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Protein

ATP-dependent 6-phosphofructokinase, liver type

Gene

PFKL

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Catalyzes the phosphorylation of D-fructose 6-phosphate to fructose 1,6-bisphosphate by ATP, the first committing step of glycolysis (PubMed:22923583). Negatively regulates the phagocyte oxidative burst in response to bacterial infection by controlling cellular NADPH biosynthesis and NADPH oxidase-derived reactive oxygen species. Upon macrophage activation, drives the metabolic switch toward glycolysis, thus preventing glucose turnover that produces NADPH via pentose phosphate pathway (By similarity).UniRule annotationBy similarity1 Publication

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 activity 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 (PubMed:22923583).1 Publication

Catalytic activityi

ATP + D-fructose 6-phosphate = ADP + D-fructose 1,6-bisphosphate.UniRule annotation1 Publication

Cofactori

Enzyme regulationi

Allosterically activated by ADP, AMP, or fructose 2,6-bisphosphate, and allosterically inhibited by ATP or citrate. GlcNAcylation by OGT overcomes allosteric regulation.UniRule annotation1 Publication

Pathwayi: glycolysis

This protein is involved in step 3 of the subpathway that synthesizes D-glyceraldehyde 3-phosphate and glycerone phosphate from D-glucose.UniRule annotation
Proteins known to be involved in the 4 steps of the subpathway in this organism are:
  1. no protein annotated in this organism
  2. Glucose-6-phosphate isomerase, Glucose-6-phosphate isomerase, Glucose-6-phosphate isomerase (GPI), Glucose-6-phosphate isomerase (GPI), Glucose-6-phosphate isomerase (pgi), Glucose-6-phosphate isomerase (GPI), Glucose-6-phosphate isomerase (GPI), Glucose-6-phosphate isomerase, Glucose-6-phosphate isomerase (GPI)
  3. ATP-dependent 6-phosphofructokinase (PFKM), ATP-dependent 6-phosphofructokinase (PFKM), ATP-dependent 6-phosphofructokinase, liver type (PFKL), ATP-dependent 6-phosphofructokinase, muscle type (PFKM), ATP-dependent 6-phosphofructokinase, platelet type (PFKP)
  4. Fructose-bisphosphate aldolase, Fructose-bisphosphate aldolase (ALDOB), Fructose-bisphosphate aldolase, Fructose-bisphosphate aldolase, Fructose-bisphosphate aldolase, Fructose-bisphosphate aldolase, Fructose-bisphosphate aldolase (ALDOA), Fructose-bisphosphate aldolase, Fructose-bisphosphate aldolase C (ALDOC), Fructose-bisphosphate aldolase (HEL-S-87p), Fructose-bisphosphate aldolase, Fructose-bisphosphate aldolase (ALDOA), Fructose-bisphosphate aldolase (ALDOC), Fructose-bisphosphate aldolase, Fructose-bisphosphate aldolase, Fructose-bisphosphate aldolase (ALDOB), Fructose-bisphosphate aldolase (ALDOA), Fructose-bisphosphate aldolase (BQ8482_350140), Fructose-bisphosphate aldolase (ALDOA), Fructose-bisphosphate aldolase B (ALDOB), Fructose-bisphosphate aldolase A (ALDOA), Fructose-bisphosphate aldolase (ALDOC), Fructose-bisphosphate aldolase
This subpathway is part of the pathway glycolysis, which is itself part of Carbohydrate degradation.
View all proteins of this organism that are known to be involved in the subpathway that synthesizes D-glyceraldehyde 3-phosphate and glycerone phosphate from D-glucose, the pathway glycolysis and in Carbohydrate degradation.

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei25ATP; via amide nitrogenUniRule annotation1
Metal bindingi119Magnesium; catalyticUniRule annotation1
Active sitei166Proton acceptorUniRule annotation1
Binding sitei201Substrate; shared with dimeric partnerUniRule annotation1
Binding sitei264SubstrateUniRule annotation1
Binding sitei292Substrate; shared with dimeric partnerUniRule annotation1
Binding sitei470Allosteric activator fructose 2,6-bisphosphateUniRule annotation1
Binding sitei565Allosteric activator fructose 2,6-bisphosphate; shared with dimeric partnerUniRule annotation1
Binding sitei628Allosteric activator fructose 2,6-bisphosphateUniRule annotation1
Binding sitei654Allosteric activator fructose 2,6-bisphosphate; shared with dimeric partnerUniRule annotation1
Binding sitei734Allosteric activator fructose 2,6-bisphosphateUniRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi88 – 89ATPUniRule annotation2
Nucleotide bindingi118 – 121ATPUniRule annotation4

