P14618 (KPYM_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Pyruvate kinase isozymes M1/M2
EC=2.7.1.40

Alternative name(s):
Cytosolic thyroid hormone-binding protein
Short name=CTHBP
Opa-interacting protein 3
Short name=OIP-3
Pyruvate kinase 2/3
Pyruvate kinase muscle isozyme
Thyroid hormone-binding protein 1
Short name=THBP1
Tumor M2-PK
p58

Gene names

Name:	PKM
Synonyms:	OIP3, PK2, PK3, PKM2

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	531 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Glycolytic enzyme that catalyzes the transfer of a phosphoryl group from phosphoenolpyruvate (PEP) to ADP, generating ATP. Stimulates POU5F1-mediated transcriptional activation. Plays a general role in caspase independent cell death of tumor cells. The ratio betwween the highly active tetrameric form and nearly inactive dimeric form determines whether glucose carbons are channeled to biosynthetic processes or used for glycolytic ATP production. The transition between the 2 forms contributes to the control of glycolysis and is important for tumor cell proliferation and survival. Ref.21 Ref.23 Ref.31
Catalytic activity	ATP + pyruvate = ADP + phosphoenolpyruvate. Ref.12 Ref.35
Cofactor	Magnesium. Potassium.
Enzyme regulation	Isoform M2 is allosterically activated by D-fructose 1,6-bisphosphate (FBP). Inhibited by oxalate and 3,3',5-triiodo-L-thyronine (T3). The activity of the tetrameric form is inhibited by PML. Selective binding to tyrosine-phosphorylated peptides releases the allosteric activator FBP, leading to inhibition of PKM enzymatic activity, this diverts glucose metabolites from energy production to anabolic processes when cells are stimulated by certain growth factors. Glycolytic flux are highly dependent on de novo biosynthesis of serine and glycine, and serine is a natural ligand and allosteric activator of isoform M2. Ref.2 Ref.12 Ref.22 Ref.35 Ref.37 Ref.38
Pathway	Carbohydrate degradation; glycolysis; pyruvate from D-glyceraldehyde 3-phosphate: step 5/5.
Subunit structure	Monomer and homotetramer. Exists as a monomer in the absence of FBP, and reversibly associates to form a homotetramer in the presence of FBP. The monomeric form binds T3. Tetramer formation induces pyruvate kinase activity. The tetrameric form has high affinity for the substrate and is associated within the glycolytic enzyme complex. Exists in a nearly inactive dimeric form in tumor cells and the dimeric form has less affinity for the substrate. Binding to certain oncoproteins such as HPV-16 E7 oncoprotein can trigger dimerization. FBP stimulates the formation of tetramers from dimers. Interacts with HERC1, POU5F1 and PML. Interacts (isoform M2) with EGLN3; the interaction hydroxylates PKM under hypoxia and enhances binding to HIF1A. Interacts (isoform M2) with HIF1A; the interaction is enhanced by binding of EGLN3, promoting enhanced transcription activity under hypoxia. Ref.2 Ref.12 Ref.16 Ref.22 Ref.23 Ref.31 Ref.32 Ref.35 Ref.38
Subcellular location	Cytoplasm. Nucleus. Note: Translocates to the nucleus in response to different apoptotic stimuli. Nuclear translocation is sufficient to induce cell death that is caspase independent, isoform-specific and independent of its enzymatic activity. Ref.21 Ref.22 Ref.23 Ref.31
Tissue specificity	Specifically expressed in proliferating cells, such as embryonic stem cells, embryonic carcinoma cells, as well as cancer cells. Ref.23
Post-translational modification	ISGylated. Ref.17 Under hypoxia, hydroxylated by EGLN3. Acetylation at Lys-305 is stimulated by high glucose concentration, it decreases enzyme activity and promotes its lysosomal-dependent degradation via chaperone-mediated autophagy.
Miscellaneous	There are 4 isozymes of pyruvate kinase in mammals (L, R, M1, M2) encoded by 2 different genes: PKLR and PKM. The L and R isozymes are generated from the PKLR by differential splicing of RNA; the M1 and M2 forms are produced from the PKM gene by differential splicing. L type is major isozyme in the liver, R is found in red cells, M1 is the main form in muscle, heart and brain, and M2 is found in early fetal tissues as well as in most cancer cells.
Sequence similarities	Belongs to the pyruvate kinase family.
Biophysicochemical properties	Kinetic parameters: KM=2.7 mM for phosphoenolpyruvate (at 32 degrees Celsius, pH 8.0) Ref.12 Ref.35 KM=0.17 mM for phosphoenolpyruvate (in the presence of 2 mM FBP, at 32 degrees Celsius, pH 8.0) KM=0.34 mM for ADP (at 32 degrees Celsius, pH 8.0) KM=0.24 mM for ADP (in the presence of 2 mM FBP, at 32 degrees Celsius, pH 8.0) KM=0.13 mM for phosphoenolpyruvate (in the presence of 2 mM FBP, at 25 degrees Celsius) KM=0.63 mM for ADP (in the presence of 2 mM FBP, at 25 degrees Celsius) pH dependence: Optimum pH for T3 binding is 6.0-6.5. Increase in pH causes T3 binding to drop, does not bind T3 above pH 9.0 or below pH 5.0.
Sequence caution	The sequence BAG57589.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.

