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Questions and Answers
Which statement accurately describes the role of glucagon and glucocorticoids in gluconeogenesis?
Which statement accurately describes the role of glucagon and glucocorticoids in gluconeogenesis?
- They have no effect on the transcription of the gluconeogenesis-related genes.
- They decrease the transcription of the gene for fructose 1,6-bisphosphatase.
- They increase the transcription of the gene for PEP-carboxykinase. (correct)
- They inhibit the transcription of the gene for PEP-carboxykinase.
What is the consequence of a deficiency in glucose 6-phosphatase?
What is the consequence of a deficiency in glucose 6-phosphatase?
- It causes liver necrosis due to excess glucose.
- It results in severe fasting hypoglycemia. (correct)
- It leads to prolonged hyperglycemia in fasting states.
- It leads to increased production of fructose 2,6-bisphosphate.
Which of the following statements about the conversion of fructose 1,6-bisphosphate to fructose 6-phosphate is true?
Which of the following statements about the conversion of fructose 1,6-bisphosphate to fructose 6-phosphate is true?
- It is weakened by elevated levels of ATP.
- It is promoted by fructose 2,6-bisphosphate. (correct)
- It is stimulated by increased amounts of AMP.
- It is inhibited when ATP levels are high.
In which cellular location does gluconeogenesis primarily occur?
In which cellular location does gluconeogenesis primarily occur?
How does elevated AMP affect the enzyme fructose 1,6-bisphosphatase?
How does elevated AMP affect the enzyme fructose 1,6-bisphosphatase?
What is one of the primary functions of pyruvate carboxylase in liver and kidney cells?
What is one of the primary functions of pyruvate carboxylase in liver and kidney cells?
Which molecule acts as an allosteric activator of pyruvate carboxylase?
Which molecule acts as an allosteric activator of pyruvate carboxylase?
How is oxaloacetate transported from the mitochondria to the cytosol for gluconeogenesis?
How is oxaloacetate transported from the mitochondria to the cytosol for gluconeogenesis?
In muscle cells, what is the primary use of OAA produced by pyruvate carboxylase?
In muscle cells, what is the primary use of OAA produced by pyruvate carboxylase?
What is the consequence of low levels of acetyl CoA on pyruvate carboxylase activity?
What is the consequence of low levels of acetyl CoA on pyruvate carboxylase activity?
Which enzyme is responsible for converting OAA to PEP in humans?
Which enzyme is responsible for converting OAA to PEP in humans?
Which cofactor is required by pyruvate carboxylase and other carboxylases mentioned?
Which cofactor is required by pyruvate carboxylase and other carboxylases mentioned?
What must occur to OAA before it can be transported into the cytosol?
What must occur to OAA before it can be transported into the cytosol?
What effect do decreased levels of insulin have on gluconeogenesis?
What effect do decreased levels of insulin have on gluconeogenesis?
Which coenzymes are primarily provided by fatty acid catabolism for gluconeogenesis?
Which coenzymes are primarily provided by fatty acid catabolism for gluconeogenesis?
What role does acetyl CoA play in gluconeogenesis during fasting?
What role does acetyl CoA play in gluconeogenesis during fasting?
How does AMP affect the regulation of fructose 1,6-bisphosphatase?
How does AMP affect the regulation of fructose 1,6-bisphosphatase?
Which of the following statements is true regarding gluconeogenic precursors?
Which of the following statements is true regarding gluconeogenic precursors?
Which enzymes are responsible for the irreversible reactions in gluconeogenesis?
Which enzymes are responsible for the irreversible reactions in gluconeogenesis?
Which product of pyruvate carboxylase is crucial for the gluconeogenesis pathway?
Which product of pyruvate carboxylase is crucial for the gluconeogenesis pathway?
Which organs are capable of releasing free glucose from glucose 6-phosphate?
Which organs are capable of releasing free glucose from glucose 6-phosphate?
What happens to acetyl CoA during fasting conditions?
What happens to acetyl CoA during fasting conditions?
What regulatory mechanism is shared between glycolysis and gluconeogenesis?
What regulatory mechanism is shared between glycolysis and gluconeogenesis?
What role does glucose 6-phosphatase play in glucose metabolism?
What role does glucose 6-phosphatase play in glucose metabolism?
What characterizes Type Ia glycogen storage disease?
What characterizes Type Ia glycogen storage disease?
How many irreversible reactions do glycolysis and gluconeogenesis share?
How many irreversible reactions do glycolysis and gluconeogenesis share?
Which enzymes are involved in circumventing the irreversible steps of glycolysis during gluconeogenesis?
Which enzymes are involved in circumventing the irreversible steps of glycolysis during gluconeogenesis?