GO - Molecular functioni

  • 6-phosphofructokinase activity Source: UniProtKB
  • ATP binding Source: UniProtKB
  • fructose-6-phosphate binding Source: BHF-UCL
  • fructose binding Source: BHF-UCL
  • identical protein binding Source: IntAct
  • kinase binding Source: BHF-UCL
  • metal ion binding Source: UniProtKB-KW

GO - Biological processi

  • canonical glycolysis Source: Reactome
  • fructose 1,6-bisphosphate metabolic process Source: UniProtKB
  • fructose 6-phosphate metabolic process Source: UniProtKB
  • glycolytic process Source: UniProtKB
  • negative regulation of insulin secretion Source: Ensembl
  • neutrophil degranulation Source: Reactome
  • protein complex oligomerization Source: BHF-UCL
  • protein homotetramerization Source: Ensembl
  • response to glucose Source: UniProtKB

Keywordsi

Molecular functionAllosteric enzyme, Kinase, Transferase
Biological processGlycolysis
LigandATP-binding, Magnesium, Metal-binding, Nucleotide-binding

Enzyme and pathway databases

BioCyciMetaCyc:HS06881-MONOMER
ReactomeiR-HSA-6798695 Neutrophil degranulation
R-HSA-70171 Glycolysis
SABIO-RKiP17858
UniPathwayiUPA00109; UER00182

Names & Taxonomyi

Protein namesi
Recommended name:
ATP-dependent 6-phosphofructokinase, liver typeUniRule annotation (EC:2.7.1.11UniRule annotation)
Short name:
ATP-PFKUniRule annotation
Short name:
PFK-L
Alternative name(s):
6-phosphofructokinase type B
Phosphofructo-1-kinase isozyme B
Short name:
PFK-B
PhosphohexokinaseUniRule annotation
Gene namesi
Name:PFKLImported
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 21

Organism-specific databases

EuPathDBiHostDB:ENSG00000141959.16
HGNCiHGNC:8876 PFKL
MIMi171860 gene
neXtProtiNX_P17858

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi527T → A: Does not affect GlcNAcylation. 1 Publication1
Mutagenesisi529S → A: Prevents GlcNAcylation and enhance enzyme activity. 1 Publication1

Organism-specific databases

DisGeNETi5211
OpenTargetsiENSG00000141959
PharmGKBiPA33215

Polymorphism and mutation databases

BioMutaiPFKL
DMDMi134048493

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Initiator methionineiRemovedCombined sources1 Publication
ChainiPRO_00001120212 – 780ATP-dependent 6-phosphofructokinase, liver typeAdd BLAST779

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei2N-acetylalanineCombined sources1 Publication1
Modified residuei377PhosphoserineBy similarity1
Glycosylationi529O-linked (GlcNAc) serine1 Publication1
Modified residuei640PhosphotyrosineBy similarity1
Modified residuei775PhosphoserineCombined sources1

Post-translational modificationi

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.1 Publication

Keywords - PTMi

Acetylation, Glycoprotein, Phosphoprotein

Proteomic databases

EPDiP17858
MaxQBiP17858
PaxDbiP17858
PeptideAtlasiP17858
PRIDEiP17858
ProteomicsDBi53520
53521 [P17858-2]
TopDownProteomicsiP17858-1 [P17858-1]

PTM databases

iPTMnetiP17858
PhosphoSitePlusiP17858
SwissPalmiP17858

Miscellaneous databases

PMAP-CutDBiP17858

Expressioni

Gene expression databases

BgeeiENSG00000141959
CleanExiHS_PFKL
ExpressionAtlasiP17858 baseline and differential
GenevisibleiP17858 HS

Organism-specific databases

HPAiHPA030047

Interactioni

Subunit structurei

Homo- and heterotetramers (By similarity). Phosphofructokinase (PFK) enzyme functions as a tetramer composed of different combinations of 3 types of subunits, called PFKM (where M stands for Muscle), PFKL (Liver) and PFKP (Platelet). The composition of the PFK tetramer differs according to the tissue type it is present in. In muscles, it is composed of 4 PFKM subunits (also called M4). In the liver, the predominant form is a tetramer of PFKL subunits (L4). In erythrocytes, both PFKM and PFKL subunits randomly tetramerize to form M4, L4 and other combinations (ML3, M2L2, M3L). The kinetic and regulatory properties of the tetrameric enzyme are dependent on the subunit composition, hence can vary across tissues (Probable).UniRule annotationCurated

