Principles of Biochemistry Volume 2 - A. Lehninger 1985

Bioenergetics and Metabolism
Carbohydrate Biosynthesis in Animal Tissues
Reciprocal Regulation of Gluconeogenesis and Glycolysis

Fig. 20-2 shows the regulatory sites of Gluconeogenesis and Glycolysis. The first such site in gluconeogenesis is the reaction catalyzed by the regulatory enzyme Pyruvate carboxylase. This enzyme is virtually inactive in the absence of acetyl-CoA, which acts as a positive allosteric modulator. Therefore, the Biosynthesis OF GLUCOSE from pyruvate is enhanced whenever The Cell accumulates more mitochondrial acetyl-CoA than it currently requires as fuel for The Citric Acid Cycle. Because acetyl-CoA also serves as a negative, or inhibitory, modulator of the pyruvate dehydrogenase complex, its accumulation slows down the Oxidation of Pyruvate to acetyl-CoA and promotes the biosynthetic conversion of pyruvate into glucose.

The second regulatory site of gluconeogenesis is the reaction catalyzed by fructose diphosphatase, an enzyme that is strongly inhibited by AMP. Since the corresponding enzyme of The Glycolytic Pathway, Phosphofructokinase, is activated by AMP and ADP, and inhibited by citrate and ATP (Section 15.3), these two opposing steps of gluconeogenesis and glycolysis are regulated in a coordinated, reciprocal manner. Whenever there is sufficient fuel for The Citric Acid cycle (either as acetyl-CoA or as citrate, the first intermediate of this cycle) or when the cell is fully supplied with ATP, conditions favor the biosynthetic pathway—i.e., The formation of glucose from pyruvate and, consequently, the storage of glucose as Glycogen.

To a certain extent, gluconeogenesis is also regulated indirectly via pyruvate kinase, one of the glycolytic Enzymes not involved in gluconeogenesis. Pyruvate kinase exists in two forms: L (Liver) and M (Muscle). The L-form, which predominates in Tissues capable of gluconeogenesis, is allosterically inhibited by excess ATP and Certain Amino Acids, primarily Alanine, a key precursor of glucose in gluconeogenesis. Under conditions of adequate energy supply and in the presence of glucose precursors, glycolysis slows down due to the inhibition of L-pyruvate kinase, thereby creating conditions favorable for gluconeogenesis. M-pyruvate kinase is not subject to this type of regulation.

In Chapter 25, we will see that gluconeogenesis is also regulated by certain Hormones.