Regulation by Fatty Acids
Phosphofructokinase-1 catalyzes the first committed step of glycolysis and is therefore tightly regulated. One such mechanism of regulation is by acylation by long-chain acyl-CoA molecules such as palmitoyl-CoA. Interestingly, PFK-1 is not regulated by short-chain acyl-CoA molecules. Long-chain acyl-CoA molecules inhibit PFK-1 through acylation, which causes increased membrane association. This acylation can then be reversed by cellular thioesterases.
A variety of allosteric regulators play a role in the regulation of PFK-1 by acyl-CoA molecules, making the mechanism quite complex. For example, AMP and ADP protect PFK-1 from inhibition by acyl-CoA, while ATP does not. As a consequence, glycolysis can continue to occur even when fatty acid oxidation is increased, such as under hypoxic conditions. Another complexity of the acyl-CoA regulation system involves the calmodulin bonding site of PFK-1. Acylation changes the conformation of this bonding site, allowing calmodulin association. Calmodulin previously had been identified as a regulator of PFK-1; this new information gives insight into the regulation mechanism of calmodulin.
Knowledge of the regulation by acyl-CoA molecules, the product of the branch point between lipid anabolism and catabolism in lipid metabolism, of glycolytic pathways has vast medical implications. As the prevalence of lipid-related diseases, such as diabetes, increases, understanding of this interplay is vital for medicine and pharmacology.
Decreased Fat Stores
Triacylglycerol synthesis require glucose metabolism because the glycerol component is synthesized from the glycerol phosphate intermediate of glycolysis. Previously, the rate limiting step in this process was thought to be uptake of glucose. Recently, however, it has been shown that phosphofructokinase-1 also plays a large role in the regulation of triacylglycerol synthesis. In fact, mice that are deficient in PFK-1 have significantly decreased fat stores. They do not have a decreased number of adipocytes; rather, the number of triacylglycerides contained by the adipocytes is decreased. Multiple forms (isozymes) of PFK-1 exist in the body. This decrease in fat storage was seen only in response to a deficiency in the muscle isozyme of PFK-1, indicating something special about PFK-M.
The mechanism by which PFK-M regulates adipocyte metabolism remains under discussion. The current thought is based on the fact that PFK-M is more strongly activated by its product, fructose 1,6-bisphosphate, than other PFK isozymes. This leads to the generation of glycolytic oscillations, which produce pulses of glycerol phosphate, the precursor for triacylglycerol. When PFK-M is lacking, these pulses do not occur. Subsequently, triacylglycerol synthesis is decreased.
Glycogen Storage Disease
Phosphofructokinase-1 catalyzes the commited step of glycolysis (Fructose 6-phosphate +ATP à 1,6-Fructose bisphosphate). A deficiency in this enzyme results the blockage of glycolysis and an accumulation of the first substrates of glycolysis, specifically glucose and glucose 6-phosphate. This has a variety of medical applications. First, the lack of ability to metabolize glucose 6-phosphate, the product of glycogen breakdown, leads to an accumulation of glycogen, known as glycogen storage disease. In both mice and humans, this glycogen accumulation results in an enlarged heart and early mortality.
Second, a deficiency in PFK-1 causes decreases exercise tolerance, as ATP cannot be generated by glucose metabolism. The body compensates for this by up-regulating the enzymes of the citric acid cycle, which can produce energy from acetyl-CoA produced by fatty acid oxidation, and the enzymes of the pentose phosphate pathway, which siphons off glucose 6-phosphate for nucleotide generation. This compensation, however, is not enough to overcome the blockage of glycolysis. This chronic lack of ATP results in degradation of skeletal muscle fibers.
A third medical implication of PFK-1 deficiency involves erythrocytes. The accumulation of glucose and glucose 6-phosphate in the red blood cells causes water to enter the cell via osmosis, leading to hemolysis (rupturing of red blood cells). Consequently, the concentration of reticulocytes, immature red blood cells, increases. Because the spleen removes old erythrocytes, the spleen also enlarges. Finally, when PFK-1 activity in erythrocytes is blocked, the concentration of 2,3-bisphosphoglycerate, a later intermediate in glycolysis, decreases. 2,3-BPG increases heme affinity for oxygen, meaning that the amount of available oxygen decreases. This may be one reason why up-regulation of oxidative energy producing pathways is not enough to compensate for a lack of glycolysis.
As you can see, defective PFK-1 can have some pretty nasty implications. Don't worry though--it's only important in people who eat.