F263_HUMAN
ID F263_HUMAN Reviewed; 520 AA.
AC Q16875; B7Z955; O43622; O75902; Q5VX15; Q5VX18; Q5VX19;
DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1996, sequence version 1.
DT 03-AUG-2022, entry version 211.
DE RecName: Full=6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3;
DE Short=6PF-2-K/Fru-2,6-P2ase 3;
DE Short=PFK/FBPase 3;
DE AltName: Full=6PF-2-K/Fru-2,6-P2ase brain/placenta-type isozyme;
DE AltName: Full=Renal carcinoma antigen NY-REN-56;
DE AltName: Full=iPFK-2;
DE Includes:
DE RecName: Full=6-phosphofructo-2-kinase;
DE EC=2.7.1.105 {ECO:0000269|PubMed:10077634, ECO:0000269|PubMed:17499765, ECO:0000305|PubMed:16316985, ECO:0000305|PubMed:22275052};
DE Includes:
DE RecName: Full=Fructose-2,6-bisphosphatase;
DE EC=3.1.3.46 {ECO:0000305|PubMed:16316985, ECO:0000305|PubMed:17499765, ECO:0000305|PubMed:22275052};
GN Name=PFKFB3;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Placenta;
RX PubMed=8830046; DOI=10.1093/oxfordjournals.jbchem.a021270;
RA Sakai A., Kato M., Fukasawa M., Ishiguro M., Furuya E., Sakakibara R.;
RT "Cloning of cDNA encoding for a novel isozyme of fructose 6-phosphate, 2-
RT kinase/fructose 2,6-bisphosphatase from human placenta.";
RL J. Biochem. 119:506-511(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=9146922; DOI=10.1023/a:1018482511456;
RA Nicholl J., Hamilton J.A., Sutherland G.R., Sutherland R.L., Watts C.K.;
RT "The third human isoform of 6-phosphofructo-2-kinase/fructose-2,6-
RT bisphosphatase (PFKFB3) map position 10p14-p15.";
RL Chromosome Res. 5:150-150(1997).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Brain;
RX PubMed=10072580; DOI=10.1159/000015181;
RA Manzano A., Rosa J.L., Ventura F., Perez J.X., Nadal M., Estivill X.,
RA Ambrosio S., Gil J., Bartrons R.;
RT "Molecular cloning, expression, and chromosomal localization of a
RT ubiquitously expressed human 6-phosphofructo-2-kinase/ fructose-2, 6-
RT bisphosphatase gene (PFKFB3).";
RL Cytogenet. Cell Genet. 83:214-217(1998).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 1).
RC TISSUE=Brain;
RA El-Maghrabi M.R.;
RT "Human brain 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase.";
RL Submitted (JAN-1998) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), FUNCTION, AND CATALYTIC ACTIVITY.
RC TISSUE=Skeletal muscle;
RX PubMed=10077634; DOI=10.1073/pnas.96.6.3047;
RA Chesney J., Mitchell R.A., Benigni F., Bacher M., Spiegel L., Al-Abed Y.,
RA Han J.H., Metz C., Bucala R.;
RT "An inducible gene product for 6-phosphofructo-2-kinase with an AU-rich
RT instability element: role in tumor cell glycolysis and the Warburg
RT effect.";
RL Proc. Natl. Acad. Sci. U.S.A. 96:3047-3052(1999).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 4).
RC TISSUE=Trachea;
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., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., 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., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA 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 [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164054; DOI=10.1038/nature02462;
RA Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L.,
RA Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K.,
RA Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L.,
RA Taylor A., Battles J., Bird C.P., Ainscough R., Almeida J.P.,
RA Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J.,
RA Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J., Brown J.Y.,
RA Burford D.C., Burrill W., Burton J., Cahill P., Camire D., Carter N.P.,
RA Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., Corby N.,
RA Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., Frankish A.,
RA Frankland J.A., Garner P., Garnett J., Gribble S., Griffiths C.,
RA Grocock R., Gustafson E., Hammond S., Harley J.L., Hart E., Heath P.D.,
RA Ho T.P., Hopkins B., Horne J., Howden P.J., Huckle E., Hynds C.,
RA Johnson C., Johnson D., Kana A., Kay M., Kimberley A.M., Kershaw J.K.,
RA Kokkinaki M., Laird G.K., Lawlor S., Lee H.M., Leongamornlert D.A.,
RA Laird G., Lloyd C., Lloyd D.M., Loveland J., Lovell J., McLaren S.,
RA McLay K.E., McMurray A., Mashreghi-Mohammadi M., Matthews L., Milne S.,
RA Nickerson T., Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V.,
RA Peck A.I., Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A.,
RA Ross M.T., Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M.,
RA Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., Tracey A.,
RA Tromans A., Tsolas J., Wall M., Walsh J., Wang H., Weinstock K., West A.P.,
RA Willey D.L., Whitehead S.L., Wilming L., Wray P.W., Young L., Chen Y.,
RA Lovering R.C., Moschonas N.K., Siebert R., Fechtel K., Bentley D.,
RA Durbin R.M., Hubbard T., Doucette-Stamm L., Beck S., Smith D.R., Rogers J.;
RT "The DNA sequence and comparative analysis of human chromosome 10.";
RL Nature 429:375-381(2004).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Testis;
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 project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [10]
RP IDENTIFICATION AS A RENAL CANCER ANTIGEN.
