00906-MONOMER; -.
DR Reactome; REACT_111217; Metabolism.
DR SABIO-RK; P14618; -.
DR UniPathway; UPA00109; UER00188.
DR ChiTaRS; PKM2; human.
DR EvolutionaryTrace; P14618; -.
DR GeneWiki; PKM2; -.
DR GenomeRNAi; 5315; -.
DR NextBio; 20554; -.
DR PRO; PR:P14618; -.
DR ArrayExpress; P14618; -.
DR Bgee; P14618; -.
DR CleanEx; HS_PKM2; -.
DR Genevestigator; P14618; -.
DR GO; GO:0005929; C:cilium; IEA:Ensembl.
DR GO; GO:0005829; C:cytosol; NAS:UniProtKB.
DR GO; GO:0070062; C:extracellular vesicular exosome; IDA:UniProtKB.
DR GO; GO:0005739; C:mitochondrion; IEA:Ensembl.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IDA:HPA.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0000287; F:magnesium ion binding; IEA:InterPro.
DR GO; GO:0030955; F:potassium ion binding; IEA:InterPro.
DR GO; GO:0004743; F:pyruvate kinase activity; TAS:UniProtKB.
DR GO; GO:0006096; P:glycolysis; NAS:UniProtKB.
DR GO; GO:0012501; P:programmed cell death; IDA:UniProtKB.
DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome.
DR Gene3D; 2.40.33.10; -; 1.
DR Gene3D; 3.20.20.60; -; 2.
DR Gene3D; 3.40.1380.20; -; 1.
DR InterPro; IPR001697; Pyr_Knase.
DR InterPro; IPR015813; Pyrv/PenolPyrv_Kinase-like_dom.
DR InterPro; IPR011037; Pyrv_Knase-like_insert_dom.
DR InterPro; IPR015794; Pyrv_Knase_a/b.
DR InterPro; IPR018209; Pyrv_Knase_AS.
DR InterPro; IPR015793; Pyrv_Knase_brl.
DR InterPro; IPR015795; Pyrv_Knase_C.
DR InterPro; IPR015806; Pyrv_Knase_insert_dom.
DR PANTHER; PTHR11817; PTHR11817; 1.
DR Pfam; PF00224; PK; 1.
DR Pfam; PF02887; PK_C; 1.
DR PRINTS; PR01050; PYRUVTKNASE.
DR SUPFAM; SSF50800; SSF50800; 1.
DR SUPFAM; SSF51621; SSF51621; 2.
DR SUPFAM; SSF52935; SSF52935; 1.
DR TIGRFAMs; TIGR01064; pyruv_kin; 1.
DR PROSITE; PS00110; PYRUVATE_KINASE; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Allosteric enzyme; Alternative splicing;
KW ATP-binding; Complete proteome; Cytoplasm; Direct protein sequencing;
KW Glycolysis; Hydroxylation; Kinase; Magnesium; Metal-binding;
KW Nucleotide-binding; Nucleus; Phosphoprotein; Polymorphism; Potassium;
KW Pyruvate; Reference proteome; Transferase; Ubl conjugation.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 531 Pyruvate kinase PKM.
FT /FTId=PRO_0000112088.
FT REGION 307 531 Interaction with POU5F1.