Binary interactionsi

Show more details

GO - Molecular functioni

  • identical protein binding Source: IntAct
  • kinase binding Source: BHF-UCL

Protein-protein interaction databases

BioGridi111232, 59 interactors
ComplexPortaliCPX-1998 6-phosphofructokinase, L4 homotetramer
CPX-2000 6-phosphofructokinase, ML3 heterotetramer
CPX-2001 6-phosphofructokinase, M2L2 heterotetramer
CPX-2002 6-phosphofructokinase, M3L heterotetramer
CORUMiP17858
IntActiP17858, 34 interactors
MINTiP17858
STRINGi9606.ENSP00000269848

Structurei

3D structure databases

ProteinModelPortaliP17858
SMRiP17858
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni2 – 390N-terminal catalytic PFK domain 1Add BLAST389
Regioni164 – 166Substrate bindingUniRule annotation3
Regioni208 – 210Substrate bindingUniRule annotation3
Regioni298 – 301Substrate bindingUniRule annotation4
Regioni391 – 400Interdomain linker10
Regioni401 – 780C-terminal regulatory PFK domain 2Add BLAST380
Regioni527 – 531Allosteric activator fructose 2,6-bisphosphate bindingUniRule annotation5
Regioni572 – 574Allosteric activator fructose 2,6-bisphosphate bindingUniRule annotation3
Regioni660 – 663Allosteric activator fructose 2,6-bisphosphate bindingUniRule annotation4

Sequence similaritiesi

Belongs to the phosphofructokinase type A (PFKA) family. ATP-dependent PFK group I subfamily. Eukaryotic two domain clade "E" sub-subfamily.UniRule annotation

Phylogenomic databases

eggNOGiKOG2440 Eukaryota
COG0205 LUCA
GeneTreeiENSGT00390000013209
HOGENOMiHOG000200154
HOVERGENiHBG000976
InParanoidiP17858
KOiK00850
OMAiVQEVGWH
OrthoDBiEOG091G01YN
PhylomeDBiP17858
TreeFamiTF300411

Family and domain databases

HAMAPiMF_03184 Phosphofructokinase_I_E, 1 hit
InterProiView protein in InterPro
IPR009161 6-Pfructokinase_euk
IPR022953 ATP_PFK
IPR015912 Phosphofructokinase_CS
IPR000023 Phosphofructokinase_dom
IPR035966 PKF_sf
PfamiView protein in Pfam
PF00365 PFK, 2 hits
PIRSFiPIRSF000533 ATP_PFK_euk, 1 hit
PRINTSiPR00476 PHFRCTKINASE
SUPFAMiSSF53784 SSF53784, 2 hits
TIGRFAMsiTIGR02478 6PF1K_euk, 1 hit
PROSITEiView protein in PROSITE
PS00433 PHOSPHOFRUCTOKINASE, 2 hits

Sequences (2)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: P17858-1) [UniParc]FASTAAdd to basket

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.