Ontologies

Keywords
Biological process	Glycolysis
Cellular component	Cytoplasm Nucleus
Coding sequence diversity	Alternative splicing Polymorphism
Ligand	ATP-binding Magnesium Metal-binding Nucleotide-binding Potassium Pyruvate
Molecular function	Kinase Transferase
PTM	Acetylation Hydroxylation Phosphoprotein Ubl conjugation
Technical term	3D-structure Allosteric enzyme Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	glycolysis Non-traceable author statement. Source: UniProtKB programmed cell death Inferred from direct assay Ref.21. Source: UniProtKB small molecule metabolic process Traceable author statement. Source: Reactome
Cellular_component	cytosol Non-traceable author statement Ref.2. Source: UniProtKB extracellular vesicular exosome Inferred from direct assay PubMed 21362503. Source: UniProtKB mitochondrion Inferred from electronic annotation. Source: Compara nucleus Inferred from direct assay Ref.21Ref.23. Source: UniProtKB plasma membrane Inferred from direct assay. Source: HPA
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW magnesium ion binding Inferred from electronic annotation. Source: InterPro potassium ion binding Inferred from electronic annotation. Source: InterPro pyruvate kinase activity Traceable author statement Ref.4Ref.2Ref.1. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
ARRB1	P49407	3	EBI-353408,EBI-743313
ARRB2	P32121	4	EBI-353408,EBI-714559
EGLN3	Q9H6Z9	2	EBI-4304679,EBI-1175354
HIF1A	Q16665	7	EBI-4304679,EBI-447269
RAF1	P04049	3	EBI-353408,EBI-365996

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]

Isoform M2 (identifier: P14618-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform M1 (identifier: P14618-2)

The sequence of this isoform differs from the canonical sequence as follows:
     389-433: IYHLQLFEEL...CSGAIIVLTK → MFHRKLFEEL...LAAALIVLTE

Isoform 3 (identifier: P14618-3)

The sequence of this isoform differs from the canonical sequence as follows:
     1-82: MSKPHSEAGT...RLNFSHGTHE → MSPEAQPQRT...PGTLASSVPL

Note: No experimental confirmation available.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Initiator methionine

