|Topic:||Regulation of Glycolytic Flux by PFK-1 .|
|Details:|| PFK-1 is a tetrameric enzyme that exists in two conformational states termed R and T that are in equilibrium. ATP is both a substrate and an allosteric inhibitor of PFK-1. Each subunit has two ATP binding sites, a substrate site and an inhibitor site. The substrate site binds ATP equally well when the tetramer is in either conformation. The inhibitor site binds ATP essentially only when the enzyme is in the T state. F6P is the other substrate for PFK-1 and it also binds preferentially to the R state enzyme. At high concentrations of ATP, the inhibitor site becomes occupied and shifting the equilibrium of PFK-1 conformation to that of the T state decreasing PFK-1's ability to bind F6P. The inhibition of PFK-1 by ATP is overcome by AMP which binds to the R state of the enzyme and, therefore, stabilizes the conformation of the enzyme capable of binding F6P. The most important allosteric regulator of both glycolysis and gluconeogenesis is fructose 2,6-bisphosphate (F2,6BP) which is not an intermediate in glycolysis or in gluconeogenesis.
The activity of PFK-1 is also regulated by reversible glycosylation, specifically O-GlcNAcylation. In response to hypoxia, a serine (Ser529) in PFK-1 is O-GlcNAcylated and inhibited. This phenomenon confers a growth advantage to certain cancer cells because glucose is diverted into the pentose phosphate pathway allowing the carbon atoms to be utilized for biomass production. The pathological significance of this mode of PFK-1 regulation if that targeting the enzyme for inhibition of the glycosylation has been shown to inhibit cancer growth and impairs tumor formation.
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