RC TISSUE=Renal cell carcinoma;
RX PubMed=10508479;
RX DOI=10.1002/(sici)1097-0215(19991112)83:4<456::aid-ijc4>3.0.co;2-5;
RA Scanlan M.J., Gordan J.D., Williamson B., Stockert E., Bander N.H.,
RA Jongeneel C.V., Gure A.O., Jaeger D., Jaeger E., Knuth A., Chen Y.-T.,
RA Old L.J.;
RT "Antigens recognized by autologous antibody in patients with renal-cell
RT carcinoma.";
RL Int. J. Cancer 83:456-464(1999).
RN [11]
RP PHOSPHORYLATION AT SER-461.
RX PubMed=12065600; DOI=10.1074/jbc.m205213200;
RA Marsin A.S., Bouzin C., Bertrand L., Hue L.;
RT "The stimulation of glycolysis by hypoxia in activated monocytes is
RT mediated by AMP-activated protein kinase and inducible 6-phosphofructo-2-
RT kinase.";
RL J. Biol. Chem. 277:30778-30783(2002).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-461; THR-463 AND SER-467, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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 [13]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-461 AND SER-467, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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 [14]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-461 AND SER-467, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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., Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full phosphorylation
RT site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [15]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-461, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma, and Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [16]
RP X-RAY CRYSTALLOGRAPHY (2.10 ANGSTROMS) IN COMPLEX WITH ADP AND FRUCTOSE
RP 6-PHOSPHATE, SUBUNIT, FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=16316985; DOI=10.1074/jbc.m511019200;
RA Kim S.G., Manes N.P., El-Maghrabi M.R., Lee Y.H.;
RT "Crystal structure of the hypoxia-inducible form of 6-phosphofructo-2-
RT kinase/fructose-2,6-bisphosphatase (PFKFB3): a possible new target for
RT cancer therapy.";
RL J. Biol. Chem. 281:2939-2944(2006).
RN [17]
RP X-RAY CRYSTALLOGRAPHY (2.25 ANGSTROMS) IN COMPLEXES WITH ADP; ATP; FRUCTOSE
RP 6-PHOSPHATE; FRUCTOSE-2,6-BISPHOSPHATE AND PHOSPHOENOLPYRUVATE, FUNCTION,
RP CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, AND MUTAGENESIS OF
RP ALA-45 AND LYS-169.
RX PubMed=17499765; DOI=10.1016/j.jmb.2007.03.038;
RA Kim S.G., Cavalier M., El-Maghrabi M.R., Lee Y.H.;
RT "A direct substrate-substrate interaction found in the kinase domain of the
RT bifunctional enzyme, 6-phosphofructo-2-kinase/fructose-2,6-
RT bisphosphatase.";
RL J. Mol. Biol. 370:14-26(2007).
RN [18]
RP X-RAY CRYSTALLOGRAPHY (2.25 ANGSTROMS), ACTIVE SITE, FUNCTION, AND
RP CATALYTIC ACTIVITY.
RX PubMed=22275052; DOI=10.1002/prot.24015;
RA Cavalier M.C., Kim S.G., Neau D., Lee Y.H.;
RT "Molecular basis of the fructose-2,6-bisphosphatase reaction of PFKFB3:
RT transition state and the C-terminal function.";
RL Proteins 80:1143-1153(2012).
RN [19]
RP X-RAY CRYSTALLOGRAPHY (2.03 ANGSTROMS) IN COMPLEX WITH
RP FRUCTOSE-2,6-BISPHOSPHATE.