1

1

Removed Ref.11 Ref.12 Ref.13

Chain

2 – 531

530

Pyruvate kinase isozymes M1/M2

PRO_0000112088

Regions

Region

307 – 531

225

Interaction with POU5F1

Region

389 – 433

45

Intersubunit contact

Region

432 – 437

6

D-fructose 1,6-bisphosphate binding; part of allosteric site

Region

514 – 521

8

D-fructose 1,6-bisphosphate binding; part of allosteric site

Sites

Metal binding

75

1

Potassium By similarity

Metal binding

77

1

Potassium By similarity

Metal binding

113

1

Potassium

Metal binding

114

1

Potassium; via carbonyl oxygen By similarity

Metal binding

272

1

Magnesium

Metal binding

296

1

Magnesium

Binding site

70

1

Serine

Binding site

73

1

Substrate By similarity

Binding site

106

1

Serine

Binding site

295

1

Substrate; via amide nitrogen By similarity

Binding site

296

1

Substrate; via amide nitrogen By similarity

Binding site

328

1

Substrate By similarity

Binding site

464

1

Serine

Binding site

482

1

D-fructose 1,6-bisphosphate; part of allosteric site

Binding site

489

1

D-fructose 1,6-bisphosphate; part of allosteric site

Site

270

1

Transition state stabilizer

Site

433

1

Crucial for phosphotyrosine binding

Amino acid modifications

Modified residue

2

1

N-acetylserine Ref.11

Modified residue

37

1

Phosphoserine Ref.19 Ref.20 Ref.24 Ref.25 Ref.26 Ref.27 Ref.29 Ref.34

Modified residue

62

1

N6-acetyllysine Ref.28

Modified residue

89

1

N6-acetyllysine Ref.28

Modified residue

105

1

Phosphotyrosine Ref.18

Modified residue

148

1

Phosphotyrosine By similarity

Modified residue

166

1

N6-acetyllysine Ref.28

Modified residue

175

1

Phosphotyrosine Ref.27

Modified residue

195

1

Phosphothreonine Ref.27

Modified residue

266

1

N6-acetyllysine Ref.28

Modified residue

305

1

N6-acetyllysine Ref.33

Modified residue

403

1

4-hydroxyproline Ref.31

Modified residue

408

1

4-hydroxyproline Ref.31

Modified residue

433

1

N6-acetyllysine Ref.28

Natural variations

Alternative sequence

1 – 82

82

MSKPH…HGTHE → MSPEAQPQRTKGPQQPCRSP IVKPGLPSFRPSSCTQPWLT HSWSTCAAWTLIHHPSQPGT LASSVPL in isoform 3.

VSP_043370

Alternative sequence

389 – 433

45

IYHLQ…IVLTK → MFHRKLFEELVRASSHSTDL MEAMAMGSVEASYKCLAAAL IVLTE in isoform M1.

VSP_011101

Natural variant

204

1

G → V. Ref.10
Corresponds to variant rs17853396 [ dbSNP | Ensembl ].

VAR_033067

Experimental info

Mutagenesis

403

1

P → A: Significant reduction in hydroxylation and in PKM-mediated transcriptional activity of HIF1A; when associated with A-408. Ref.31

Mutagenesis

408

1

P → A: Significant reduction in hydroxylation and in PKM-mediated transcriptional activity of HIF1A; when associated with A-403. Ref.31

Mutagenesis

437

1

S → Y: Unable to bind FBP but still activated by serine. Ref.38

Mutagenesis

464

1

H → A: Abolishes serine binding and allosteric activation. Ref.38

Sequence conflict

7

1

E → Q in AAH12811. Ref.10

Sequence conflict

54

1

A → T in BAG52542. Ref.5

Sequence conflict

103

1

I → Y in AAA36672. Ref.2

Sequence conflict

132

1

V → L in AAA36672. Ref.2

Sequence conflict

187

1

Q → R in BAD96647. Ref.6

Sequence conflict

252

1

H → R in BAD96647. Ref.6

Sequence conflict

339

1

R → P in CAA39849. Ref.4

Sequence conflict

349

1

A → V in BAG52542. Ref.5

Sequence conflict

379

1

H → N in AAA36449. Ref.1

Sequence conflict

507

1

D → H in AAH12811. Ref.10

Secondary structure

1

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531

Helix Strand Turn

Details...

