Pyruvate Kinase Is Allosterically Inhibited by ATP

At least three isozymes of pyruvate kinase are found in vertebrates, differing in their tissue distribution and their response to modulators. High concentrations of ATP, acetyl-CoA, and long-chain fatty acids (signs of abundant energy supply) allosterically inhibit all isozymes of pyruvate kinase (Fig. 15-19). The liver isozyme (L form), but not the muscle isozyme (M form), is subject to further regulation by phosphorylation. When low blood glucose causes glucagon release, cAMP-dependent protein kinase phosphorylates the L isozyme of pyruvate kinase, inactivating it. This slows the use of glucose as a fuel in liver, sparing it for export to the brain and other organs. In muscle, the effect of increased [cAMP] is quite different. In response to epinephrine, cAMP activates glycogen breakdown and glycolysis and provides the fuel needed for the fight-or-flight response.

FIGURE 15-18 Phosphofructokinase-1 (PFK-1) and its regulation.

(a) Ribbon diagram of E. coli phosphofructokinase-1, showing two of its four identical subunits (PDB ID 1PFK). Each subunit has its own catalytic site, where ADP (blue) and fructose 1,6-bisphosphate (yellow) are almost in contact, and its own binding sites for the allosteric regulator ADP (blue), located at the interface between subunits. (b) Allosteric regulation of muscle PFK-1 by ATP, shown by a substrate-activity curve. At low concentrations of ATP, the K0.5 for fructose 6-phosphate is relatively low, enabling the enzyme to function at a high rate at relatively low concentrations of fructose 6-phosphate. (Recall from Chapter 6 that K0.5 or Km is equivalent to the substrate concentration at which half-maximal enzyme activity occurs.) When the concentration of ATP is high, K0.5 for fructose 6-phosphate is greatly increased, as indicated by the sigmoid relationship between substrate concentration and enzyme activity. (c) Summary of the regulators affecting PFK-1 activity.

(a)
[Fructose 6-phosphate] (b)

ATP AMP, ADP

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