FT REGION 389 433 Intersubunit contact.
FT REGION 432 437 D-fructose 1,6-bisphosphate binding; part
FT of allosteric site.
FT REGION 514 521 D-fructose 1,6-bisphosphate binding; part
FT of allosteric site.
FT METAL 75 75 Potassium (By similarity).
FT METAL 77 77 Potassium (By similarity).
FT METAL 113 113 Potassium.
FT METAL 114 114 Potassium; via carbonyl oxygen (By
FT similarity).
FT METAL 272 272 Magnesium.
FT METAL 296 296 Magnesium.
FT BINDING 70 70 Serine.
FT BINDING 73 73 Substrate (By similarity).
FT BINDING 106 106 Serine.
FT BINDING 295 295 Substrate; via amide nitrogen (By
FT similarity).
FT BINDING 296 296 Substrate; via amide nitrogen (By
FT similarity).
FT BINDING 328 328 Substrate (By similarity).
FT BINDING 464 464 Serine.
FT BINDING 482 482 D-fructose 1,6-bisphosphate; part of
FT allosteric site.
FT BINDING 489 489 D-fructose 1,6-bisphosphate; part of
FT allosteric site.
FT SITE 270 270 Transition state stabilizer.
FT SITE 433 433 Crucial for phosphotyrosine binding.
FT MOD_RES 2 2 N-acetylserine.
FT MOD_RES 37 37 Phosphoserine.
FT MOD_RES 62 62 N6-acetyllysine.
FT MOD_RES 89 89 N6-acetyllysine.
FT MOD_RES 105 105 Phosphotyrosine.
FT MOD_RES 148 148 Phosphotyrosine (By similarity).
FT MOD_RES 166 166 N6-acetyllysine.
FT MOD_RES 175 175 Phosphotyrosine.
FT MOD_RES 195 195 Phosphothreonine.
FT MOD_RES 266 266 N6-acetyllysine.
FT MOD_RES 305 305 N6-acetyllysine.
FT MOD_RES 403 403 4-hydroxyproline.
FT MOD_RES 408 408 4-hydroxyproline.
FT MOD_RES 433 433 N6-acetyllysine.
FT VAR_SEQ 1 82 MSKPHSEAGTAFIQTQQLHAAMADTFLEHMCRLDIDSPPIT
FT ARNTGIICTIGPASRSVETLKEMIKSGMNVARLNFSHGTHE
FT -> MSPEAQPQRTKGPQQPCRSPIVKPGLPSFRPSSCTQPW
FT LTHSWSTCAAWTLIHHPSQPGTLASSVPL (in isoform
FT 3).
FT /FTId=VSP_043370.
FT VAR_SEQ 389 433 IYHLQLFEELRRLAPITSDPTEATAVGAVEASFKCCSGAII
FT VLTK -> MFHRKLFEELVRASSHSTDLMEAMAMGSVEASY
FT KCLAAALIVLTE (in isoform M1).
FT /FTId=VSP_011101.
FT VARIANT 204 204 G -> V (in dbSNP:rs17853396).
FT /FTId=VAR_033067.
FT MUTAGEN 403 403 P->A: Significant reduction in
FT hydroxylation and in PKM-mediated
FT transcriptional activity of HIF1A; when
FT associated with A-408.
FT MUTAGEN 408 408 P->A: Significant reduction in
FT hydroxylation and in PKM-mediated
FT transcriptional activity of HIF1A; when
FT associated with A-403.
