User:Abhinav2009/phosphofructokinase 1

Phosphofructokinase-1 (PFK-1) is one of the most important regulatory

. Glycolysis is the foundation for respiration, both anaerobic and aerobic. Because phosphofructokinase (PFK) catalyzes the ATP-dependent phosphorylation to convert fructose-6-phosphate into fructose 1,6-bisphosphate and ADP, it is one of the key regulatory and rate limiting step of glycolysis. PFK is able to regulate glycolysis through allosteric inhibition, and in this way, the cell can increase or decrease the rate of glycolysis in response to the cell’s energy requirements. For example high ratio of ATP to ADP will inhibit PFK and glycolysis. There is a key difference between the regulation of PFK in eukaryotes and prokaryotes is that in eukaryotes, PFK is activated by fructose-2,6-bisphospate. The purpose of fructose-2,6-bisphospate is to supersede ATP inhibition, thus allowing eukaryotes to have greater sensitivity to regulation by hormones like glucagon and insulin.

β-D-fructose 6-phosphate	{{{forward_enzyme}}}		β-D-fructose 1,6-bisphosphate
	{{{minor_forward_substrate(s)}}}	{{{minor_forward_product(s)}}}
	[[image:Biochem_reaction_arrow_{{{reaction_direction_(forward/reversible/reverse)}}}_NNYY_horiz_med.svg|75px]]
	Pi	H2O
	Fructose bisphosphatase

Structure

Mammalian PFK1 is a 340kd

PFK1 is an allosteric enzyme and has a structure similar to that of hemoglobin insofar as it is a dimer of a dimer.^[3] One half of each dimer contains the ATP binding site whereas the other half the substrate (fructose-6-phosphate or (F6P)) binding site as well as a separate allosteric binding site.^[4]

Mechanism

PFK1 is an allosteric enzyme whose activity can be described using the

Allosteric activators such as AMP and ADP bind to the allosteric site as to facilitate the formation of the R state by inducing structural changes in the enzyme. Similarly, inhibitors such as ATP and PEP bind to the same allosteric site and facilitate the formation of the T state, thereby inhibiting enzyme activity.

Regulation

PFK1 is the most important control site in the mammalian glycolytic pathway. This step is subject to extensive regulation since it is not only highly

PFK1 is also inhibited by low pH levels which augment the inhibitory effect of ATP. The pH falls when muscle is functioning anaerobically and producing excessive quantities of lactic acid. This inhibitory effect serves to protect the muscle from damage that would result from the accumulation of too much acid.^[1]

Finally, PFK1 is allosterically inhibited by both PEP and citrate. Phosphoenolpyruvic acid is a product further downstream the glycolytic pathway and citrate is an early intermediate in the citric acid cycle. Citrate buildup is a sign of the citric acid cycle reaching saturation and thus glycolysis slows down as there is no longer any need to commit more glucose to degradation.

PFK1 is

• PFKL - liver
• PFKM - muscle
• PFKP - platelet

Disease

A genetic mutation in the

• PFK2
  (converts fructose 6-phosphate to fructose 2,6-bisphosphate through on site, or the opposite, on another site)
• PFP (reversibly interconverts fructose 6-phosphate and fructose 1,6-bisphosphate using inorganic pyrophosphate rather than ATP)
• fructose bisphosphatase (hydrolyses fructose 1,6-bisphosphate to fructose 6-phosphate)

References