Coordinated Regulation of Glycolysis and Gluconeogenesis:- Gluconeogenesis Is Regulated at Several Steps
In the pathway leading from pyruvate to glucose, the first control point determines the fate of pyruvate in the mitochondrion. Pyruvate can be converted either to acetyl-CoA (by the pyruvate dehydrogenase complex; Chapter 16) to fuel the citric acid cycle, or to oxaloacetate (by pyruvate carboxylase) to start the process of gluconeogenesis (Fig. 15–20). When fatty acids are readily available as fuels, their breakdown in liver mitochondria yields acetyl-CoA, a signal that further oxidation of glucose for fuel is not necessary. Acetyl-CoA is a positive allosteric modulator of pyruvate carboxylase and a negative modulator of pyruvate dehydrogenase, through stimulation of a protein kinase that inactivates the dehydrogenase. When the cell’s energetic needs are being met, oxidative phosphorylation slows, NADH rises relative to NAD and inhibits the citric acid cycle, and acetyl-CoA accumulates. The increased concentration of acetyl-CoA inhibits the pyruvate dehydrogenase complex, slowing the formation of acetyl-CoA from pyruvate, and stimulates gluconeogenesis by activating pyruvate carboxylase, allowing excess pyruvate to be converted to glucose. The second control point in gluconeogenesis is the reaction catalyzed by FBPase-1 (Fig. 15–21), which is strongly inhibited by AMP. The corresponding glycolytic enzyme, PFK-1, is stimulated by AMP and ADP but inhibited by citrate and ATP. Thus, these opposing steps in the two pathways are regulated in a coordinated and reciprocal manner. In general, when sufficient concentrations of acetyl-CoA or citrate (the product of acetyl CoA condensation with oxaloacetate) are present, or when a high proportion of the cell’s adenylate is in the form of ATP, gluconeogenesis is favored. AMP promotes glycogen degradation and glycolysis by activating glycogen phosphorylase (via activation of phosphorylase ki nase) and stimulating the activity of PFK-1. All the regulatory actions discussed here are triggered by changes inside the cell and are mediated by very rapid, instantly reversible, allosteric mechanisms. Another set of regulatory processes is triggered from outside the cell by the hormone's insulin and glucagon, which signal too much or too little glucose in the blood, respectively, or by epinephrine, which signals the impending need for fuel for a fight-or-flight response. These hormonal signals bring about covalent modification (phosphorylation or dephosphorylation) of target proteins inside the cell; this takes place on a somewhat longer time scale than the internally driven allosteric mechanisms—seconds or minutes, rather than milliseconds.
FIGURE 15–20 Two alternative fates for pyruvate. Pyruvate can be converted to glucose and glycogen via gluconeogenesis or oxidized to acetyl-CoA for energy production. The first enzyme in each path is regulated allosterically; acetyl-CoA, produced either by fatty acid oxidation or by the pyruvate dehydrogenase complex, stimulates pyruvate carboxylase and inhibits pyruvate dehydrogenase.
FIGURE 15–21 Regulation of fructose 1,6-bisphosphatase-1 (FBPase-1) and phosphofructokinase-1 (PFK-1). The important role of fructose 2,6-bisphosphate in the regulation of this substrate cycle is detailed in subsequent figures.