FT MUTAGEN 437 437 S->Y: Unable to bind FBP but still
FT activated by serine.
FT MUTAGEN 464 464 H->A: Abolishes serine binding and
FT allosteric activation.
FT CONFLICT 7 7 E -> Q (in Ref. 10; AAH12811).
FT CONFLICT 54 54 A -> T (in Ref. 5; BAG52542).
FT CONFLICT 103 103 I -> Y (in Ref. 2; AAA36672).
FT CONFLICT 132 132 V -> L (in Ref. 2; AAA36672).
FT CONFLICT 187 187 Q -> R (in Ref. 6; BAD96647).
FT CONFLICT 252 252 H -> R (in Ref. 6; BAD96647).
FT CONFLICT 339 339 R -> P (in Ref. 4; CAA39849).
FT CONFLICT 349 349 A -> V (in Ref. 5; BAG52542).
FT CONFLICT 379 379 H -> N (in Ref. 1; AAA36449).
FT CONFLICT 507 507 D -> H (in Ref. 10; AAH12811).
FT HELIX 15 17
FT HELIX 18 21
FT HELIX 26 31
FT STRAND 35 37
FT STRAND 45 50
FT TURN 53 55
FT HELIX 58 67
FT STRAND 71 75
FT HELIX 81 96
FT TURN 97 100
FT TURN 102 104
FT STRAND 109 113
FT STRAND 119 121
FT STRAND 127 129
FT STRAND 132 134
FT STRAND 139 143
FT HELIX 146 148
FT STRAND 154 160
FT HELIX 164 167
FT STRAND 173 176
FT TURN 177 180
FT STRAND 181 188
FT STRAND 190 199
FT STRAND 201 203
FT STRAND 204 206
FT STRAND 208 210
FT STRAND 212 214
FT HELIX 223 234
FT STRAND 238 242
FT HELIX 248 258
FT TURN 259 264
FT STRAND 265 271
FT HELIX 274 278
FT HELIX 280 286
FT STRAND 287 293
FT HELIX 294 300
FT HELIX 303 305
FT HELIX 306 320
FT STRAND 324 329
FT HELIX 332 335
FT STRAND 337 339
FT HELIX 342 354
FT STRAND 357 362
FT HELIX 363 366
FT STRAND 367 369
FT HELIX 371 387
FT HELIX 391 401
FT TURN 402 404
FT HELIX 408 422
FT STRAND 428 431
FT STRAND 433 435
FT HELIX 436 442
FT STRAND 450 455
FT HELIX 457 462
FT HELIX 463 465
FT STRAND 469 473
FT HELIX 482 499
FT STRAND 508 518
FT STRAND 522 529
SQ SEQUENCE 531 AA; 57937 MW; AA94D7818ED6BBAD CRC64;
MSKPHSEAGT AFIQTQQLHA AMADTFLEHM CRLDIDSPPI TARNTGIICT IGPASRSVET
LKEMIKSGMN VARLNFSHGT HEYHAETIKN VRTATESFAS DPILYRPVAV ALDTKGPEIR
TGLIKGSGTA EVELKKGATL KITLDNAYME KCDENILWLD YKNICKVVEV GSKIYVDDGL
ISLQVKQKGA DFLVTEVENG GSLGSKKGVN LPGAAVDLPA VSEKDIQDLK FGVEQDVDMV
FASFIRKASD VHEVRKVLGE KGKNIKIISK IENHEGVRRF DEILEASDGI MVARGDLGIE
IPAEKVFLAQ KMMIGRCNRA GKPVICATQM LESMIKKPRP TRAEGSDVAN AVLDGADCIM
LSGETAKGDY PLEAVRMQHL IAREAEAAIY HLQLFEELRR LAPITSDPTE ATAVGAVEAS
FKCCSGAIIV LTKSGRSAHQ VARYRPRAPI IAVTRNPQTA RQAHLYRGIF PVLCKDPVQE
AWAEDVDLRV NFAMNVGKAR GFFKKGDVVI VLTGWRPGSG FTNTMRVVPV P
//

