PHOSPHOFRUCTOKINASE-1 (PFK-1)

• Catalyzes rate-limiting step in glycolysis
• Catalyzes irreversible phosphorylation of F6P to F1,6P.
• Allosterically regulated (hormonally regulated in liver)

PFK-1 INHIBITION

• Citrate, intermediate of citric acid cycle
• ATP, final product of glycolysis and cellular respiration
• H+, symptom of lactic acid buildup in exercising muscle

PFK-1 ACTIVATION

• AMP, marker of ATP depletion.
• Fructose-2,6-bisphosphate (special case)

PFK-2/FBP-2 (BIFUNCTIONAL ENZYME)

• PFK-2: F6P –> F2,6P (activates PFK-1)
• FBP-2 (fructose-2,6-bisphosphatase): F2,6P –> F6P (deactivates PFK-1)
• PFK-2/FBP-2 regulated differently in different tissues

Skeletal muscle

• Feed-forward activation
• Substrate-level regulation: F6P
• When F6P HIGH: FBP-2 inactive and PFK-2 active (activate PFK-1)
• When F6P LOW: FBP-2 active and PFK-2 inactive (inhibits PFK-1 activity)

Liver

• Hormonal regulation: PFK-2 has phosphorylation site (unlike muscle)
• PFK-2 is INACTIVE when phosphorylated
• Glucagon activates protein kinase A (PKA), which phosphorylates PFK-2
• Insulin activates phosphoprotein phosphatase (PPP), which dephosphorylates PFK-2

FED STATE

• HIGH blood glucose
• INSULIN secreted –> PPP activated –> PFK-2 dephosphorylated (ACTIVE)
• HIGH F2,6P activates PFK-1
• Promotes glycolysis

FAST

• LOW blood glucose
• GLUCAGON secreted –> PKA activated –> PFK-2 phosphorylated (INACTIVE)
• LOW F2,6P deactivates PFK-1
• NO glycolysis

Liver responds to entire body’s glucose needs

• Site of gluconeogenesis: glucose synthesized from non-carbohydrate precursors and released into the bloodstream