RX PubMed=25849762; DOI=10.1021/acs.jmedchem.5b00352;
RA Boyd S., Brookfield J.L., Critchlow S.E., Cumming I.A., Curtis N.J.,
RA Debreczeni J., Degorce S.L., Donald C., Evans N.J., Groombridge S.,
RA Hopcroft P., Jones N.P., Kettle J.G., Lamont S., Lewis H.J., MacFaull P.,
RA McLoughlin S.B., Rigoreau L.J., Smith J.M., St-Gallay S., Stock J.K.,
RA Turnbull A.P., Wheatley E.R., Winter J., Wingfield J.;
RT "Structure-based design of potent and selective inhibitors of the metabolic
RT kinase PFKFB3.";
RL J. Med. Chem. 58:3611-3625(2015).
CC -!- FUNCTION: Catalyzes both the synthesis and degradation of fructose 2,6-
CC bisphosphate. {ECO:0000269|PubMed:10077634,
CC ECO:0000269|PubMed:17499765, ECO:0000305|PubMed:16316985}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=beta-D-fructose 2,6-bisphosphate + H2O = beta-D-fructose 6-
CC phosphate + phosphate; Xref=Rhea:RHEA:17289, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:43474, ChEBI:CHEBI:57634, ChEBI:CHEBI:58579; EC=3.1.3.46;
CC Evidence={ECO:0000305|PubMed:16316985, ECO:0000305|PubMed:17499765,
CC ECO:0000305|PubMed:22275052};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:17290;
CC Evidence={ECO:0000305|PubMed:16316985};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + beta-D-fructose 6-phosphate = ADP + beta-D-fructose 2,6-
CC bisphosphate + H(+); Xref=Rhea:RHEA:15653, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:57634, ChEBI:CHEBI:58579,
CC ChEBI:CHEBI:456216; EC=2.7.1.105;
CC Evidence={ECO:0000269|PubMed:10077634, ECO:0000269|PubMed:17499765,
CC ECO:0000305|PubMed:16316985};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:15654;
CC Evidence={ECO:0000305|PubMed:10077634};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=10.2 uM for fructose 6-phosphate {ECO:0000269|PubMed:17499765};
CC KM=16.9 uM for ATP {ECO:0000269|PubMed:17499765};
CC -!- SUBUNIT: Homodimer. {ECO:0000269|PubMed:16316985}.
CC -!- INTERACTION:
CC Q16875; P16118: PFKFB1; NbExp=3; IntAct=EBI-764464, EBI-709807;
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=1;
CC IsoId=Q16875-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q16875-2; Sequence=VSP_004680;
CC Name=3;
CC IsoId=Q16875-3; Sequence=VSP_047165;
CC Name=4;
CC IsoId=Q16875-4; Sequence=VSP_054549;
CC -!- TISSUE SPECIFICITY: Ubiquitous.
CC -!- PTM: Phosphorylation by AMPK stimulates activity.
CC {ECO:0000269|PubMed:12065600}.
CC -!- SIMILARITY: In the C-terminal section; belongs to the phosphoglycerate
CC mutase family. {ECO:0000305}.
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DR EMBL; D49817; BAA08624.1; -; mRNA.
DR EMBL; L77662; AAL40083.1; -; mRNA.
DR EMBL; AF109735; AAD08818.1; -; mRNA.
DR EMBL; AF041831; AAB99795.1; -; Genomic_DNA.
DR EMBL; AF041823; AAB99795.1; JOINED; Genomic_DNA.
DR EMBL; AF041824; AAB99795.1; JOINED; Genomic_DNA.
DR EMBL; AF041825; AAB99795.1; JOINED; Genomic_DNA.
DR EMBL; AF041826; AAB99795.1; JOINED; Genomic_DNA.
DR EMBL; AF041827; AAB99795.1; JOINED; Genomic_DNA.
DR EMBL; AF041828; AAB99795.1; JOINED; Genomic_DNA.
DR EMBL; AF041829; AAB99795.1; JOINED; Genomic_DNA.
DR EMBL; AF041830; AAB99795.1; JOINED; Genomic_DNA.
DR EMBL; AF056320; AAC62000.1; -; mRNA.
DR EMBL; AK291263; BAF83952.1; -; mRNA.
DR EMBL; AK304450; BAH14191.1; -; mRNA.