MIM 179050
*RECORD*
*FIELD* NO
179050
*FIELD* TI
*179050 PYRUVATE KINASE, MUSCLE, 2; PKM2
;;PYRUVATE KINASE 3; PK3;;
PKM;;
OPA-INTERACTING PROTEIN 3; OIP3;;
read moreTHYROID HORMONE-BINDING PROTEIN, CYTOSOLIC; THBP1
PYRUVATE KINASE, MUSCLE, 1, INCLUDED; PKM1, INCLUDED
*FIELD* TX

DESCRIPTION

Pyruvate kinase (ATP:pyruvate phosphotransferase, EC 2.7.1.40) is a
glycolytic enzyme that catalyzes the transfer of a phosphoryl group from
phosphoenolpyruvate (PEP) to ADP, generating ATP (summary by Ikeda and
Noguchi, 1998).

CLONING

Tsutsumi et al. (1988) showed that pyruvate kinase occurs in 4 isozymic
forms (L, R, M1, M2) and that these are encoded by 2 different genes,
PKLR (609712) and PKM2. The L and R isozymes are generated from the PKLR
gene by differential splicing of RNA; the M1 and M2 forms are produced
from the PKM2 gene by differential splicing. Northern blot analysis with
RNA from a human hepatoma demonstrated that the M2-type PK was
predominantly expressed in hepatoma cells, whereas L-type PK was
preferentially expressed in the nontumor portion of the liver.

Kitagawa et al. (1987) purified a human cytosolic thyroid
hormone-binding protein (THBP1; p58) from human epidermoid carcinoma
cells, which comprised a single polypeptide chain with a molecular mass
of 58 kD. The sequence of the cDNA for p58 indicated that it was
homologous to pyruvate kinase subtype M2.

GENE STRUCTURE

Takenaka et al. (1991) reported that the gene that encodes both the M1
and the M2 isozymes is approximately 32 kb long and comprises 12 exons
and 11 introns. Exons 9 and 10 contain sequences specific for the M1 and
M2 types, respectively, indicating that the human fetal and adult
isozymes are produced from the same gene by alternative splicing. The
gene is transcribed from multiple start sites, and the 5-prime flanking
region contains putative SP1 (189906)-binding sites, but no TATA or CAAT
boxes.

GENE FUNCTION

The activity of pyruvate kinase subtype M2 is increased by fructose
1,6-bisphosphate (Fru-1,6-P2). Ashizawa et al. (1991) manipulated the
intracellular Fru-1,6-P2 concentration in several mammalian cell lines,
including human, by varying the glucose concentration in the media.
Glucose rapidly and reversibly changed the ratio of cytosolic monomeric
PKM2 to tetrameric PKM2. In the physiologic range of glucose, the
majority of PKM2 existed as tetramer. However, tetrameric PKM2
dissociated into monomeric form within minutes after cells were deprived
of glucose, thus shutting off the glycolytic pathway. Inhibition of
glucose uptake through its specific transporter also converted the
tetramer to the monomeric form within 20 to 30 minutes. Ashizawa et al.
(1991) concluded that Fru-1,6-P2 is the metabolite in the glycolytic
pathway that regulates PK activity.

The M1 and M2 isozymes of PK differ by 21 amino acids, and the region in
which they differ encodes the 2 alpha helices that participate in
intersubunit contact. While the M2 isozyme is activated homotropically
by phosphoenolpyruvate and heterotropically by Fru-1,6-P2, the M1
isozyme remains fully active, likely due to its intrinsic active
conformation. Ikeda and Noguchi (1998) determined that cys423, located
in the vicinity of the second alpha helix in rat Pkm2, plays an
important role in the allosteric effect of the M2 isozyme.

Neisseria gonorrhoeae opacity-associated (Opa) proteins are a family of
outer membrane proteins involved in gonococcal adhesion to and invasion
of human cells. Opa expression appears to be necessary for gonococcal
disease. Using the yeast 2-hybrid system to screen a HeLa cell cDNA
library with an N. gonorrhoeae Opa protein as bait, Williams et al.
(1998) identified partial cDNAs encoding Opa-interacting protein-1
(OIP1, or TRIP6; 602933), OIP2 (606019), OIP3, OIP4 (PRAME; 606021), and
OIP5 (606020). Sequence analysis predicted that the partial OIP3 cDNA
encodes a 164-amino acid peptide that is 100% identical to the
C-terminal third of PKM2. OIP3 contains a cluster of basic residues, but
unlike OIP1, OIP4, and OIP5, it has no cysteine motif. Binding analysis
confirmed the interaction of OIP3 with Opa. Gonococcal strains not
expressing Opa bound OIP3, or PK, weakly compared with Opa-positive
strains. Immunofluorescence microscopy demonstrated that intracellular
but not extracellular Opa-positive gonococci colocalized with PK in
endocervical epithelial cells. Opa-negative bacteria did not colocalize
with PK. Mutation analysis indicated that pyruvate is required as a
substrate for the intracellular survival and growth of N. gonorrhoeae.
Williams et al. (1998) proposed that gonococci acquire host PK on their
surface to create a microenvironment rich in pyruvate for growth.

