Phosphatase Subfamily PFKFB

Phosphatase Classification: Fold HP: Superfamily HP (histidine phosphatase): HP, branch1 family: Subfamily PFKFB

PFKFB stands for PFK-2 (6-phosphofructo-2-kinase)/ FBPase-2 (fructose-2,6-bisphosphatase), which catalyses both the synthesis and degradation of fructose 2,6-bisphosphate (Fru-2,6-P2). Fru-2,6-P2 is a signal molecule that controls glycolysis.

Evolution

PFKFB has two enzymatic domains responsible for the synthesis and hydrolysis, 6-phosphofructo-2-kinase (PFK-2) and fructose-2,6-bisphosphatase (FBPase-2). Both domains are present in all major eukaryotic groups. Phylogenetic analysis suggests that PFKFB emerged through gene fusion event that happened in a common ancestor of all extant eukaryotes. 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]

Domain

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.

Functions

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].

References

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 |
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 |
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 |