Close your eyes and imagine this: it’s a Friday night and you’re sitting back, relaxing, reading a good ol’ biochemistry journal. The sun is coming down, the air is fresh…it’s a beautiful night. And then you come across it—phosphofructokinase-2/fructose-2,6-bisphosphatase (PFK-2/FBPase). Phosphofructowhaaat? Who gives something such a long name! Maybe such a long name would make sense if you were in a Hispanic Literature course reading a book by someone with a name like Jose Manuel Antonio Gutierrez Ortiz; sure, then a long name makes sense. But for an enzyme?

But that’s what makes this enzyme so great; the bigger name means more enzymatic activities! As you may recall, fructose 2,6-bisphosphate (F26BP) is an activator of glycolysis. It increases the activity of the rate-limiting enzyme phosphofructokinase-1 (PFK1) by acting as an allosteric activator. So how is this enzyme special? It is able to regulate PFK1 all by itself because it’s bifunctional! If you’re anything like me—a “one-track-minded” kind of person—you can quickly appreciate this. Think about those times when you’re studying hard and someone sits down to ask you a question. Or when you are typing away at the computer for hours and all of a sudden your mom calls. It’s so hard to just up and switch activities.

Thankfully for us, however, this is no problem for our friend PFK-2/FBPase. With a quick phosphoylation, this enzyme can change activity. One minute the enzyme is functioning as a kinase, phosphorylating F6P to F26BP to increase glycolytic flux, and the next its acting as a bisphosphatase, removing phosphates from F26BP to decrease glycolytic flux.

Kinase Activity

Bifunctionality of PFK-2/FBPase

So at your next meal remember to say thank you to our long-named enzymatic helper phosphofructokinase-2/fructose-2,6-bisphosphatase . Because while you have the luxury of focusing on that big, juicy, well-marinated steak, this enzyme is ready to respond to your body’s glycolytic needs.

What This "Thing" Does

What does the bifunctional enzyme do?

Fructose 2,6-bisphosphate (F26BP) is an activator of glycolysis. This molecule increases the activity of the important rate-limiting enzyme phosphofructokinase-1 (PFK-1) by acting as an allosteric activator. The concentration of F26BP is directly linked to the activity of the unique bifunctional enzyme, more formally known as phosphofructokinase-2/fructose-2,6-bisphosphatase (PFK-2/FBPase), or PFKFB3. When the kinase activity is high, F26BP concentrations, and consequently glycolytic flux, increase. On the other hand, when the bisphosphatase activity is dominant, the concentration of F26BP decreases, removing the allosteric activator of PFK-1, and decreasing glycolytic flux (1,3). 

How is the bifunctional enzyme relevant and applicable?

Glycolysis is an important process for cellular growth and research of its regulation, including the important bifunctional enzyme, has gained much attention. Cancer cell growth is attributed to high glycolytic flux and may be directly related to the bifunctional enzyme. Better understanding this enzyme may open up the door to cancer understanding and treatment. Recent research has shown that the bifunctional enzyme is directly affected by hypoxic conditions, which is the typical environment for neoplastic cells. Hypoxia activates both the bifunctional enzyme itself and HIF-1 (a transcription factor), which upregulates the expression of the bifunctional enzyme (4). Therefore, hypoxia produces more of the bifunctional enzyme and increases the activity of these enzymes. This obviously permits cancer cells to grow more quickly and rapidly. Additionally, it has been shown that ethylenediaminetetraacetic (EDTA) binds to the kinase active site of the bifunctional enzyme with high affinity. By blocking this site, F26BP cannot be made, inhibiting its activating effects on glycolysis (2). In conclusion, research marks the bifunctional enzyme as a potential for the treatment of cancer tumors (either directly or through the inhibition of HIF-1) and provides EDTA as a promising starting molecule for this treatment.

Sources:

1. Bando H, Atsumi T, Nishio T, et al. Phosphorylation of the 6-Phosphofructo-2-Kinase/Fructose 2,6-Bisphosphatase/PFKFB3 Family of Glycolytic Regulators in Human Cancer. Clinical Cancer Research 2005; 11:5784-5792.
2. Kim S, Manes N, El-Maghrabi R, Lee Y. Crystal Structure of the Hypoxia-inducible Form of 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3). Journal of Biochemistry 2006; 281:2939-2944.
3. Chesney J. 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase and tumor cell glycolysis. Curr Opin Clin Nutr Metab Care 2006; 9(5):535-953.
4. Bartrons R, Caro J. Hypoxia, glucose metabolism and the Warburg's effect. J Bioenerg Biomembr, 2007; 39(3):223-229.

Enzyme Images

                                                        GO KNIGHTS!

                                                                      
*Prosthetic groups include ADP, Fructose 6-Phosphate and Fructose-2,6-Bisphosphate,

The Bifunctional Enzyme PFKFB3

The exact enzyme that I am working with is:

PDB Code: 2I1V

Name: Crystal structure of PFKFB3 in complex with ADP and Fructose-2,6-bisphosphate

This is my first post...ever

I've never blogged before.