DR EMBL; AL359960; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL157395; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471072; EAW86398.1; -; Genomic_DNA.
DR EMBL; CH471072; EAW86399.1; -; Genomic_DNA.
DR EMBL; BC040482; AAH40482.1; -; mRNA.
DR CCDS; CCDS44353.1; -. [Q16875-3]
DR CCDS; CCDS60479.1; -. [Q16875-4]
DR CCDS; CCDS7078.1; -. [Q16875-1]
DR CCDS; CCDS81439.1; -. [Q16875-2]
DR PIR; JC4626; JC4626.
DR RefSeq; NP_001269559.1; NM_001282630.2. [Q16875-4]
DR RefSeq; NP_001300992.1; NM_001314063.1. [Q16875-2]
DR RefSeq; NP_004557.1; NM_004566.3. [Q16875-1]
DR PDB; 2AXN; X-ray; 2.10 A; A=1-520.
DR PDB; 2DWO; X-ray; 2.25 A; A=1-520.
DR PDB; 2DWP; X-ray; 2.70 A; A=1-520.
DR PDB; 2I1V; X-ray; 2.50 A; B=1-520.
DR PDB; 3QPU; X-ray; 2.30 A; A=1-520.
DR PDB; 3QPV; X-ray; 2.50 A; A=1-520.
DR PDB; 3QPW; X-ray; 2.25 A; A=1-520.
DR PDB; 4D4J; X-ray; 3.00 A; A=1-449.
DR PDB; 4D4K; X-ray; 3.24 A; A=1-449.
DR PDB; 4D4L; X-ray; 3.16 A; A=1-449.
DR PDB; 4D4M; X-ray; 2.32 A; A=1-449.
DR PDB; 4MA4; X-ray; 2.23 A; A=1-520.
DR PDB; 5AJV; X-ray; 3.01 A; B=1-520.
DR PDB; 5AJW; X-ray; 2.50 A; A=1-520.
DR PDB; 5AJX; X-ray; 2.58 A; A=1-520.
DR PDB; 5AJY; X-ray; 2.37 A; A=1-520.
DR PDB; 5AJZ; X-ray; 2.35 A; A=1-520.
DR PDB; 5AK0; X-ray; 2.03 A; A=1-520.
DR PDB; 6ETJ; X-ray; 2.51 A; A=1-520.
DR PDB; 6HVH; X-ray; 2.36 A; A=1-520.
DR PDB; 6HVI; X-ray; 1.96 A; A=1-520.
DR PDB; 6HVJ; X-ray; 2.28 A; A=1-520.
DR PDB; 6IBX; X-ray; 2.11 A; A=4-447.
DR PDB; 6IBY; X-ray; 2.51 A; A=4-447.
DR PDB; 6IBZ; X-ray; 2.44 A; A=4-447.
DR PDB; 6IC0; X-ray; 2.60 A; A=4-446.
DR PDBsum; 2AXN; -.
DR PDBsum; 2DWO; -.
DR PDBsum; 2DWP; -.
DR PDBsum; 2I1V; -.
DR PDBsum; 3QPU; -.
DR PDBsum; 3QPV; -.
DR PDBsum; 3QPW; -.
DR PDBsum; 4D4J; -.
DR PDBsum; 4D4K; -.
DR PDBsum; 4D4L; -.
DR PDBsum; 4D4M; -.
DR PDBsum; 4MA4; -.
DR PDBsum; 5AJV; -.
DR PDBsum; 5AJW; -.
DR PDBsum; 5AJX; -.
DR PDBsum; 5AJY; -.
DR PDBsum; 5AJZ; -.
DR PDBsum; 5AK0; -.
DR PDBsum; 6ETJ; -.
DR PDBsum; 6HVH; -.
DR PDBsum; 6HVI; -.
DR PDBsum; 6HVJ; -.
DR PDBsum; 6IBX; -.
DR PDBsum; 6IBY; -.
DR PDBsum; 6IBZ; -.
DR PDBsum; 6IC0; -.
DR AlphaFoldDB; Q16875; -.
DR SMR; Q16875; -.
DR BioGRID; 111230; 54.
DR ComplexPortal; CPX-1995; 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 complex.
DR DIP; DIP-33964N; -.
DR IntAct; Q16875; 28.
DR MINT; Q16875; -.
DR STRING; 9606.ENSP00000443319; -.
DR BindingDB; Q16875; -.
DR ChEMBL; CHEMBL2331053; -.