« Hide

        10         20         30         40         50
MAAVDLEKLR ASGAGKAIGV LTSGGDAQGM NAAVRAVTRM GIYVGAKVFL
60 70 80 90 100
IYEGYEGLVE GGENIKQANW LSVSNIIQLG GTIIGSARCK AFTTREGRRA
110 120 130 140 150
AAYNLVQHGI TNLCVIGGDG SLTGANIFRS EWGSLLEELV AEGKISETTA
160 170 180 190 200
RTYSHLNIAG LVGSIDNDFC GTDMTIGTDS ALHRIMEVID AITTTAQSHQ
210 220 230 240 250
RTFVLEVMGR HCGYLALVSA LASGADWLFI PEAPPEDGWE NFMCERLGET
260 270 280 290 300
RSRGSRLNII IIAEGAIDRN GKPISSSYVK DLVVQRLGFD TRVTVLGHVQ
310 320 330 340 350
RGGTPSAFDR ILSSKMGMEA VMALLEATPD TPACVVTLSG NQSVRLPLME
360 370 380 390 400
CVQMTKEVQK AMDDKRFDEA TQLRGGSFEN NWNIYKLLAH QKPPKEKSNF
410 420 430 440 450
SLAILNVGAP AAGMNAAVRS AVRTGISHGH TVYVVHDGFE GLAKGQVQEV
460 470 480 490 500
GWHDVAGWLG RGGSMLGTKR TLPKGQLESI VENIRIYGIH ALLVVGGFEA
510 520 530 540 550
YEGVLQLVEA RGRYEELCIV MCVIPATISN NVPGTDFSLG SDTAVNAAME
560 570 580 590 600
SCDRIKQSAS GTKRRVFIVE TMGGYCGYLA TVTGIAVGAD AAYVFEDPFN
610 620 630 640 650
IHDLKVNVEH MTEKMKTDIQ RGLVLRNEKC HDYYTTEFLY NLYSSEGKGV
660 670 680 690 700
FDCRTNVLGH LQQGGAPTPF DRNYGTKLGV KAMLWLSEKL REVYRKGRVF
710 720 730 740 750
ANAPDSACVI GLKKKAVAFS PVTELKKDTD FEHRMPREQW WLSLRLMLKM
760 770 780
LAQYRISMAA YVSGELEHVT RRTLSMDKGF
Length:780
Mass (Da):85,018
Last modified:March 6, 2007 - v6
Checksum:i0D686CE074E9626D
GO
Isoform 2 (identifier: P17858-2) [UniParc]FASTAAdd to basket
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.
Show »
Length:827
Mass (Da):90,203
Checksum:iADBECCB9B1FB234C
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti27A → R in CAA33597 (PubMed:2533063).Curated1
Sequence conflicti27A → R in CAB46744 (PubMed:2139864).Curated1
Sequence conflicti86S → T in CAB46744 (PubMed:2139864).Curated1
Sequence conflicti89C → S in CAA33597 (PubMed:2533063).Curated1
Sequence conflicti89C → S in CAB46744 (PubMed:2139864).Curated1
Sequence conflicti103Y → N in CAB46744 (PubMed:2139864).Curated1
Sequence conflicti236E → EAPPE in CAB46744 (PubMed:2139864).Curated1
Sequence conflicti386K → R in CAB46744 (PubMed:2139864).Curated1
Sequence conflicti389A → T in CAA33597 (PubMed:2533063).Curated1
Sequence conflicti389A → T in CAB46744 (PubMed:2139864).Curated1
Sequence conflicti648K → N in AAH08964 (PubMed:15489334).Curated1
Sequence conflicti648K → N in AAH09919 (PubMed:15489334).Curated1
Sequence conflicti717V → A in AAH08964 (PubMed:15489334).Curated1
Sequence conflicti717V → A in AAH09919 (PubMed:15489334).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_00607081G → A1 Publication1
Natural variantiVAR_006071151R → W1 PublicationCorresponds to variant dbSNP:rs755851304Ensembl.1
Natural variantiVAR_030872237D → V. Corresponds to variant dbSNP:rs1057037EnsemblClinVar.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0118541 – 28MAAVD…GGDAQ → MCNQGRGRESSRGGLHVQGS CRGLSRSPQQETGFAKAPAG TDCFFHCSPGSRGQGDRKEE VTSEPGGTSIMSRLG in isoform 2. 1 PublicationAdd BLAST28

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
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
CCDSiCCDS33582.1 [P17858-1]
PIRiA33639
RefSeqiNP_001002021.2, NM_001002021.2
NP_002617.3, NM_002626.5 [P17858-1]
UniGeneiHs.255093

Genome annotation databases

EnsembliENST00000349048; ENSP00000269848; ENSG00000141959 [P17858-1]
GeneIDi5211
KEGGihsa:5211
UCSCiuc002zel.4 human [P17858-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Entry informationi

Entry nameiPFKAL_HUMAN
AccessioniPrimary (citable) accession number: P17858
Secondary accession number(s): Q96A64, Q96IH4, Q9BR91
Entry historyiIntegrated into UniProtKB/Swiss-Prot: August 1, 1990
Last sequence update: March 6, 2007
Last modified: July 18, 2018
This is version 215 of the entry and version 6 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny 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.

Miscellaneousi

Keywords - Technical termi

Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. Human chromosome 21
    Human chromosome 21: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PATHWAY comments
    Index of metabolic and biosynthesis pathways
  6. SIMILARITY comments
    Index of protein domains and families

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