Helix

15 – 17

3

Helix

18 – 21

4

Helix

26 – 31

6

Beta strand

45 – 50

6

Turn

53 – 55

3

Helix

58 – 67

10

Beta strand

71 – 75

5

Helix

81 – 96

16

Turn

97 – 100

4

Turn

102 – 104

3

Beta strand

109 – 113

5

Beta strand

119 – 121

3

Beta strand

127 – 129

3

Beta strand

132 – 134

3

Beta strand

139 – 143

5

Helix

146 – 148

3

Beta strand

154 – 160

7

Helix

164 – 167

4

Beta strand

173 – 176

4

Turn

177 – 180

4

Beta strand

181 – 188

8

Beta strand

190 – 199

10

Beta strand

201 – 203

3

Beta strand

208 – 210

3

Beta strand

212 – 214

3

Helix

223 – 234

12

Beta strand

238 – 242

5

Helix

248 – 258

11

Turn

259 – 264

6

Beta strand

265 – 271

7

Helix

274 – 278

5

Helix

280 – 286

7

Beta strand

287 – 293

7

Helix

294 – 300

7

Helix

303 – 305

3

Helix

306 – 320

15

Beta strand

324 – 329

6

Helix

332 – 335

4

Beta strand

337 – 339

3

Helix

342 – 354

13

Beta strand

357 – 362

6

Helix

363 – 366

4

Beta strand

367 – 369

3

Helix

371 – 387

17

Helix

391 – 401

11

Turn

402 – 404

3

Helix

408 – 422

15

Beta strand

428 – 431

4

Beta strand

433 – 435

3

Helix

436 – 442

7

Beta strand

450 – 455

6

Helix

457 – 462

6

Helix

463 – 465

3

Beta strand

469 – 473

5

Helix

482 – 499

18

Beta strand

508 – 518

11

Beta strand

522 – 529

8

Sequences

	Sequence		Length	Mass (Da)
	Isoform M2 [UniParc]. Last modified January 23, 2007. Version 4. Checksum: AA94D7818ED6BBAD	FASTA	531	57,937
	10 20 30 40 50 60 MSKPHSEAGT AFIQTQQLHA AMADTFLEHM CRLDIDSPPI TARNTGIICT IGPASRSVET 70 80 90 100 110 120 LKEMIKSGMN VARLNFSHGT HEYHAETIKN VRTATESFAS DPILYRPVAV ALDTKGPEIR 130 140 150 160 170 180 TGLIKGSGTA EVELKKGATL KITLDNAYME KCDENILWLD YKNICKVVEV GSKIYVDDGL 190 200 210 220 230 240 ISLQVKQKGA DFLVTEVENG GSLGSKKGVN LPGAAVDLPA VSEKDIQDLK FGVEQDVDMV 250 260 270 280 290 300 FASFIRKASD VHEVRKVLGE KGKNIKIISK IENHEGVRRF DEILEASDGI MVARGDLGIE 310 320 330 340 350 360 IPAEKVFLAQ KMMIGRCNRA GKPVICATQM LESMIKKPRP TRAEGSDVAN AVLDGADCIM 370 380 390 400 410 420 LSGETAKGDY PLEAVRMQHL IAREAEAAIY HLQLFEELRR LAPITSDPTE ATAVGAVEAS 430 440 450 460 470 480 FKCCSGAIIV LTKSGRSAHQ VARYRPRAPI IAVTRNPQTA RQAHLYRGIF PVLCKDPVQE 490 500 510 520 530 AWAEDVDLRV NFAMNVGKAR GFFKKGDVVI VLTGWRPGSG FTNTMRVVPV P
	Isoform M1 [UniParc] [UniParc]. Checksum: AB9B5B2308D26B79	FASTA	531	58,062
	10 20 30 40 50 60 MSKPHSEAGT AFIQTQQLHA AMADTFLEHM CRLDIDSPPI TARNTGIICT IGPASRSVET 70 80 90 100 110 120 LKEMIKSGMN VARLNFSHGT HEYHAETIKN VRTATESFAS DPILYRPVAV ALDTKGPEIR 130 140 150 160 170 180 TGLIKGSGTA EVELKKGATL KITLDNAYME KCDENILWLD YKNICKVVEV GSKIYVDDGL 190 200 210 220 230 240 ISLQVKQKGA DFLVTEVENG GSLGSKKGVN LPGAAVDLPA VSEKDIQDLK FGVEQDVDMV 250 260 270 280 290 300 FASFIRKASD VHEVRKVLGE KGKNIKIISK IENHEGVRRF DEILEASDGI MVARGDLGIE 310 320 330 340 350 360 IPAEKVFLAQ KMMIGRCNRA GKPVICATQM LESMIKKPRP TRAEGSDVAN AVLDGADCIM 370 380 390 400 410 420 LSGETAKGDY PLEAVRMQHL IAREAEAAMF HRKLFEELVR ASSHSTDLME AMAMGSVEAS 430 440 450 460 470 480 YKCLAAALIV LTESGRSAHQ VARYRPRAPI IAVTRNPQTA RQAHLYRGIF PVLCKDPVQE 490 500 510 520 530 AWAEDVDLRV NFAMNVGKAR GFFKKGDVVI VLTGWRPGSG FTNTMRVVPV P
	Isoform 3 [UniParc]. Checksum: 23200C40C7C42045	FASTA	516	56,273
	10 20 30 40 50 60 MSPEAQPQRT KGPQQPCRSP IVKPGLPSFR PSSCTQPWLT HSWSTCAAWT LIHHPSQPGT 70 80 90 100 110 120 LASSVPLYHA ETIKNVRTAT ESFASDPILY RPVAVALDTK GPEIRTGLIK GSGTAEVELK 130 140 150 160 170 180 KGATLKITLD NAYMEKCDEN ILWLDYKNIC KVVEVGSKIY VDDGLISLQV KQKGADFLVT 190 200 210 220 230 240 EVENGGSLGS KKGVNLPGAA VDLPAVSEKD IQDLKFGVEQ DVDMVFASFI RKASDVHEVR 250 260 270 280 290 300 KVLGEKGKNI KIISKIENHE GVRRFDEILE ASDGIMVARG DLGIEIPAEK VFLAQKMMIG 310 320 330 340 350 360 RCNRAGKPVI CATQMLESMI KKPRPTRAEG SDVANAVLDG ADCIMLSGET AKGDYPLEAV 370 380 390 400 410 420 RMQHLIAREA EAAIYHLQLF EELRRLAPIT SDPTEATAVG AVEASFKCCS GAIIVLTKSG 430 440 450 460 470 480 RSAHQVARYR PRAPIIAVTR NPQTARQAHL YRGIFPVLCK DPVQEAWAED VDLRVNFAMN 490 500 510 VGKARGFFKK GDVVIVLTGW RPGSGFTNTM RVVPVP