DR GuidetoPHARMACOLOGY; 2937; -.
DR DEPOD; PFKFB3; -.
DR GlyGen; Q16875; 2 sites, 1 O-linked glycan (2 sites).
DR iPTMnet; Q16875; -.
DR PhosphoSitePlus; Q16875; -.
DR BioMuta; PFKFB3; -.
DR DMDM; 3023733; -.
DR EPD; Q16875; -.
DR jPOST; Q16875; -.
DR MassIVE; Q16875; -.
DR MaxQB; Q16875; -.
DR PaxDb; Q16875; -.
DR PeptideAtlas; Q16875; -.
DR PRIDE; Q16875; -.
DR ProteomicsDB; 61114; -. [Q16875-1]
DR ProteomicsDB; 61115; -. [Q16875-2]
DR ProteomicsDB; 65570; -.
DR ProteomicsDB; 7006; -.
DR Antibodypedia; 10861; 346 antibodies from 38 providers.
DR DNASU; 5209; -.
DR Ensembl; ENST00000360521.7; ENSP00000353712.2; ENSG00000170525.21. [Q16875-2]
DR Ensembl; ENST00000379775.9; ENSP00000369100.4; ENSG00000170525.21. [Q16875-1]
DR Ensembl; ENST00000379789.8; ENSP00000369115.4; ENSG00000170525.21. [Q16875-3]
DR Ensembl; ENST00000536985.6; ENSP00000443319.2; ENSG00000170525.21. [Q16875-4]
DR GeneID; 5209; -.
DR KEGG; hsa:5209; -.
DR MANE-Select; ENST00000379775.9; ENSP00000369100.4; NM_004566.4; NP_004557.1.
DR UCSC; uc001ijd.4; human. [Q16875-1]
DR CTD; 5209; -.
DR DisGeNET; 5209; -.
DR GeneCards; PFKFB3; -.
DR HGNC; HGNC:8874; PFKFB3.
DR HPA; ENSG00000170525; Tissue enhanced (adipose tissue, skeletal muscle).
DR MIM; 605319; gene.
DR neXtProt; NX_Q16875; -.
DR OpenTargets; ENSG00000170525; -.
DR PharmGKB; PA33213; -.
DR VEuPathDB; HostDB:ENSG00000170525; -.
DR eggNOG; KOG0234; Eukaryota.
DR GeneTree; ENSGT00950000182835; -.
DR InParanoid; Q16875; -.
DR OMA; AEDTRIC; -.
DR OrthoDB; 392001at2759; -.
DR PhylomeDB; Q16875; -.
DR TreeFam; TF313541; -.
DR BioCyc; MetaCyc:HS10144-MON; -.
DR BRENDA; 2.7.1.105; 2681.
DR BRENDA; 3.1.3.46; 2681.
DR PathwayCommons; Q16875; -.
DR Reactome; R-HSA-9634600; Regulation of glycolysis by fructose 2,6-bisphosphate metabolism.
DR SABIO-RK; Q16875; -.
DR SignaLink; Q16875; -.
DR SIGNOR; Q16875; -.
DR BioGRID-ORCS; 5209; 13 hits in 1085 CRISPR screens.
DR ChiTaRS; PFKFB3; human.
DR EvolutionaryTrace; Q16875; -.
DR GeneWiki; PFKFB3; -.
DR GenomeRNAi; 5209; -.
DR Pharos; Q16875; Tchem.
DR PRO; PR:Q16875; -.
DR Proteomes; UP000005640; Chromosome 10.
DR RNAct; Q16875; protein.
DR Bgee; ENSG00000170525; Expressed in pancreatic ductal cell and 192 other tissues.
DR ExpressionAtlas; Q16875; baseline and differential.
DR Genevisible; Q16875; HS.
DR GO; GO:0005829; C:cytosol; IBA:GO_Central.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0003873; F:6-phosphofructo-2-kinase activity; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0004331; F:fructose-2,6-bisphosphate 2-phosphatase activity; IBA:GO_Central.
DR GO; GO:0007420; P:brain development; IEA:Ensembl.
DR GO; GO:0006003; P:fructose 2,6-bisphosphate metabolic process; IBA:GO_Central.
DR GO; GO:0006000; P:fructose metabolic process; IEA:InterPro.
DR CDD; cd07067; HP_PGM_like; 1.
DR Gene3D; 3.40.50.1240; -; 1.
