P17858 (K6PL_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
6-phosphofructokinase, liver type
EC=2.7.1.11

Alternative name(s):
Phosphofructo-1-kinase isozyme B
Short name=PFK-B
Phosphofructokinase 1
Phosphohexokinase

Gene names

Name:

PFKL

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	780 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	Catalyzes the third step of glycolysis, the phosphorylation of fructose-6-phosphate (F6P) by ATP to generate fructose-1,6-bisphosphate (FBP) and ADP. Ref.9
Catalytic activity	ATP + D-fructose 6-phosphate = ADP + D-fructose 1,6-bisphosphate. Ref.9
Cofactor	Magnesium.
Enzyme regulation	Allosteric enzyme activated by ADP, AMP, or fructose bisphosphate and inhibited by ATP or citrate. GlcNAcylation by OGT overcomes allosteric regulation. Ref.9
Pathway	Carbohydrate degradation; glycolysis; D-glyceraldehyde 3-phosphate and glycerone phosphate from D-glucose: step 3/4.
Subunit structure	Tetramer. Muscle is M4, liver is L4, and red cell is M3L, M2L2, or ML3.
Post-translational modification	GlcNAcylation at Ser-529 by OGT decreases enzyme activity, leading to redirect glucose flux through the oxidative pentose phosphate pathway. Glycosylation is stimulated by both hypoxia and glucose deprivation.
Miscellaneous	In human PFK exists as a system of 3 types of subunits, PFKM (muscle), PFKL (liver) and PFKP (platelet) isoenzymes. Glycosylation may play a role in cancer cell proliferation: inhibition of 6-phosphofructokinase acitivity and subsequent redirection of the glucose flux through the oxidative pentose phosphate pathway confers a selective growth advantage on cancer cells. Moreover GlcNAcylation is observed in multiple cancer cell lines and tissue samples and GlcNAcylation leads to larger xenografts tunors in mice (Ref.9).
Sequence similarities	Belongs to the phosphofructokinase family. Two domains subfamily.

Ontologies

Keywords
Biological process	Glycolysis
Coding sequence diversity	Alternative splicing Polymorphism
Domain	Repeat
Ligand	ATP-binding Magnesium Metal-binding Nucleotide-binding
Molecular function	Kinase Transferase
PTM	Acetylation Glycoprotein Phosphoprotein
Technical term	Allosteric enzyme Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	fructose 1,6-bisphosphate metabolic process Inferred from direct assay Ref.9. Source: UniProtKB fructose 6-phosphate metabolic process Inferred from direct assay PubMed 6444532PubMed 6444721. Source: UniProtKB glycolysis Inferred from direct assay Ref.9PubMed 6227635PubMed 6444532. Source: UniProtKB negative regulation of insulin secretion Inferred from electronic annotation. Source: Compara protein homotetramerization Inferred from electronic annotation. Source: Compara protein oligomerization Inferred from direct assay PubMed 6444721. Source: BHF-UCL response to glucose stimulus Inferred from direct assay Ref.9. Source: UniProtKB small molecule metabolic process Traceable author statement. Source: Reactome
Cellular_component	6-phosphofructokinase complex Inferred from direct assay PubMed 6444532PubMed 6444721. Source: UniProtKB
Molecular_function	6-phosphofructokinase activity Inferred from direct assay Ref.9PubMed 6444532PubMed 6444721PubMed 8780720. Source: UniProtKB ATP binding Inferred from direct assay PubMed 8780720. Source: UniProtKB fructose binding Inferred from direct assay PubMed 8780720. Source: BHF-UCL fructose-6-phosphate binding Inferred from direct assay PubMed 6444721. Source: BHF-UCL metal ion binding Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
itself		2	EBI-487243,EBI-487243
PFKM	P08237	6	EBI-487243,EBI-514788

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: P17858-1)

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 2 (identifier: P17858-2)

Also known as: a;

The sequence of this isoform differs from the canonical sequence as follows:
     1-28: MAAVDLEKLRASGAGKAIGVLTSGGDAQ → MCNQGRGRES...GGTSIMSRLG

