A 35-year-old woman comes to the emergency department with nausea, vomiting, and fever. Her symptoms began 24 hours ago, and she has been unable to eat or drink anything since. She has a 3-year-old daughter who had similar symptoms 2 days earlier but is now fine. Laboratory studies show a blood glucose level of 82 mg/dL despite her 24-hour fast. Maintenance of this patient's blood glucose levels is facilitated by hepatic conversion of pyruvate into glucose. Which of the following substances directly stimulates the first enzyme involved in this process?
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During gluconeogenesis, substances such as lactate and alanine are converted to pyruvate. However, pyruvate cannot be converted to phosphoenolpyruvate directly as pyruvate kinase is unidirectional. To convert pyruvate to phosphoenolpyruvate, pyruvate first undergoes biotin-dependent carboxylation to oxaloacetate in the mitochondria. This reaction is catalyzed by pyruvate carboxylase. The activity of pyruvate carboxylase is increased by acetyl-CoA. This critical regulatory step diverts pyruvate to pyruvate dehydrogenase when acetyl-CoA levels are too low, preventing the cell from becoming energy starved. When acetyl-CoA levels are high (as with increased beta oxidation of fatty acids during fasting), pyruvate carboxylase can operate at full capacity and convert most of the pyruvate into oxaloacetate for use in gluconeogenesis.
(Choice B) Muscle converts pyruvate to alanine via transamination, which is then transported to the liver where it is converted back to pyruvate for use in gluconeogenesis. Alanine allosterically inhibits pyruvate kinase, preventing phosphoenolpyruvate from being consumed by glycolysis during the gluconeogenic state.
(Choice C) Citrate is formed within mitochondria in the first reaction of the Krebs cycle, and elevated levels act as an indicator of high cellular energy stores and abundant biosynthetic intermediates. Citrate is therefore an important positive regulator of acetyl-CoA carboxylase and fructose-1,6-bisphosphatase, key enzymes involved in fatty acid synthesis and gluconeogenesis, respectively.
(Choice D) Regulation of glycolysis and gluconeogenesis occurs mainly through the inverse regulation of phosphofructokinase-1 and fructose 1,6-bisphosphatase by fructose 2,6-bisphosphate. High levels of fructose 2,6-bisphosphate activate phosphofructokinase-1 and accelerate glycolysis; low levels disinhibit fructose 1,6-bisphosphatase and promote gluconeogenesis.
(Choice E) Lactate is an important source of carbon atoms for glucose synthesis during gluconeogenesis. During anaerobic glycolysis in skeletal muscle, pyruvate is reduced to lactate by lactate dehydrogenase. Lactate formed in the contracting muscles is released into the bloodstream and transported to the liver, where it is converted back into glucose.
(Choice F) Oxaloacetate is the product of pyruvate carboxylase during gluconeogenesis. As such, increased levels of oxaloacetate would decrease the activity of the enzyme.
Educational objective:
Acetyl-CoA stimulates gluconeogenesis by increasing the activity of pyruvate carboxylase when acetyl-CoA is abundant. This regulatory step allows pyruvate to be shunted toward acetyl-CoA production when acetyl-CoA levels are low, preventing the cell from becoming depleted of energy.