DR Gene3D; 3.40.50.300; -; 1.
DR InterPro; IPR003094; 6Pfruct_kin.
DR InterPro; IPR013079; 6Phosfructo_kin.
DR InterPro; IPR013078; His_Pase_superF_clade-1.
DR InterPro; IPR029033; His_PPase_superfam.
DR InterPro; IPR027417; P-loop_NTPase.
DR InterPro; IPR001345; PG/BPGM_mutase_AS.
DR PANTHER; PTHR10606; PTHR10606; 1.
DR Pfam; PF01591; 6PF2K; 1.
DR Pfam; PF00300; His_Phos_1; 1.
DR PRINTS; PR00991; 6PFRUCTKNASE.
DR SMART; SM00855; PGAM; 1.
DR SUPFAM; SSF52540; SSF52540; 1.
DR SUPFAM; SSF53254; SSF53254; 1.
DR PROSITE; PS00175; PG_MUTASE; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; ATP-binding; Hydrolase; Kinase;
KW Multifunctional enzyme; Nucleotide-binding; Phosphoprotein;
KW Reference proteome; Transferase.
FT CHAIN 1..520
FT /note="6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase
FT 3"
FT /id="PRO_0000179968"
FT REGION 1..245
FT /note="6-phosphofructo-2-kinase"
FT REGION 246..520
FT /note="Fructose-2,6-bisphosphatase"
FT REGION 443..520
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 125
FT /evidence="ECO:0000255"
FT ACT_SITE 155
FT /evidence="ECO:0000255"
FT ACT_SITE 254
FT /note="Tele-phosphohistidine intermediate"
FT /evidence="ECO:0000269|PubMed:22275052"
FT ACT_SITE 323
FT /note="Proton donor/acceptor"
FT /evidence="ECO:0000269|PubMed:22275052"
FT BINDING 42..50
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:16316985,
FT ECO:0000269|PubMed:17499765, ECO:0000269|PubMed:22275052"
FT BINDING 75
FT /ligand="beta-D-fructose 6-phosphate"
FT /ligand_id="ChEBI:CHEBI:57634"
FT /evidence="ECO:0000269|PubMed:16316985"
FT BINDING 99
FT /ligand="beta-D-fructose 6-phosphate"
FT /ligand_id="ChEBI:CHEBI:57634"
FT /evidence="ECO:0000269|PubMed:16316985"
FT BINDING 127
FT /ligand="beta-D-fructose 6-phosphate"
FT /ligand_id="ChEBI:CHEBI:57634"
FT /evidence="ECO:0000269|PubMed:16316985"
FT BINDING 133
FT /ligand="beta-D-fructose 6-phosphate"
FT /ligand_id="ChEBI:CHEBI:57634"
FT /evidence="ECO:0000269|PubMed:16316985"
FT BINDING 164..169
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:16316985,
FT ECO:0000269|PubMed:17499765, ECO:0000269|PubMed:22275052"
FT BINDING 169
FT /ligand="beta-D-fructose 6-phosphate"
FT /ligand_id="ChEBI:CHEBI:57634"
FT /evidence="ECO:0000269|PubMed:16316985"
FT BINDING 190
FT /ligand="beta-D-fructose 6-phosphate"
FT /ligand_id="ChEBI:CHEBI:57634"
FT /evidence="ECO:0000269|PubMed:16316985"
FT BINDING 194
FT /ligand="beta-D-fructose 6-phosphate"
FT /ligand_id="ChEBI:CHEBI:57634"
FT /evidence="ECO:0000269|PubMed:16316985"
FT BINDING 253
FT /ligand="beta-D-fructose 2,6-bisphosphate"
FT /ligand_id="ChEBI:CHEBI:58579"
FT /evidence="ECO:0000269|PubMed:25849762"
FT BINDING 260
FT /ligand="beta-D-fructose 2,6-bisphosphate"
FT /ligand_id="ChEBI:CHEBI:58579"
FT /evidence="ECO:0000269|PubMed:25849762"
FT BINDING 266
FT /ligand="beta-D-fructose 2,6-bisphosphate"
FT /ligand_id="ChEBI:CHEBI:58579"