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Human M2-type pyruvate kinase: cDNA cloning, chromosomal assignment and expression in hepatoma." Tani K., Yoshida M.C., Satoh H., Mitamura K., Noguchi T., Tanaka T., Fujii H., Miwa S. Gene 73:509-516(1988) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM M2). Tissue: Liver.
[2]	"Cytosolic thyroid hormone-binding protein is a monomer of pyruvate kinase." Kato H., Fukuda T., Parkison C., McPhie P., Cheng S.-Y. Proc. Natl. Acad. Sci. U.S.A. 86:7861-7865(1989) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM M2), PROTEIN SEQUENCE OF 70-98, SUBUNIT, ENZYME REGULATION.
[3]	Erratum Kato H., Fukuda T., Parkison C., McPhie P., Cheng S.-Y. Proc. Natl. Acad. Sci. U.S.A. 87:1625-1625(1990)
[4]	"Isolation and characterization of the human pyruvate kinase M gene." Takenaka M., Noguchi T., Sadahiro S., Hirai H., Yamada K., Matsuda T., Imai E., Tanaka T. Eur. J. Biochem. 198:101-106(1991) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], ALTERNATIVE SPLICING.
[5]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS M1 AND 3). Tissue: Astrocyte and Fetal brain.
[6]	Suzuki Y., Sugano S., Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S. Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM M2). Tissue: Kidney.
[7]	NIEHS SNPs program Submitted (JUL-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[8]	"Analysis of the DNA sequence and duplication history of human chromosome 15." Zody M.C., Garber M., Sharpe T., Young S.K., Rowen L., O'Neill K., Whittaker C.A., Kamal M., Chang J.L., Cuomo C.A., Dewar K., FitzGerald M.G., Kodira C.D., Madan A., Qin S., Yang X., Abbasi N., Abouelleil A. , Arachchi H.M., Baradarani L., Birditt B., Bloom S., Bloom T., Borowsky M.L., Burke J., Butler J., Cook A., DeArellano K., DeCaprio D., Dorris L. III, Dors M., Eichler E.E., Engels R., Fahey J., Fleetwood P., Friedman C., Gearin G., Hall J.L., Hensley G., Johnson E., Jones C., Kamat A., Kaur A., Locke D.P., Madan A., Munson G., Jaffe D.B., Lui A., Macdonald P., Mauceli E., Naylor J.W., Nesbitt R., Nicol R., O'Leary S.B., Ratcliffe A., Rounsley S., She X., Sneddon K.M.B., Stewart S., Sougnez C., Stone S.M., Topham K., Vincent D., Wang S., Zimmer A.R., Birren B.W., Hood L., Lander E.S., Nusbaum C. Nature 440:671-675(2006) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[9]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[10]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM M2), VARIANT VAL-204. Tissue: Kidney, Lung carcinoma, Ovary, Retina and Rhabdomyosarcoma.
[11]	Bienvenut W.V. Submitted (JUL-2005) to UniProtKB Cited for: PROTEIN SEQUENCE OF 2-43; 57-73; 93-115; 126-135; 167-186; 231-246; 271-311; 401-422; 448-455 AND 490-498, CLEAVAGE OF INITIATOR METHIONINE, ACETYLATION AT SER-2, MASS SPECTROMETRY. Tissue: B-cell lymphoma.
[12]	"An in vitro novel mechanism of regulating the activity of pyruvate kinase M2 by thyroid hormone and fructose 1, 6-bisphosphate." Ashizawa K., McPhie P., Lin K.-H., Cheng S.-Y. Biochemistry 30:7105-7111(1991) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 2-18, CATALYTIC ACTIVITY, ENZYME REGULATION, BIOPHYSICOCHEMICAL PROPERTIES, SUBUNIT, INTERACTION WITH THYROID HORMONE.
[13]	"Exploring proteomes and analyzing protein processing by mass spectrometric identification of sorted N-terminal peptides." Gevaert K., Goethals M., Martens L., Van Damme J., Staes A., Thomas G.R., Vandekerckhove J. Nat. Biotechnol. 21:566-569(2003) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 2-32. Tissue: Platelet.
[14]	Lubec G., Vishwanath V. Submitted (MAR-2007) to UniProtKB Cited for: PROTEIN SEQUENCE OF 74-89, MASS SPECTROMETRY. Tissue: Brain and Cajal-Retzius cell.
[15]	"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." Williams J.M., Chen G.-C., Zhu L., Rest R.F. Mol. Microbiol. 27:171-186(1998) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 368-531 (ISOFORM M2).
[16]	"Interaction between HERC1 and M2-type pyruvate kinase." Garcia-Gonzalo F.R., Cruz C., Munoz P., Mazurek S., Eigenbrodt E., Ventura F., Bartrons R., Rosa J.L. FEBS Lett. 539:78-84(2003) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH HERC1.
[17]	"Proteomic identification of proteins conjugated to ISG15 in mouse and human cells." Giannakopoulos N.V., Luo J.K., Papov V., Zou W., Lenschow D.J., Jacobs B.S., Borden E.C., Li J., Virgin H.W., Zhang D.E. Biochem. Biophys. Res. Commun. 336:496-506(2005) [PubMed] [Europe PMC] [Abstract] Cited for: ISGYLATION.
[18]	"Immunoaffinity profiling of tyrosine phosphorylation in cancer cells." Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H., Zha X.-M., Polakiewicz R.D., Comb M.J. Nat. Biotechnol. 23:94-101(2005) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-105, MASS SPECTROMETRY.
[19]	"Global, in vivo, and site-specific phosphorylation dynamics in signaling networks." Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M. Cell 127:635-648(2006) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-37, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[20]	"A probability-based approach for high-throughput protein phosphorylation analysis and site localization." Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P. Nat. Biotechnol. 24:1285-1292(2006) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-37, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[21]	"Nuclear translocation of the tumor marker pyruvate kinase M2 induces programmed cell death." Stetak A., Veress R., Ovadi J., Csermely P., Keri G., Ullrich A. Cancer Res. 67:1602-1608(2007) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION.