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.5 Ref.6
	Chain	2 – 780	779	6-phosphofructokinase, liver type		PRO_0000112021
Regions
	Nucleotide binding	35 – 39	5	ATP By similarity
	Nucleotide binding	193 – 197	5	ATP By similarity
	Nucleotide binding	210 – 226	17	ATP By similarity
Sites
	Active site	166	1	Proton acceptor By similarity
	Metal binding	224	1	Magnesium; via carbonyl oxygen By similarity
	Binding site	201	1	Substrate By similarity
	Binding site	292	1	Substrate By similarity
	Binding site	298	1	Substrate By similarity
	Binding site	301	1	Substrate By similarity
Amino acid modifications
	Modified residue	2	1	N-acetylalanine Ref.6
	Modified residue	640	1	Phosphotyrosine By similarity
	Modified residue	775	1	Phosphoserine Ref.7
	Glycosylation	529	1	O-linked (GlcNAc...) Ref.9
Natural variations
	Alternative sequence	1 – 28	28	MAAVD…GGDAQ → MCNQGRGRESSRGGLHVQGS CRGLSRSPQQETGFAKAPAG TDCFFHCSPGSRGQGDRKEE VTSEPGGTSIMSRLG in isoform 2.		VSP_011854
	Natural variant	81	1	G → A. Ref.2		VAR_006070
	Natural variant	151	1	R → W. Ref.1		VAR_006071
	Natural variant	237	1	D → V. Corresponds to variant rs1057037 [ dbSNP | Ensembl ].		VAR_030872
Experimental info
	Mutagenesis	527	1	T → A: Does not affect GlcNAcylation. Ref.9
	Mutagenesis	529	1	S → A: Prevents GlcNAcylation and enhance enzyme activity. Ref.9
	Sequence conflict	27	1	A → R in CAA33597. Ref.1
	Sequence conflict	27	1	A → R in CAB46744. Ref.2
	Sequence conflict	86	1	S → T in CAB46744. Ref.2
	Sequence conflict	89	1	C → S in CAA33597. Ref.1
	Sequence conflict	89	1	C → S in CAB46744. Ref.2
	Sequence conflict	103	1	Y → N in CAB46744. Ref.2
	Sequence conflict	236	1	E → EAPPE in CAB46744. Ref.2
	Sequence conflict	386	1	K → R in CAB46744. Ref.2
	Sequence conflict	389	1	A → T in CAA33597. Ref.1
	Sequence conflict	389	1	A → T in CAB46744. Ref.2
	Sequence conflict	648	1	K → N in AAH08964. Ref.4
	Sequence conflict	648	1	K → N in AAH09919. Ref.4
	Sequence conflict	717	1	V → A in AAH08964. Ref.4
	Sequence conflict	717	1	V → A in AAH09919. Ref.4

