phosphofructokinase

PFK-1 catalyzes the third step of glycolysis, phosphorylating fructose-6-phosphate to fructose-1,6-bisphosphate, committing the substrate to glycolytic breakdown. It is allosterically regulated: ATP and citrate act as negative allosteric inhibitors (signaling energy sufficiency), while AMP and fructose-2,6-bisphosphate (produced by PFK-2 under the influence of insulin) are positive allosteric activators, promoting glycolysis when energy is needed. This enzyme is a key target of hormonal regulation—insulin promotes PFK-2 activity (raising F2,6BP and stimulating PFK-1), while glucagon has the opposite effect in the liver, favoring gluconeogenesis. Clinically, PFK-1 deficiency causes Tarui disease (glycogen storage disease type VII), an autosomal recessive disorder presenting with exercise intolerance, myopathy, hemolytic anemia, and exercise-induced myalgia/cramps, similar to McArdle disease but with hemolysis as a distinguishing feature since red blood cells also depend on glycolysis for ATP. Understanding PFK-1 regulation is essential for grasping the interplay between glycolysis and gluconeogenesis, especially the reciprocal regulation via fructose-2,6-bisphosphate levels controlled by PFK-2/fructose bisphosphatase-2 (a bifunctional enzyme regulated by phosphorylation status, which itself is controlled by glucagon/insulin ratio via cAMP-PKA pathway in the liver). This makes PFK-1 a classic USMLE topic bridging biochemistry, metabolism, and endocrinology.