What is the main function of glucose 6-phosphate translocase?
What is the main function of glucose 6-phosphate translocase?
What does high glucose 6-phosphate level indicate about gluconeogenesis?
What does high glucose 6-phosphate level indicate about gluconeogenesis?
What is the role of lactate in the Cori cycle?
What is the role of lactate in the Cori cycle?
Which of these statements about glucose transporters (GLUTs) is correct?
Which of these statements about glucose transporters (GLUTs) is correct?
During fasting, what primarily provides glucose to the body?
During fasting, what primarily provides glucose to the body?
Which of the following is true about the conversion of pyruvate to glucose?
Which of the following is true about the conversion of pyruvate to glucose?
What happens to the equilibrium of reversible reactions of glycolysis during gluconeogenesis?
What happens to the equilibrium of reversible reactions of glycolysis during gluconeogenesis?
Which of the following is a characteristic of gluconeogenesis?
Which of the following is a characteristic of gluconeogenesis?
What is one of the irreversible reactions in glycolysis that must be circumvented in gluconeogenesis?
What is one of the irreversible reactions in glycolysis that must be circumvented in gluconeogenesis?
Which compounds cannot contribute to a net synthesis of glucose?
Which compounds cannot contribute to a net synthesis of glucose?
What coenzyme is required for the enzyme pyruvate carboxylase?
What coenzyme is required for the enzyme pyruvate carboxylase?
What is the product formed when pyruvate undergoes carboxylation?
What is the product formed when pyruvate undergoes carboxylation?
Which of the following statements is correct concerning α-keto acids?
Which of the following statements is correct concerning α-keto acids?
What is the primary function of the transport protein in the Cori cycle?
What is the primary function of the transport protein in the Cori cycle?
Which amino acids cannot yield glucose due to the pyruvate dehydrogenase reaction?
Which amino acids cannot yield glucose due to the pyruvate dehydrogenase reaction?
How does glucagon influence the activity of fructose 1,6-bisphosphatase in gluconeogenesis?
How does glucagon influence the activity of fructose 1,6-bisphosphatase in gluconeogenesis?
What is the primary effect of covalent modification of pyruvate kinase due to glucagon signaling?
What is the primary effect of covalent modification of pyruvate kinase due to glucagon signaling?
Which substrate is crucial for gluconeogenesis during fasting, particularly for providing carbon skeletons?
Which substrate is crucial for gluconeogenesis during fasting, particularly for providing carbon skeletons?
What role does acetyl CoA play in the regulation of pyruvate carboxylase during fasting?
What role does acetyl CoA play in the regulation of pyruvate carboxylase during fasting?
Which process is a result of glucagon promoting the transcription of the gene for PEP-carboxykinase?
Which process is a result of glucagon promoting the transcription of the gene for PEP-carboxykinase?
What primarily provides the necessary coenzymes ATP and NADH for gluconeogenesis?
What primarily provides the necessary coenzymes ATP and NADH for gluconeogenesis?
Which mechanism is responsible for the decrease in gluconeogenesis when insulin levels are high?
Which mechanism is responsible for the decrease in gluconeogenesis when insulin levels are high?
What is the outcome of glucoagon-induced activation of PEP-carboxykinase on gluconeogenesis?
What is the outcome of glucoagon-induced activation of PEP-carboxykinase on gluconeogenesis?
What is the effect of decreasing levels of fructose 2,6-bisphosphate in gluconeogenesis regulation?
What is the effect of decreasing levels of fructose 2,6-bisphosphate in gluconeogenesis regulation?
What indicates a high level of acetyl CoA during fasting in liver cells?
What indicates a high level of acetyl CoA during fasting in liver cells?
What is the primary clinical consequence of a deficiency in glucose 6-phosphatase?
What is the primary clinical consequence of a deficiency in glucose 6-phosphatase?
Which substrate is essential for the activity of pyruvate carboxylase, an important enzyme in gluconeogenesis?
Which substrate is essential for the activity of pyruvate carboxylase, an important enzyme in gluconeogenesis?
What effect does a decrease in the insulin-to-glucagon ratio have on gluconeogenesis?
What effect does a decrease in the insulin-to-glucagon ratio have on gluconeogenesis?
Which reaction is unique to the gluconeogenesis pathway?
Which reaction is unique to the gluconeogenesis pathway?
Which enzyme activity is inhibited by excessive levels of avidin?
Which enzyme activity is inhibited by excessive levels of avidin?
What is the primary effect of elevated levels of acetyl CoA in the liver?
What is the primary effect of elevated levels of acetyl CoA in the liver?