Using a novel proteomic screen for phosphotyrosine-binding proteins,
Christofk et al. (2008) observed that PKM2 binds directly and
selectively to tyrosine-phosphorylated peptides. The authors showed that
binding of phosphotyrosine peptides to PKM2 results in release of the
allosteric activator fructose-1,6-bisphosphate, leading to inhibition of
PKM2 enzymatic activity. Christofk et al. (2008) also provided evidence
that this regulation of PKM2 by phosphotyrosine signaling diverts
glucose metabolites from energy production to anabolic processes when
cells are stimulated by certain growth factors. Collectively, Christofk
et al. (2008) concluded that expression of this phosphotyrosine-binding
form of pyruvate kinase is critical for rapid growth in cancer cells.

Christofk et al. (2008) showed that a single switch in a splice isoform
of the glycolytic enzyme pyruvate kinase is necessary for the shift in
cellular metabolism to aerobic glycolysis and that this shift promotes
tumorigenesis. Tumor cells express exclusively the embryonic M2 isoform
of pyruvate kinase. Christofk et al. (2008) used short hairpin RNA to
knock down pyruvate kinase M2 expression in human cancer cell lines and
replace it with pyruvate kinase M1. Switching pyruvate kinase expression
to the M1 (adult) isoform led to reversal of the Warburg effect, which
is the persistence of high lactate production by tumors in the presence
of oxygen, as judged by reduced lactate production and increased oxygen
consumption, and this correlated with a reduced ability to form tumors
in nude mouse xenografts. Christofk et al. (2008) concluded that M2
expression is necessary for aerobic glycolysis and that this metabolic
phenotype provides a selective growth advantage for tumor cells in vivo.

The embryonic pyruvate kinase isoform PKM2 is almost universally
reexpressed in cancer and promotes aerobic glycolysis, whereas the adult
isoform PKM1 promotes oxidative phosphorylation. These 2 isoforms result
from mutually exclusive alternative splicing of the PKM pre-mRNA,
reflecting inclusion of exon 9 (PKM1) or exon 10 (PKM2). David et al.
(2010) showed that 3 heterogeneous nuclear ribonucleoprotein (hnRNP)
proteins, polypyrimidine tract-binding protein (PTB, also known as
hnRNPI; 600693), hnRNPA1 (164017), and hnRNPA2 (600124), bind
repressively to sequences flanking exon 9 of the PKM2 gene, resulting in
exon 10 inclusion and the expression of the PKM2 isoform. David et al.
(2010) also demonstrated that the oncogenic transcription factor c-MYC
(190080) upregulates transcription of PTB, hnRNPA1, and hnRNPA2,
ensuring a high PKM2/PKM1 ratio. Establishing a relevance to cancer,
David et al. (2010) showed that human gliomas (137800) overexpress
c-Myc, PTB, hnRNPA1, and hnRNPA2 in a manner that correlates with PKM2
expression. David et al. (2010) concluded that their results defined a
pathway that regulates an alternative splicing event required for tumor
cell proliferation.

Anastasiou et al. (2011) showed that, in human lung cancer cells, acute
increases in intracellular concentrations of reactive oxygen species
caused inhibition of the glycolytic enzyme PKM2 through oxidation of
cysteine at position 358. This inhibition of PKM2 is required to divert
glucose flux into the pentose phosphate pathway and thereby generate
sufficient reducing potential for detoxification of reactive oxygen
species. Lung cancer cells in which endogenous PKM2 was replaced with
the cys358-to-ser oxidation-resistant mutant exhibited increased
sensitivity to oxidative stress and impaired tumor formation in a
xenograft model. Anastasiou et al. (2011) concluded that besides
promoting metabolic changes required for proliferation, the regulatory
properties of PKM2 may confer an additional advantage to cancer cells by
allowing them to withstand oxidative stress.

