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