Which allosteric regulator inhibits fructose 1,6-bisphosphatase?
Which allosteric regulator inhibits fructose 1,6-bisphosphatase?
During fasting, which metabolic pathway helps maintain blood glucose levels primarily?
During fasting, which metabolic pathway helps maintain blood glucose levels primarily?
How does fructose 2,6-bisphosphate influence metabolic pathways?
How does fructose 2,6-bisphosphate influence metabolic pathways?
How does high AMP concentration affect gluconeogenesis?
How does high AMP concentration affect gluconeogenesis?
What role does pyruvate carboxylase play in gluconeogenesis?
What role does pyruvate carboxylase play in gluconeogenesis?
In which cellular compartment does gluconeogenesis primarily take place?
In which cellular compartment does gluconeogenesis primarily take place?
Which of the following statements is accurate regarding gluconeogenesis?
Which of the following statements is accurate regarding gluconeogenesis?
What triggers the transcription of PEP-carboxykinase gene?
What triggers the transcription of PEP-carboxykinase gene?
Which process is directly inhibited by elevated levels of pyruvate dehydrogenase complex activity?
Which process is directly inhibited by elevated levels of pyruvate dehydrogenase complex activity?
Which substrate cannot be converted into glucose through gluconeogenesis?
Which substrate cannot be converted into glucose through gluconeogenesis?
What metabolic state primarily contributes to the accumulation of acetyl CoA in the liver?
What metabolic state primarily contributes to the accumulation of acetyl CoA in the liver?
Which enzyme's activity is specifically downregulated by high AMP levels?
Which enzyme's activity is specifically downregulated by high AMP levels?
What type of molecule is primarily transformed into glucose via gluconeogenesis?
What type of molecule is primarily transformed into glucose via gluconeogenesis?
Which metabolic pathway is enhanced when energy needs increase and AMP levels rise?
Which metabolic pathway is enhanced when energy needs increase and AMP levels rise?
What is the effect of adenosine monophosphate (AMP) on gluconeogenesis?
What is the effect of adenosine monophosphate (AMP) on gluconeogenesis?
How does the increase in NADH affect oxaloacetate availability during ethanol metabolism?
How does the increase in NADH affect oxaloacetate availability during ethanol metabolism?
What role does acetyl coenzyme A play in the regulation of gluconeogenesis?
What role does acetyl coenzyme A play in the regulation of gluconeogenesis?
Which molecule is responsible for reciprocal regulation of glycolysis and gluconeogenesis?
Which molecule is responsible for reciprocal regulation of glycolysis and gluconeogenesis?
What happens to gluconeogenesis when ethanol is metabolized?
What happens to gluconeogenesis when ethanol is metabolized?
What is the primary effect of fructose 2,6-bisphosphate on glycolysis and gluconeogenesis?
What is the primary effect of fructose 2,6-bisphosphate on glycolysis and gluconeogenesis?
How does an increase in lactic acid affect gluconeogenesis?
How does an increase in lactic acid affect gluconeogenesis?
What is the main effect of fatty acid oxidation on gluconeogenesis?
What is the main effect of fatty acid oxidation on gluconeogenesis?
Which condition is likely to augment gluconeogenesis?
Which condition is likely to augment gluconeogenesis?
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Study Notes
Pyruvate Carboxylase Reaction
- Occurs in mitochondria of liver and kidney cells, providing substrate for gluconeogenesis and replenishing TCA cycle intermediates.
- Muscle cells utilize pyruvate carboxylase only for replenishment (anaplerotic) and do not synthesize glucose.
- Requires biotin, a coenzyme, for function and is activated by acetyl CoA.
Allosteric Regulation of Pyruvate Carboxylase
- Activated by elevated acetyl CoA levels, signaling increased OAA synthesis required during fasting.
- Pyruvate is primarily oxidized by the PDH complex when acetyl CoA is low.
Transport of Oxaloacetate
- OAA must be converted to PEP to continue gluconeogenesis; this conversion occurs both in mitochondria and cytosol.
- OAA cannot cross the mitochondrial membrane; converted to malate for transport.
- Malate is reoxidized to OAA in the cytosol by cytosolic malate dehydrogenase.
Lactate Production and the Cori Cycle
- Exercising muscle and cells without mitochondria (like RBCs) release lactate into the bloodstream.
- Lactate is converted back to glucose in the liver, completing the Cori cycle.
Role of Amino Acids
- Glucogenic amino acids contribute to glucose production during fasting by generating α-keto acids.
- α-Keto acids can enter the TCA cycle to form OAA, leading to glucose synthesis.
