Metabolism Case 3


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Glucose is so important that organisms are able to take it up from the environment (as we have discussed thus far) and synthesize it from simple precursors through a process called gluconeogenesis. Gluconeogenesis is not simply a reversal of glycolysis. Review the text or other resources to address the following questions.

1. Create a table of the reactions are components of gluconeogenesis but not glycolysis. For each of
these new reactions, please include the following information:

a. What is the name of the enzyme that catalyzes this reaction? b. What does the enzyme’s name indicate about its function? c. Which reaction of glycolysis is bypassed by this step?
Gluconeogenesis-specific Enzymatic Reactions Step 1 → Pyruvate carboxylase

- Carboxylates pyruvate to oxaloacetate - Enables bypass of phosphorylation of pyruvate
Step 2 → Phosphoenolpyruvate carboxykinase

- Decarboxylates oxaloacetate to phosphoenolpyruvate - Bypasses phosphorylation of pyruvate
Step 3 → Fructose-1,6-bisphosphatase

- Hydrolyses fructose-1,6-bisphosphate to fructose-6-phosphate - Bypasses dephosphorylation of fructose-1,6-diphosphate
Step 4 → Glucose-6-phosphatase

- Hydrolyses glucose-6-phosphate into glucose

Metabolism Case 3


- Bypasses the dephosphorylation of glucose-6-phosphate 2. Why do you think these particular steps differ between glycolysis and gluconeogenesis?
The corresponding pathways in glycolysis are heavily unfavorable pathways. Essentially the reverse of the highly spontaneous forward reactions of glycolysis, the gluconeogenesis pathways forge alternate routes of synthesis.

3. Which steps of gluconeogesis are simply reversals of glycolytic reactions?
Phosphoenolpyruvate → Phosphoglycerate (via Enolase) Phosphoglycerate → 1,3-Bisphosphoglycerate (via Phosphoglycerokinase) Fructose-6-phosphate → Glucose-6-phosphate (via Phosphoglucomutase)

4. Why are the enzymes that catalyze reactions in glycolysis able to “moonlight” in gluconeogenesis
(i.e., catalyze reactions in gluconeogenesis)? These reactions are favored in either direction and are generally at equilibrium in the body. As the forward direction of glycolysis is running smoothly, an abundance of product, along with substrate, becomes available. The corresponding enzyme will catalyze the product back through to substrate. It has been shown that muscle pyruvate kinase (PK) responds hyperbolically to its substrate, phosphoenolpyruvate (PEP), but the liver form of the enzyme responds sigmoidally. Fructose-1,6bisphosphate (F-1,6-BP) is an allosteric activator of liver PK, but apparently has no effect on the muscle enzyme. 5. Liver is primarily a gluconeogenic tissue, whereas muscle is primarily glycolytic. Why does this division of labor make physiological sense? Muscles need energy provided by glycolysis, whereas the liver is the organ most responsible for controlling the body’s blood sugar content. Alternatively, glycolysis serves to trap needed glucose in the muscle tissue by phosphorylation to of glucose. Gluconeogenesis sees the liberation of sugar into the blood by the dephosphorylation of glucose-6-phosphate.

6. Draw velocity versus [substrate] curves for both liver and muscle PK including the F-1,6-BP effect.
Why does this regulation make sense?

Metabolism Case 3


7. What is the metabolic advantage of having the liver PK activated by F-1,6-BP?
Liver pyruvate kinase can rapidly produce pyruvate when a high concentration of early substrate like fructose-1,6-phosphate exists. In this way, a negative feedback loop exists where the liver will not constantly churn out glucose.

8. If the liver PK responded hyperbolically to phosphoenolpyruvate (PEP) and were otherwise
unregulated, how might gluconeogenesis be affected? The process would continue indefinitely, consuming pyruvate and producing glucose. Blood would become hyperglycemic.

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