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified March 6, 2007. Version 6. Checksum: 0D686CE074E9626D	FASTA	780	85,018
	10 20 30 40 50 60 MAAVDLEKLR ASGAGKAIGV LTSGGDAQGM NAAVRAVTRM GIYVGAKVFL IYEGYEGLVE 70 80 90 100 110 120 GGENIKQANW LSVSNIIQLG GTIIGSARCK AFTTREGRRA AAYNLVQHGI TNLCVIGGDG 130 140 150 160 170 180 SLTGANIFRS EWGSLLEELV AEGKISETTA RTYSHLNIAG LVGSIDNDFC GTDMTIGTDS 190 200 210 220 230 240 ALHRIMEVID AITTTAQSHQ RTFVLEVMGR HCGYLALVSA LASGADWLFI PEAPPEDGWE 250 260 270 280 290 300 NFMCERLGET RSRGSRLNII IIAEGAIDRN GKPISSSYVK DLVVQRLGFD TRVTVLGHVQ 310 320 330 340 350 360 RGGTPSAFDR ILSSKMGMEA VMALLEATPD TPACVVTLSG NQSVRLPLME CVQMTKEVQK 370 380 390 400 410 420 AMDDKRFDEA TQLRGGSFEN NWNIYKLLAH QKPPKEKSNF SLAILNVGAP AAGMNAAVRS 430 440 450 460 470 480 AVRTGISHGH TVYVVHDGFE GLAKGQVQEV GWHDVAGWLG RGGSMLGTKR TLPKGQLESI 490 500 510 520 530 540 VENIRIYGIH ALLVVGGFEA YEGVLQLVEA RGRYEELCIV MCVIPATISN NVPGTDFSLG 550 560 570 580 590 600 SDTAVNAAME SCDRIKQSAS GTKRRVFIVE TMGGYCGYLA TVTGIAVGAD AAYVFEDPFN 610 620 630 640 650 660 IHDLKVNVEH MTEKMKTDIQ RGLVLRNEKC HDYYTTEFLY NLYSSEGKGV FDCRTNVLGH 670 680 690 700 710 720 LQQGGAPTPF DRNYGTKLGV KAMLWLSEKL REVYRKGRVF ANAPDSACVI GLKKKAVAFS 730 740 750 760 770 780 PVTELKKDTD FEHRMPREQW WLSLRLMLKM LAQYRISMAA YVSGELEHVT RRTLSMDKGF
	Isoform 2 (a) [UniParc]. Checksum: ADBECCB9B1FB234C	FASTA	827	90,203
	10 20 30 40 50 60 MCNQGRGRES SRGGLHVQGS CRGLSRSPQQ ETGFAKAPAG TDCFFHCSPG SRGQGDRKEE 70 80 90 100 110 120 VTSEPGGTSI MSRLGGMNAA VRAVTRMGIY VGAKVFLIYE GYEGLVEGGE NIKQANWLSV 130 140 150 160 170 180 SNIIQLGGTI IGSARCKAFT TREGRRAAAY NLVQHGITNL CVIGGDGSLT GANIFRSEWG 190 200 210 220 230 240 SLLEELVAEG KISETTARTY SHLNIAGLVG SIDNDFCGTD MTIGTDSALH RIMEVIDAIT 250 260 270 280 290 300 TTAQSHQRTF VLEVMGRHCG YLALVSALAS GADWLFIPEA PPEDGWENFM CERLGETRSR 310 320 330 340 350 360 GSRLNIIIIA EGAIDRNGKP ISSSYVKDLV VQRLGFDTRV TVLGHVQRGG TPSAFDRILS 370 380 390 400 410 420 SKMGMEAVMA LLEATPDTPA CVVTLSGNQS VRLPLMECVQ MTKEVQKAMD DKRFDEATQL 430 440 450 460 470 480 RGGSFENNWN IYKLLAHQKP PKEKSNFSLA ILNVGAPAAG MNAAVRSAVR TGISHGHTVY 490 500 510 520 530 540 VVHDGFEGLA KGQVQEVGWH DVAGWLGRGG SMLGTKRTLP KGQLESIVEN IRIYGIHALL 550 560 570 580 590 600 VVGGFEAYEG VLQLVEARGR YEELCIVMCV IPATISNNVP GTDFSLGSDT AVNAAMESCD 610 620 630 640 650 660 RIKQSASGTK RRVFIVETMG GYCGYLATVT GIAVGADAAY VFEDPFNIHD LKVNVEHMTE 670 680 690 700 710 720 KMKTDIQRGL VLRNEKCHDY YTTEFLYNLY SSEGKGVFDC RTNVLGHLQQ GGAPTPFDRN 730 740 750 760 770 780 YGTKLGVKAM LWLSEKLREV YRKGRVFANA PDSACVIGLK KKAVAFSPVT ELKKDTDFEH 790 800 810 820 RMPREQWWLS LRLMLKMLAQ YRISMAAYVS GELEHVTRRT LSMDKGF