Yang et al. (2011) demonstrated in human cancer cells that EGFR (131550)
activation induces translocation of PKM2, but not PKM1, into the
nucleus, where K433 of PKM2 binds to c-Src-phosphorylated Y333 of
beta-catenin (116806). This interaction is required for both proteins to
be recruited to the CCND1 (168461) promoter, leading to HDAC3 (605166)
removal from the promoter, histone H3 acetylation, and cyclin D1
expression. PKM2-dependent beta-catenin transactivation is instrumental
in EGFR-promoted tumor cell proliferation and brain tumor development.
In addition, positive correlations were identified between c-Src
activity, beta-catenin Y333 phosphorylation, and PKM2 nuclear
accumulation in human glioblastoma specimens. Furthermore, levels of
beta-catenin phosphorylation and nuclear PKM2 were correlated with
grades of glioma malignancy and prognosis. Yang et al. (2011) concluded
that their findings revealed that EGF induces beta-catenin
transactivation via a mechanism distinct from that induced by
Wnt/Wingless (see 164820) and highlighted the essential nonmetabolic
functions of PKM2 in EGFR-promoted beta-catenin transactivation, cell
proliferation, and tumorigenesis.

Using knockdown and overexpression studies with several human cell
lines, Luo et al. (2011) showed that PKM2, but not PKM1, interacted with
HIF1A (603348) and stimulated HIF1A transactivation activity under
hypoxic conditions. Mutation analysis showed that PKM2 interacted with
HIF1A at multiple sites. PKM2, but not PKM1, contains a prolyl
hydroxylation motif, LxxLAP, that was hydroxylated by PHD3 (EGLN3;
606426), and this hydroxylation was required for PKM2-mediated HIF1A
activation. Chromatin immunoprecipitation analysis demonstrated
colocalization of PKM2, PHD3, and HIF1A with p300 (EP300; 602700) at
hypoxia response elements under hypoxic conditions. PKM2, PHD3, and
HIF1A were all required to induce transcription of glycolytic genes and
the glucose transporter-1 gene (GLUT1, or SLC2A1; 138140). HIF1A also
induced PKM2 expression in a positive-feedback loop during the shift
from oxidative to glycolytic metabolism.

Chaneton et al. (2012) described a rheostat-like mechanistic
relationship between PKM2 activity and serine biosynthesis. The authors
showed that serine can bind to and activate human PKM2, and that PKM2
activity in cells is reduced in response to serine deprivation. This
reduction in PKM2 activity shifts cells to a fuel-efficient mode in
which more pyruvate is diverted to the mitochondria and more
glucose-derived carbon is channeled into serine biosynthesis to support
cell proliferation.

Keller et al. (2012) reported that SAICAR
(succinylaminoimidazolecarboxamide ribose-5-prime-phosphate), an
intermediate of the de novo purine nucleotide synthesis pathway,
specifically stimulates PKM2. Upon glucose starvation, cellular SAICAR
concentration increased in an oscillatory manner and stimulated PKM2
activity in cancer cells. Changes in SAICAR amounts in cancer cells
altered cellular energy level, glucose uptake, and lactate production.
The SAICAR-PKM2 interaction also promoted cancer cell survival in
glucose-limited conditions. SAICAR accumulation was not observed in
normal adult epithelial cells or lung fibroblasts, regardless of glucose
conditions. Keller et al. (2012) concluded that this allosteric
regulation may explain how cancer cells coordinate different metabolic
pathways to optimize their growth in the nutrient-limited conditions
commonly observed in the tumor microenvironment.