[22]	"Modulation of M2-type pyruvate kinase activity by the cytoplasmic PML tumor suppressor protein." Shimada N., Shinagawa T., Ishii S. Genes Cells 13:245-254(2008) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH PML, ENZYME REGULATION, SUBUNIT, SUBCELLULAR LOCATION.
[23]	"Pyruvate kinase isozyme type M2 (PKM2) interacts and cooperates with Oct-4 in regulating transcription." Lee J., Kim H.K., Han Y.-M., Kim J. Int. J. Biochem. Cell Biol. 40:1043-1054(2008) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH POU5F1, IDENTIFICATION BY MASS SPECTROMETRY, FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY.
[24]	"Phosphoproteome of resting human platelets." Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J., Schuetz C., Walter U., Gambaryan S., Sickmann A. J. Proteome Res. 7:526-534(2008) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-37, MASS SPECTROMETRY. Tissue: Platelet.
[25]	"Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle." Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., Greff Z., Keri G., Stemmann O., Mann M. Mol. Cell 31:438-448(2008) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-37, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[26]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-37, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[27]	"Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions." Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., Rodionov V., Han D.K. Sci. Signal. 2:RA46-RA46(2009) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-37; TYR-175 AND THR-195, MASS SPECTROMETRY. Tissue: Leukemic T-cell.
[28]	"Lysine acetylation targets protein complexes and co-regulates major cellular functions." Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C., Olsen J.V., Mann M. Science 325:834-840(2009) [PubMed] [Europe PMC] [Abstract] Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-62; LYS-89; LYS-166; LYS-266 AND LYS-433, MASS SPECTROMETRY.
[29]	"Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis." Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M. Sci. Signal. 3:RA3-RA3(2010) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-37, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[30]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[31]	"Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1." Luo W., Hu H., Chang R., Zhong J., Knabel M., O'Meally R., Cole R.N., Pandey A., Semenza G.L. Cell 145:732-744(2011) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH EGLN3 AND HIF1A, SUBCELLULAR LOCATION, INDUCTION, FUNCTION, MASS SPECTROMETRY, HYDROXYLATION AT PRO-403 AND PRO-408, MUTAGENESIS OF PRO-403 AND PRO-408.
[32]	"The oxygen sensor PHD3 limits glycolysis under hypoxia via direct binding to pyruvate kinase." Chen N., Rinner O., Czernik D., Nytko K.J., Zheng D., Stiehl D.P., Zamboni N., Gstaiger M., Frei C. Cell Res. 21:983-986(2011) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH EGLN3.
[33]	"Acetylation targets the M2 isoform of pyruvate kinase for degradation through chaperone-mediated autophagy and promotes tumor growth." Lv L., Li D., Zhao D., Lin R., Chu Y., Zhang H., Zha Z., Liu Y., Li Z., Xu Y., Wang G., Huang Y., Xiong Y., Guan K.L., Lei Q.Y. Mol. Cell 42:719-730(2011) [PubMed] [Europe PMC] [Abstract] Cited for: ACETYLATION AT LYS-305.
[34]	"System-wide temporal characterization of the proteome and phosphoproteome of human embryonic stem cell differentiation." Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B. Sci. Signal. 4:RS3-RS3(2011) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-37, MASS SPECTROMETRY.
[35]	"Structural basis for tumor pyruvate kinase M2 allosteric regulation and catalysis." Dombrauckas J.D., Santarsiero B.D., Mesecar A.D. Biochemistry 44:9417-9429(2005) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.82 ANGSTROMS) OF ISOFORM M2 IN COMPLEX WITH OXALATE AND FBP, CATALYTIC ACTIVITY, SUBUNIT, ENZYME MECHANISM, ENZYME REGULATION, BIOPHYSICOCHEMICAL PROPERTIES.
[36]	"Structure of human muscle pyruvate kinase (PKM2)." Structural genomics consortium (SGC) Submitted (MAY-2005) to the PDB data bank Cited for: X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS).
[37]	"Pyruvate kinase M2 is a phosphotyrosine-binding protein." Christofk H.R., Vander Heiden M.G., Wu N., Asara J.M., Cantley L.C. Nature 452:181-186(2008) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.03 ANGSTROMS) OF 14-531 ALONE AND IN COMPLEX WITH FBP, ENZYME REGULATION.
[38]	"Serine is a natural ligand and allosteric activator of pyruvate kinase M2." Chaneton B., Hillmann P., Zheng L., Martin A.C., Maddocks O.D., Chokkathukalam A., Coyle J.E., Jankevics A., Holding F.P., Vousden K.H., Frezza C., O'Reilly M., Gottlieb E. Nature 491:458-462(2012) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 2-531, ENZYME REGULATION BY SERINE, MAGNESIUM-BINDING SITES, SUBUNIT, MUTAGENESIS OF SER-437 AND HIS-464.
+	Additional computationally mapped references.