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"The primary structure of human liver type phosphofructokinase and its comparison with other types of PFK." Levanon D., Danciger E., Dafni N., Bernstein Y., Elson A., Moens W., Brandeis M., Groner Y. DNA 8:733-743(1989) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANT TRP-151. Tissue: Liver.
[2]	"The structure of the human liver-type phosphofructokinase gene." Elson A., Levanon D., Brandeis M., Dafni N., Bernstein Y., Danciger E., Groner Y. Genomics 7:47-56(1990) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 1), VARIANT ALA-81.
[3]	"The DNA sequence of human chromosome 21." Hattori M., Fujiyama A., Taylor T.D., Watanabe H., Yada T., Park H.-S., Toyoda A., Ishii K., Totoki Y., Choi D.-K., Groner Y., Soeda E., Ohki M., Takagi T., Sakaki Y., Taudien S., Blechschmidt K., Polley A. , Menzel U., Delabar J., Kumpf K., Lehmann R., Patterson D., Reichwald K., Rump A., Schillhabel M., Schudy A., Zimmermann W., Rosenthal A., Kudoh J., Shibuya K., Kawasaki K., Asakawa S., Shintani A., Sasaki T., Nagamine K., Mitsuyama S., Antonarakis S.E., Minoshima S., Shimizu N., Nordsiek G., Hornischer K., Brandt P., Scharfe M., Schoen O., Desario A., Reichelt J., Kauer G., Bloecker H., Ramser J., Beck A., Klages S., Hennig S., Riesselmann L., Dagand E., Wehrmeyer S., Borzym K., Gardiner K., Nizetic D., Francis F., Lehrach H., Reinhardt R., Yaspo M.-L. Nature 405:311-319(2000) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]	"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] (ISOFORMS 1 AND 2). Tissue: Kidney, Lung and Muscle.
[5]	"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 2-10 (ISOFORM 1). Tissue: Platelet.
[6]	Bienvenut W.V., Gao M., Leug H., Pchelintsev N., Adams P.D. Submitted (JUL-2009) to UniProtKB Cited for: PROTEIN SEQUENCE OF 2-10; 17-35 AND 185-210, CLEAVAGE OF INITIATOR METHIONINE, ACETYLATION AT ALA-2, MASS SPECTROMETRY. Tissue: Prostatic carcinoma.
[7]	"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-775, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[8]	"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].
[9]	"Phosphofructokinase 1 glycosylation regulates cell growth and metabolism." Yi W., Clark P.M., Mason D.E., Keenan M.C., Hill C., Goddard W.A. III, Peters E.C., Driggers E.M., Hsieh-Wilson L.C. Science 337:975-980(2012) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, CATALYTIC ACTIVITY, ENZYME REGULATION, GLYCOSYLATION AT SER-529, MUTAGENESIS OF THR-527 AND SER-529.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	X15573 mRNA. Translation: CAA33597.1. X16911 , X16912, X16913, X16914, X16915, X16916, X16917, X16918, X16919, X16920, X16921, X16922, X16923, X16924, X16925, X16926, X16927, X16928, X16929, X16930 Genomic DNA. Translation: CAB46744.1. AP001754 Genomic DNA. Translation: BAA95561.1. BC006422 mRNA. Translation: AAH06422.1. BC007536 mRNA. Translation: AAH07536.1. BC008964 mRNA. Translation: AAH08964.1. BC009919 mRNA. Translation: AAH09919.1.
IPI	IPI00332371. IPI00925520.
PIR	A33639.
RefSeq	NP_002617.3. NM_002626.4.
UniGene	Hs.255093.
3D structure databases
ProteinModelPortal	P17858.
ModBase	Search...
Protein-protein interaction databases
IntAct	P17858. 9 interactions.
MINT	MINT-5004093.
STRING	9606.ENSP00000269848.
PTM databases
PhosphoSite	P17858.
Polymorphism databases
DMDM	134048493.
Proteomic databases
PaxDb	P17858.
PRIDE	P17858.
Protocols and materials databases
DNASU	5211.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000349048; ENSP00000269848; ENSG00000141959. ENST00000403390; ENSP00000384038; ENSG00000141959.
GeneID	5211.
KEGG	hsa:5211.
UCSC	uc002zek.3. human. uc002zel.3. human.
Organism-specific databases
CTD	5211.
GeneCards	GC21P045719.
H-InvDB	HIX0016166.
HGNC	HGNC:8876. PFKL.
HPA	HPA030047.
MIM	171860. gene.
neXtProt	NX_P17858.
PharmGKB	PA33215.
GenAtlas	Search...
Phylogenomic databases
eggNOG	COG0205.
HOGENOM	HOG000200154.
HOVERGEN	HBG000976.
KO	K00850.
OMA	PISSSYV.
OrthoDB	EOG4RJG0W.
Enzyme and pathway databases
Pathway_Interaction_DB	hif1_tfpathway. HIF-1-alpha transcription factor network.
Reactome	REACT_111217. Metabolism.
SABIO-RK	P17858.
UniPathway	UPA00109; UER00182.
Gene expression databases
ArrayExpress	P17858.
Bgee	P17858.
CleanEx	HS_PFKL.
Genevestigator	P17858.
GermOnline	ENSG00000141959. Homo sapiens.
Family and domain databases
InterPro	IPR009161. 6-phosphofructokinase_euk. IPR022953. Phosphofructokinase. IPR015912. Phosphofructokinase_CS. IPR000023. Phosphofructokinase_dom. [Graphical view]
Pfam	PF00365. PFK. 2 hits. [Graphical view]
PIRSF	PIRSF000533. ATP_PFK_euk. 1 hit.
PRINTS	PR00476. PHFRCTKINASE.
SUPFAM	SSF53784. Ppfruckinase. 2 hits.
TIGRFAMs	TIGR02478. 6PF1K_euk. 1 hit.
PROSITE	PS00433. PHOSPHOFRUCTOKINASE. 2 hits. [Graphical view]
ProtoNet	Search...
Other
BindingDB	P17858.
ChEMBL	CHEMBL2191.
ChiTaRS	PFKL. human.
GenomeRNAi	5211.
NextBio	20154.
PMAP-CutDB	P17858.
SOURCE	Search...

Entry information

Entry name

K6PL_HUMAN

Accession

Primary (citable) accession number: P17858
Secondary accession number(s): Q96A64, Q96IH4, Q9BR91

Entry history

Integrated into UniProtKB/Swiss-Prot:	August 1, 1990
Last sequence update:	March 6, 2007
Last modified:	May 1, 2013
This is version 160 of the entry and version 6 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.