BIOCHEMICAL FEATURES

The M2 isoform of pyruvate kinase (PKM2) promotes the metabolism of
glucose by aerobic glycolysis and contributes to anabolic metabolism.
Paradoxically, decreased pyruvate kinase enzyme activity accompanies the
expression of PKM2 in rapidly dividing cancer cells and tissues. Vander
Heiden et al. (2010) demonstrated that phosphoenolpyruvate (PEP), the
substrate for pyruvate kinase in cells, can act as a phosphate donor in
mammalian cells because PEP participates in the phosphorylation of the
glycolytic enzyme phosphoglycerate mutase (PGAM1; 172250) in
PKM2-expressing cells. Vander Heiden et al. (2010) used mass
spectrometry to show that the phosphate from PEP is transferred to the
catalytic histidine (His11) on human PGAM1. This reaction occurred at
physiologic concentrations of PEP and produced pyruvate in the absence
of PKM2 activity. The presence of histidine-phosphorylated PGAM2
correlated with the expression of PKM2 in cancer cell lines and tumor
tissues. Thus, Vander Heiden et al. (2010) concluded that decreased
pyruvate kinase activity in PKM2-expressing cells allows PEP-dependent
histidine phosphorylation of PGAM1 and may provide an alternate
glycolytic pathway that decouples adenosine triphosphate production from
PEP-mediated phosphotransfer, allowing for the high rate of glycolysis
to support the anabolic metabolism observed in many proliferating cells.

MAPPING

Tani et al. (1988) isolated and sequenced 2 overlapping clones covering
the entire coding sequence of PKM2. By in situ hybridization, they
demonstrated that the PKM2 gene is located at band 15q22. By in situ
hybridization, Popescu and Cheng (1990) mapped the THBP1 gene to
15q24-q25.

Studies of somatic cell hybrids showed that the PK3 and MPI loci are
syntenic (Shows, 1972). By cell hybridization studies, Van Heyningen et
al. (1975) found that the MPI (154550) and PK3 loci are on chromosome
15. Chern et al. (1977) narrowed the assignment to 15q22-qter.

MOLECULAR GENETICS

Data on gene frequencies of allelic variants were tabulated by
Roychoudhury and Nei (1988).

*FIELD* SA
Chern and Croce (1975); Junien et al. (1980); Kahn et al. (1978);
Levine et al. (1978); Ritter et al. (1974); Shows (1973); Westerveld
et al. (1975)
*FIELD* RF
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*FIELD* CN
Ada Hamosh - updated: 1/7/2013
Ada Hamosh - updated: 12/14/2012
Patricia A. Hartz - updated: 4/24/2012
Ada Hamosh - updated: 1/4/2012
Ada Hamosh - updated: 11/2/2010
Ada Hamosh - updated: 2/18/2010
Ada Hamosh - updated: 5/21/2008
Patricia A. Hartz - updated: 5/5/2005
Paul J. Converse - updated: 6/13/2001

*FIELD* CD
Victor A. McKusick: 6/2/1986

*FIELD* ED
alopez: 04/24/2013
alopez: 1/7/2013
terry: 1/7/2013
alopez: 12/17/2012
terry: 12/14/2012
mgross: 6/4/2012
terry: 4/24/2012
alopez: 3/5/2012
alopez: 1/12/2012
terry: 1/4/2012
alopez: 11/8/2010
terry: 11/2/2010
alopez: 2/24/2010
terry: 2/18/2010
alopez: 5/22/2008
terry: 5/21/2008
carol: 11/18/2005
wwang: 6/30/2005
wwang: 6/23/2005
terry: 5/5/2005
carol: 7/17/2003
mgross: 6/15/2001
terry: 6/13/2001
dkim: 7/7/1998
mimadm: 2/25/1995
warfield: 4/21/1994
supermim: 3/16/1992
carol: 3/5/1992
carol: 9/11/1991
supermim: 3/20/1990