The short-term regulation of irreversible glycolytic enzymes involves allosteric activation/inhibition or covalent phosphorylation/dephosphorylation, which takes effect within minutes or hours. These effects on preexisting enzyme molecules are supplemented by long-term hormonal effects that influence the production of new enzyme molecules. Hormonal effects can lead to a 10- to 20-fold increase in enzyme synthesis over a period of hours to days. Regular consumption of carbohydrate-rich meals or administration of insulin triggers the production of glucokinase, PFK-1, and PK in the liver. This increase in gene transcription results in higher enzyme synthesis, promoting the conversion of glucose to pyruvate, a characteristic of the absorptive state. Conversely, during periods of high plasma glucagon and low insulin levels, such as fasting or diabetes, the gene expression of these enzymes decreases.

Pyruvate can undergo alternative metabolic pathways other than lactate formation. One important pathway is the oxidative decarboxylation of pyruvate by the PDHC, which occurs in tissues with high oxidative capacity, like cardiac muscle. This pathway irreversibly converts pyruvate into acetyl CoA, a substrate for the TCA cycle and fatty acid synthesis. Another pathway involves the carboxylation of pyruvate to oxaloacetate by pyruvate carboxylase, which is a biotin-dependent reaction. This irreversible reaction replenishes TCA cycle intermediates and provides substrate for gluconeogenesis. In microorganisms, pyruvate can be reduced to ethanol through a series of reactions summarized in Figure 8.24. However, humans do not possess the enzyme pyruvate decarboxylase required for this conversion.

In summary, the regulation of glycolytic enzymes involves short-term and long-term mechanisms. Pyruvate can be metabolized to acetyl CoA, oxaloacetate, or ethanol depending on the cellular context and organism.
Regulation of the activity of the irreversible glycolytic enzymes by allosteric activation/inhibition or covalent phosphorylation/dephosphorylation is short term (that is, the effects occur over minutes or hours). Superimposed on these effects on the activity of preexisting enzyme molecules are the long-term hormonal effects on the number of new enzyme molecules. These hormonal effects can result in 10-to 20-fold increases in enzyme synthesis that typically occur over hours to days. Regular consumption of meals rich in carbohydrate or administration of insulin initiates an increase in the amount of glucokinase, PFK-1, and PK in the liver (Fig. 8.23). The change reflects an increase in gene transcription, resulting in increased enzyme synthesis. Increased availability of these three enzymes favors the conversion of glucose to pyruvate, a characteristic of the absorptive state (see p. 321). [Note: The transcriptional effects of insulin and carbohydrate (specifically glucose) are mediated by the transcription factors sterol regulatory element–binding protein-1c and carbohydrate response element–binding protein, respectively. These factors also regulate transcription of genes involved in fatty acid synthesis (see p. 184).] Conversely, gene expression of the three enzymes is decreased when plasma glucagon is high and insulin is low (for example, as seen in fasting or diabetes).
VII. ALTERNATE FATES OF PYRUVATE
Pyruvate can be metabolized to products other than lactate.
A. Oxidative decarboxylation to acetyl CoA
Oxidative decarboxylation of pyruvate by the PDHC is an important pathway in tissues with a high oxidative capacity such as cardiac muscle (Fig. 8.24). PDHC irreversibly converts pyruvate, the end product of aerobic glycolysis, into acetyl CoA, a TCA cycle substrate (see p. 109) and the carbon source for fatty acid synthesis (see p. 183).
B. Carboxylation to oxaloacetate
Carboxylation of pyruvate to oxaloacetate by pyruvate carboxylase is a biotin-dependent reaction (see Fig. 8.24). This irreversible reaction is important because it replenishes the TCA cycle intermediate and provides substrate for gluconeogenesis (see p. 118).
C. Reduction to ethanol (microorganisms)
The reduction of pyruvate to ethanol occurs by the two reactions summarized in Figure 8.24. The decarboxylation of pyruvate to acetaldehyde by thiamine-requiring pyruvate decarboxylase occurs in yeast and certain other microorganisms but not in humans.
VIII. CHAPTER SUMMARY