FT /evidence="ECO:0000269|PubMed:25849762"
FT BINDING 334
FT /ligand="beta-D-fructose 2,6-bisphosphate"
FT /ligand_id="ChEBI:CHEBI:58579"
FT /evidence="ECO:0000269|PubMed:25849762"
FT BINDING 345..348
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P07953"
FT BINDING 348
FT /ligand="beta-D-fructose 2,6-bisphosphate"
FT /ligand_id="ChEBI:CHEBI:58579"
FT /evidence="ECO:0000269|PubMed:25849762"
FT BINDING 352
FT /ligand="beta-D-fructose 2,6-bisphosphate"
FT /ligand_id="ChEBI:CHEBI:58579"
FT /evidence="ECO:0000269|PubMed:25849762"
FT BINDING 363
FT /ligand="beta-D-fructose 2,6-bisphosphate"
FT /ligand_id="ChEBI:CHEBI:58579"
FT /evidence="ECO:0000269|PubMed:25849762"
FT BINDING 389..393
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P07953"
FT BINDING 389
FT /ligand="beta-D-fructose 2,6-bisphosphate"
FT /ligand_id="ChEBI:CHEBI:58579"
FT /evidence="ECO:0000269|PubMed:25849762"
FT BINDING 393
FT /ligand="beta-D-fructose 2,6-bisphosphate"
FT /ligand_id="ChEBI:CHEBI:58579"
FT /evidence="ECO:0000250|UniProtKB:P07953"
FT BINDING 425
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:16316985,
FT ECO:0000269|PubMed:17499765, ECO:0000269|PubMed:22275052"
FT SITE 253
FT /note="Transition state stabilizer"
FT /evidence="ECO:0000269|PubMed:22275052"
FT SITE 260
FT /note="Transition state stabilizer"
FT /evidence="ECO:0000269|PubMed:22275052"
FT SITE 388
FT /note="Transition state stabilizer"
FT /evidence="ECO:0000269|PubMed:22275052"
FT MOD_RES 461
FT /note="Phosphoserine; by AMPK"
FT /evidence="ECO:0000269|PubMed:12065600,
FT ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:19690332,
FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:23186163"
FT MOD_RES 463
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:18669648"
FT MOD_RES 467
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:20068231"
FT MOD_RES 471
FT /note="Phosphothreonine; by PKC"
FT /evidence="ECO:0000250"
FT VAR_SEQ 1..26
FT /note="MPLELTQSRVQKIWVPVDHRPSLPRS -> MPFRKA (in isoform 3)"
FT /evidence="ECO:0000305"
FT /id="VSP_047165"
FT VAR_SEQ 1..26
FT /note="MPLELTQSRVQKIWVPVDHRPSLPRS -> MGEGGQKEGDSQQAGALPLLCQ
FT LDTFSPKATVFGVSINPA (in isoform 4)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_054549"
FT VAR_SEQ 506..520
FT /note="NMKGSRSSADSSRKH -> PLLGQACLT (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:10077634"
FT /id="VSP_004680"
FT MUTAGEN 45
FT /note="A->G: 20-fold decrease in Km for ATP and 3-fold
FT decrease in Km for fructose-6 phsphate."
FT /evidence="ECO:0000269|PubMed:17499765"
FT MUTAGEN 169
FT /note="K->R,A,N: Loss of activity."
FT /evidence="ECO:0000269|PubMed:17499765"
FT CONFLICT 136
FT /note="M -> V (in Ref. 4; AAB99795)"
FT /evidence="ECO:0000305"
FT CONFLICT 141
FT /note="A -> G (in Ref. 5; AAC62000)"
FT /evidence="ECO:0000305"
FT STRAND 5..7
FT /evidence="ECO:0007829|PDB:6HVI"
FT TURN 9..11
FT /evidence="ECO:0007829|PDB:6HVI"
FT STRAND 14..16
FT /evidence="ECO:0007829|PDB:6HVI"