Web resources

Atlas of Genetics and Cytogenetics in Oncology and Haematology

NIEHS-SNPs

Wikipedia

Pyruvate kinase entry

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

M23725 mRNA. Translation: AAA36449.1.
M26252 mRNA. Translation: AAA36672.1.
X56494 Genomic DNA. Translation: CAA39849.1.
AK092369 mRNA. Translation: BAG52542.1.
AK222927 mRNA. Translation: BAD96647.1.
AK294315 mRNA. Translation: BAG57589.1. Different initiation.
AK300800 mRNA. Translation: BAG62458.1.
AK312253 mRNA. Translation: BAG35185.1.
AY352517 Genomic DNA. Translation: AAQ15274.1.
AC020779 Genomic DNA. No translation available.
CH471082 Genomic DNA. Translation: EAW77884.1.
CH471082 Genomic DNA. Translation: EAW77888.1.
BC000481 mRNA. Translation: AAH00481.3.
BC007640 mRNA. Translation: AAH07640.1.
BC007952 mRNA. Translation: AAH07952.3.
BC012811 mRNA. Translation: AAH12811.3.
BC035198 mRNA. Translation: AAH35198.1.
AF025439 mRNA. Translation: AAC39559.1.

IPI

IPI00220644.
IPI00479186.
IPI00910979.

PIR

S30038.
S64635.

RefSeq

NP_001193725.1. NM_001206796.1.
NP_001193726.1. NM_001206797.1.
NP_001193727.1. NM_001206798.1.
NP_001193728.1. NM_001206799.1.
NP_002645.3. NM_002654.4.
NP_872270.1. NM_182470.2.
NP_872271.1. NM_182471.2.

UniGene

Hs.534770.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1T5A	X-ray	2.80	A/B/C/D	1-531	[»]
1ZJH	X-ray	2.20	A	3-530	[»]
3BJF	X-ray	2.03	A/B/C/D	14-531	[»]
3BJT	X-ray	2.50	A/B/C/D	2-531	[»]
3G2G	X-ray	2.00	A/B/C/D	1-531	[»]
3GQY	X-ray	1.85	A/B/C/D	1-531	[»]
3GR4	X-ray	1.60	A/B/C/D	1-531	[»]
3H6O	X-ray	2.00	A/B/C/D	1-531	[»]
3ME3	X-ray	1.95	A/B/C/D	1-531	[»]
3SRD	X-ray	2.90	A/B/C/D	1-531	[»]
3SRF	X-ray	2.84	A/B/C/D/E/F/G/H	1-531	[»]
3SRH	X-ray	2.60	A/B/C/D	1-531	[»]
3U2Z	X-ray	2.10	A/B/C/D	1-531	[»]
4B2D	X-ray	2.30	A/B/C/D	2-531	[»]
4G1N	X-ray	2.30	A/B/C/D	14-531	[»]

ProteinModelPortal

P14618.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-31273N.