Unique Reactions in Gluconeogenesis
- Three irreversible glycolytic reactions must be bypassed in gluconeogenesis: catalyzed by pyruvate kinase, PFK-1, and hexokinase.
- Pyruvate carboxylase converts pyruvate to OAA, which is then converted to PEP by PEP carboxykinase.
Biotin and Enzyme Regulation
- Biotin is covalently bound to pyruvate carboxylase and is necessary for its activity.
- The hydrolysis of ATP forms an enzyme–biotin–CO2 intermediate that aids in carboxylating pyruvate.
Dephosphorylation of Glucose 6-Phosphate
- Glucose 6-phosphatase hydrolyzes glucose 6-phosphate, allowing free glucose release from liver and kidney cells.
- This process relies on a complex of glucose 6-phosphate translocase and glucose 6-phosphatase.
Summary of Gluconeogenesis Pathways
- 11 reactions convert pyruvate to free glucose, with 7 being reversible glycolytic reactions.
- Gluconeogenesis is influenced by substrate availability, particularly glucogenic amino acids.
Energy State and Pathway Regulation
- Fasting increases pyruvate carboxylase activity via acetyl CoA accumulation due to lipolysis.
- Fructose 1,6-bisphosphatase is inhibited by AMP and activated by ATP, providing reciprocal regulation with glycolysis.
Importance of Gluconeogenesis
- Maintains blood glucose levels during fasting when glycogen stores are depleted.
- Relies on mitochondrial and cytosolic enzymes and progresses only with sufficient glucogenic precursors, ATP, and NADH.
Regulation of Gluconeogenesis
- Gluconeogenesis is regulated by circulating glucagon levels and substrate availability.
- Slow adaptive changes in enzyme activity occur due to altered rates of enzyme synthesis or degradation.
Role of Glucagon
- Glucagon is a peptide hormone from pancreatic alpha cells that stimulates gluconeogenesis.
- It decreases fructose 2,6-bisphosphate levels, activating fructose 1,6-bisphosphatase and inhibiting PFK-1, promoting gluconeogenesis over glycolysis.
- Binds to G protein–coupled receptors, elevating cAMP and stimulating inactivation of hepatic pyruvate kinase, thus diverting PEP to glucose synthesis.
- Increases transcription of the PEP-carboxykinase gene, enhancing enzyme availability during fasting.
Substrate Availability
- Increased availability of gluconeogenic precursors, especially glucogenic amino acids, boosts glucose production.
- Decreased insulin levels lead to amino acid mobilization from muscle for gluconeogenesis.
- Fatty acid catabolism supplies ATP and NADH required for the process.
Allosteric Regulation
- Acetyl CoA activates hepatic pyruvate carboxylase during fasting, directing pyruvate towards gluconeogenesis instead of the TCA cycle.
- Fructose 1,6-bisphosphatase is inhibited by AMP, which activates PFK-1, balancing glycolysis and gluconeogenesis.
Gluconeogenic Precursors
- Precursors include glycolytic and TCA cycle intermediates, glycerol from triacylglycerol hydrolysis, lactate, and α-keto acids from glucogenic amino acids.
- Seven glycolytic reactions are reversible and utilized in gluconeogenesis; three irreversible steps must be bypassed.
Key Enzymes in Gluconeogenesis
- Pyruvate carboxylase converts pyruvate to oxaloacetate, requiring biotin and ATP, and is activated by acetyl CoA.
- PEP-carboxykinase synthesizes PEP from oxaloacetate, requiring GTP, with increased gene transcription by glucagon and glucocorticoids, and decreased by insulin.
- Fructose 1,6-bisphosphate is converted to fructose 6-phosphate by fructose 1,6-bisphosphatase, which is activated by ATP and inhibited by AMP and fructose 2,6-bisphosphate.
Key Concepts about Ethanol Metabolism
- Ethanol metabolism by alcohol dehydrogenase increases NADH, decreasing the NAD+/NADH ratio.
- This shift inhibits gluconeogenesis by reducing the availability of oxaloacetate, as malate oxidation to oxaloacetate is reversed due to high NADH levels.
- Increased NADH also drives the conversion of pyruvate to lactate, reducing substrates available for gluconeogenesis.
Role of Acetyl CoA
- Acetyl CoA produced from fatty acid oxidation cannot be converted to glucose.
- It inhibits the pyruvate dehydrogenase complex and activates pyruvate carboxylase, directing pyruvate towards gluconeogenesis.
Final Steps in Gluconeogenesis
- Glucose 6-phosphate is converted to glucose by glucose 6-phosphatase, essential for gluconeogenesis and glycogen degradation.
- Deficiency of glucose 6-phosphatase leads to severe fasting hypoglycemia.
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