FT STRAND 36..41
FT /evidence="ECO:0007829|PDB:6HVI"
FT STRAND 43..47
FT /evidence="ECO:0007829|PDB:6IBZ"
FT HELIX 48..61
FT /evidence="ECO:0007829|PDB:6HVI"
FT STRAND 66..70
FT /evidence="ECO:0007829|PDB:6HVI"
FT HELIX 71..78
FT /evidence="ECO:0007829|PDB:6HVI"
FT STRAND 79..81
FT /evidence="ECO:0007829|PDB:4D4M"
FT HELIX 85..88
FT /evidence="ECO:0007829|PDB:6HVI"
FT HELIX 93..116
FT /evidence="ECO:0007829|PDB:6HVI"
FT STRAND 120..126
FT /evidence="ECO:0007829|PDB:6HVI"
FT HELIX 131..143
FT /evidence="ECO:0007829|PDB:6HVI"
FT STRAND 147..154
FT /evidence="ECO:0007829|PDB:6HVI"
FT HELIX 158..168
FT /evidence="ECO:0007829|PDB:6HVI"
FT TURN 169..171
FT /evidence="ECO:0007829|PDB:6HVI"
FT HELIX 173..175
FT /evidence="ECO:0007829|PDB:6HVI"
FT STRAND 176..178
FT /evidence="ECO:0007829|PDB:6HVJ"
FT HELIX 180..195
FT /evidence="ECO:0007829|PDB:6HVI"
FT TURN 203..209
FT /evidence="ECO:0007829|PDB:6HVI"
FT STRAND 212..216
FT /evidence="ECO:0007829|PDB:6HVI"
FT TURN 217..220
FT /evidence="ECO:0007829|PDB:6HVI"
FT STRAND 221..225
FT /evidence="ECO:0007829|PDB:6HVI"
FT HELIX 230..241
FT /evidence="ECO:0007829|PDB:6HVI"
FT STRAND 249..253
FT /evidence="ECO:0007829|PDB:6HVI"
FT HELIX 258..261
FT /evidence="ECO:0007829|PDB:6HVI"
FT HELIX 273..289
FT /evidence="ECO:0007829|PDB:6HVI"
FT STRAND 295..298
FT /evidence="ECO:0007829|PDB:6HVI"
FT HELIX 302..309
FT /evidence="ECO:0007829|PDB:6HVI"
FT TURN 310..312
FT /evidence="ECO:0007829|PDB:6HVI"
FT STRAND 315..317
FT /evidence="ECO:0007829|PDB:2AXN"
FT HELIX 319..321
FT /evidence="ECO:0007829|PDB:6HVI"
FT HELIX 327..329
FT /evidence="ECO:0007829|PDB:6HVI"
FT HELIX 334..340
FT /evidence="ECO:0007829|PDB:6HVI"
FT HELIX 342..350
FT /evidence="ECO:0007829|PDB:6HVI"
FT TURN 352..354
FT /evidence="ECO:0007829|PDB:6HVI"
FT HELIX 363..379
FT /evidence="ECO:0007829|PDB:6HVI"
FT STRAND 381..387
FT /evidence="ECO:0007829|PDB:6HVI"
FT HELIX 389..400
FT /evidence="ECO:0007829|PDB:6HVI"
FT TURN 404..406
FT /evidence="ECO:0007829|PDB:6HVI"
FT HELIX 407..409
FT /evidence="ECO:0007829|PDB:6HVI"
FT STRAND 416..423
FT /evidence="ECO:0007829|PDB:6HVI"
FT STRAND 426..433
FT /evidence="ECO:0007829|PDB:6HVI"
FT HELIX 442..446
FT /evidence="ECO:0007829|PDB:3QPU"
FT HELIX 455..457
FT /evidence="ECO:0007829|PDB:2AXN"
SQ SEQUENCE 520 AA; 59609 MW; A7675A4ADC376879 CRC64;
MPLELTQSRV QKIWVPVDHR PSLPRSCGPK LTNSPTVIVM VGLPARGKTY ISKKLTRYLN
WIGVPTKVFN VGEYRREAVK QYSSYNFFRP DNEEAMKVRK QCALAALRDV KSYLAKEGGQ
IAVFDATNTT RERRHMILHF AKENDFKAFF IESVCDDPTV VASNIMEVKI SSPDYKDCNS
AEAMDDFMKR ISCYEASYQP LDPDKCDRDL SLIKVIDVGR RFLVNRVQDH IQSRIVYYLM
NIHVQPRTIY LCRHGENEHN LQGRIGGDSG LSSRGKKFAS ALSKFVEEQN LKDLRVWTSQ
LKSTIQTAEA LRLPYEQWKA LNEIDAGVCE ELTYEEIRDT YPEEYALREQ DKYYYRYPTG
ESYQDLVQRL EPVIMELERQ ENVLVICHQA VLRCLLAYFL DKSAEEMPYL KCPLHTVLKL
TPVAYGCRVE SIYLNVESVC THRERSEDAK KGPNPLMRRN SVTPLASPEP TKKPRINSFE
EHVASTSAAL PSCLPPEVPT QLPGQNMKGS RSSADSSRKH
