Phosphatase Subfamily PFKFB

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Phosphatase Classification: Fold HP: Superfamily HP: HP, branch1 family: Subfamily PFKFB

PFKFB is a dual kinase and phosphatase that both phosphorylates and dephosphorylates fructose to fructose 2,6-bisphosphate (Fru-2,6-P2). Fru-2,6-P2 is an allosteric activator of the key glycolysis enzyme phosphofructokinase 1 (Pfk1), so PKFKB activities both activate and deactivate glycolysis.


PFKFB is found in most eukaryotic groups, and is thought to result from an early fusion of it's two enzymatic domains (6-phosphofructo-2-kinase (PFK-2) and fructose-2,6-bisphosphatase (FBPase-2). Two distinct genes encoding PFK-2 and FBPase-2, or related enzymes with broader substrate specificity, fused resulting in a bifunctional enzyme both domains of which had, or later acquired, specificity for fructose 2,6-bisphosphate [1, 2].

This enzyme is duplicated in many lineages, sometimes losing either kinase or phosphatase activity in the duplicates, and in some parasitic lineages, the gene is lost entirely [2]


PFKFB has two domains for its two functions [1, 2]:

  • The kinase PFK-2 domain for synthesis of Fru-2,6-P2, has an adenylate kinase fold, confirmed by crystal structure.
  • The phosphatase FBPase-2 domain for degradation of Fru-2,6-P2 is a HP1 domain.


PFKFB is a homodimeric bifunctional enzyme that catalyses both the synthesis and degradation of Fru-2,6-P2 (fructose 2,6-bisphosphate) during glycolysis [1, 2]. Fru-2,6-P2 is also the substrate of Subfamily TIGAR, another subfamily of HP1 phosphatases. The four human PFKFBs have slightly different gene expression across different tissues. PFKFB3 has an isoform-specific S-glutathionylation, which mediates its functions in regulating oxidative stress homeostasis [3].


  1. Rider MH, Bertrand L, Vertommen D, Michels PA, Rousseau GG, and Hue L. 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase: head-to-head with a bifunctional enzyme that controls glycolysis. Biochem J. 2004 Aug 1;381(Pt 3):561-79. DOI:10.1042/BJ20040752 | PubMed ID:15170386 | HubMed [rider04]
  2. Michels PA and Rigden DJ. Evolutionary analysis of fructose 2,6-bisphosphate metabolism. IUBMB Life. 2006 Mar;58(3):133-41. DOI:10.1080/15216540600688280 | PubMed ID:16766380 | HubMed [michel06]
  3. Seo M and Lee YH. PFKFB3 regulates oxidative stress homeostasis via its S-glutathionylation in cancer. J Mol Biol. 2014 Feb 20;426(4):830-42. DOI:10.1016/j.jmb.2013.11.021 | PubMed ID:24295899 | HubMed [Seo14]
All Medline abstracts: PubMed | HubMed