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.
ATP AMP, ADP
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