IntAct

P14618. 64 interactions.

MINT

MINT-4998892.

PTM databases

PhosphoSite

P14618.

Polymorphism databases

DMDM

20178296.

2D gel databases

DOSAC-COBS-2DPAGE

P14618.

OGP

P14618.

REPRODUCTION-2DPAGE

IPI00220644.
IPI00479186.

UCD-2DPAGE

P14618.

Proteomic databases

PaxDb

P14618.

PRIDE

P14618.

Protocols and materials databases

DNASU

5315.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000319622; ENSP00000320171; ENSG00000067225.
ENST00000335181; ENSP00000334983; ENSG00000067225.
ENST00000389093; ENSP00000373745; ENSG00000067225.
ENST00000449901; ENSP00000403365; ENSG00000067225.
ENST00000565154; ENSP00000455901; ENSG00000067225.
ENST00000565184; ENSP00000455736; ENSG00000067225.
ENST00000568459; ENSP00000456970; ENSG00000067225.

GeneID

5315.

KEGG

hsa:5315.

UCSC

uc002atv.2. human.
uc002aty.2. human.

Organism-specific databases

CTD

5315.

GeneCards

GC15M072492.

HGNC

HGNC:9021. PKM.

HPA

CAB019421.
HPA029501.

MIM

179050. gene.

neXtProt

NX_P14618.

PharmGKB

PA33353.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG0469.

HOGENOM

HOG000021559.

HOVERGEN

HBG000941.

InParanoid

P14618.

KO

K00873.

OMA

VKMMATI.

Enzyme and pathway databases

Pathway_Interaction_DB

hif1_tfpathway. HIF-1-alpha transcription factor network.

Reactome

REACT_111217. Metabolism.

SABIO-RK

P14618.

UniPathway

UPA00109; UER00188.

Gene expression databases

ArrayExpress

P14618.

Bgee

P14618.

CleanEx

HS_PKM2.

Genevestigator

P14618.

GermOnline

ENSG00000067225. Homo sapiens.

Family and domain databases

Gene3D

2.40.33.10. 1 hit.
3.20.20.60. 2 hits.
3.40.1380.20. 1 hit.

InterPro

IPR001697. Pyr_Knase.
IPR015813. Pyrv/PenolPyrv_Kinase.
IPR011037. Pyrv_Knase-like_insert_dom.
IPR015794. Pyrv_Knase_a/b.
IPR018209. Pyrv_Knase_AS.
IPR015793. Pyrv_Knase_brl.
IPR015795. Pyrv_Knase_C.
IPR015806. Pyrv_Knase_insert_dom.
[Graphical view]

PANTHER

PTHR11817. PTHR11817. 1 hit.

Pfam

PF00224. PK. 1 hit.
PF02887. PK_C. 1 hit.
[Graphical view]

PRINTS

PR01050. PYRUVTKNASE.

SUPFAM

SSF50800. PK_B_barrel_like. 1 hit.
SSF52935. Pyruvate_kinase. 1 hit.
SSF51621. Pyrv/PenolPyrv_Kinase_cat. 1 hit.

TIGRFAMs

TIGR01064. pyruv_kin. 1 hit.

PROSITE

PS00110. PYRUVATE_KINASE. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

P14618.

ChEMBL

CHEMBL1075189.

ChiTaRS

PKM2. human.

DrugBank

DB00119. Pyruvic acid.

EvolutionaryTrace

P14618.

GenomeRNAi

5315.

NextBio

20554.

SOURCE

Search...

Entry information

Entry name

KPYM_HUMAN

Accession

Primary (citable) accession number: P14618
Secondary accession number(s): A6NFK3 , B2R5N8, B3KRY0, B4DFX8, B4DUU6, P14786, Q53GK4, Q96E76, Q9BWB5, Q9UCV6, Q9UPF2

Entry history

Integrated into UniProtKB/Swiss-Prot:	April 1, 1990
Last sequence update:	January 23, 2007
Last modified:	May 1, 2013
This is version 179 of the entry and version 4 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.