Gluconeogenesis and Pentose Phosphate Pathway

120 practice flashcards covering gluconeogenesis and PPP concepts from the provided notes.

What is the main purpose of gluconeogenesis?

To produce glucose to maintain glucose homeostasis during prolonged fasting, mainly in the liver.

Which organ carries out the majority of gluconeogenesis?

The liver (about 90% overnight fast); kidneys contribute during prolonged fast.

Name the four enzymes that bypass the irreversible steps of glycolysis in gluconeogenesis.

Pyruvate carboxylase; phosphoenolpyruvate carboxykinase (PEPCK); fructose-1,6-bisphosphatase; glucose-6-phosphatase.

How many reversible reactions are shared between glycolysis and gluconeogenesis?

Seven.

What are the major precursors of gluconeogenesis?

Lactate, pyruvate, glycerol, and α-keto acids from glucogenic amino acids.

Which substrates enter gluconeogenesis from the precursors list?

Lactate to pyruvate; glycerol to DHAP; α-keto acids to oxaloacetate and then PEP via the gluconeogenic pathway.

Why can't acetyl-CoA from fatty acids serve as a gluconeogenic substrate?

Because pyruvate dehydrogenase irreversibly converts pyruvate to acetyl-CoA, and acetyl-CoA cannot form pyruvate for gluconeogenesis.

What is the role of pyruvate carboxylase in gluconeogenesis?

Catalyzes the carboxylation of pyruvate to oxaloacetate in mitochondria.

What cofactor is required by pyruvate carboxylase?

Biotin (and ATP).

Where is pyruvate carboxylase located?

Mitochondria.

What is the role of PEP carboxykinase (PEPCK) in gluconeogenesis?

Converts oxaloacetate to phosphoenolpyruvate, using GTP.

Where does the PEPCK-catalyzed reaction occur?

Approximately half in mitochondria and half in cytosol in humans.

What happens to oxaloacetate after the PEPCK step?

It is converted to PEP in the cytosol, continuing gluconeogenesis.

What enzyme catalyzes the dephosphorylation of fructose-1,6-bisphosphate?

Fructose-1,6-bisphosphatase.

What inhibits fructose-1,6-bisphosphatase?

Fructose-2,6-bisphosphate (F-2,6-BP) and AMP.

Where is glucose-6-phosphatase located?

Endoplasmic reticulum (ER) membrane.

Which organs release free glucose from G-6-P?

Liver and kidney.

How many ATP equivalents are required to generate one glucose from pyruvate?

6 ATP equivalents (plus 2 NADH; overall ~6 ATP equivalents when accounting for NADH).

How many GTP molecules are used in gluconeogenesis?

2 GTP (in the PEPCK step).

How many NADH are required for gluconeogenesis?

2 NADH (for the reduction of 1,3-bisphosphoglycerate to glyceraldehyde-3-phosphate).

What are the energy costs of gluconeogenesis?

6 ATP and 2 NADH per glucose generated from pyruvate.

What are the Cori cycle and glucose-alanine cycle?

Cori cycle: lactate from anaerobic glycolysis is transported to liver to become glucose; glucose-alanine cycle: alanine from muscle to liver, converted to pyruvate, then glucose.

How does alanine enter gluconeogenesis?

Muscle transaminates pyruvate to alanine; alanine is transported to liver and transaminated back to pyruvate.

Why is alanine used as a gluconeogenic substrate via the liver?

It transports glucogenic carbon and an ammonia equivalent to the liver for urea cycle handling.

What is the role of α-keto acids from glucogenic amino acids in gluconeogenesis?

Enter the TCA cycle to form oxaloacetate, a direct precursor to PEP.

Why are ketogenic amino acids not used for gluconeogenesis?

They form acetyl-CoA or ketone bodies and cannot be converted into pyruvate for glucose synthesis.

What is the gluconeogenic role of glycerol?

Glycerol is phosphorylated to glycerol-3-phosphate by glycerol kinase, then converted to dihydroxyacetone phosphate (DHAP) by glycerol-3-phosphate dehydrogenase, feeding into gluconeogenesis.

What is the first enzyme in glycerol metabolism to feed gluconeogenesis?

Glycerol kinase.

What is the second enzyme in glycerol metabolism to feed gluconeogenesis?

Glycerol-3-phosphate dehydrogenase.

Where is glucose-6-phosphatase located within the cell?

Endoplasmic reticulum membrane.

What organ releases free glucose from G-6-P besides the liver?

Kidney.

What are the major products of the oxidative phase of the PPP?

NADPH, ribulose-5-phosphate, and CO2.

Which enzymes drive the oxidative steps of PPP?

Glucose-6-phosphate dehydrogenase (G6PD); gluconolactonase; 6-phosphogluconate dehydrogenase.

What is the role of NADPH in cells?

Reductive biosynthesis, maintenance of reduced glutathione, detoxification, and phagocytic ROS production.

Does NADPH production in PPP generate ATP?

No; NADPH production does not yield ATP and NADPH does not interact with Complex I of the ETC.

What are the non-oxidative steps of PPP and their enzymes?

Transketolase (transfers 2-carbon units, requires thiamine pyrophosphate) and Transaldolase (transfers 3-carbon units).

What do the non-oxidative PPP steps accomplish?

Interconvert ribose-5-phosphate, ribulose-5-phosphate, xylulose-5-phosphate, glyceraldehyde-3-phosphate, and fructose-6-phosphate; can feed back to glycolysis.

What cofactor does transketolase require?

Thiamine pyrophosphate (TPP).

What are the cellular outcomes when NADPH demand is high but ribose-5-phosphate demand is low?

Oxidative steps generate NADPH; non-oxidative steps convert ribulose-5-phosphate to glycolytic intermediates to support ATP production.

What tissues rely on PPP for reducing power (NADPH) and GSH maintenance?

Erythrocytes mainly (RBCs); also liver, adipose, gonads, adrenal cortex.

What is the disease associated with G6PD deficiency?

Hemolytic anemia due to inability to generate sufficient NADPH to keep glutathione reduced.

What are Heinz bodies?

Aggregates of oxidized hemoglobin seen in red blood cells under oxidative stress (G6PD deficiency).

What triggers hemolytic crises in G6PD deficiency?

Oxidative drugs (e.g., primaquine, sulfa drugs), infections, and fava beans.

What is the estimated prevalence of G6PD deficiency among African American males?

About 10% are carriers.

Why is NADPH important for phagocytes?

NADPH is used by NADPH oxidase to generate ROS for destroying ingested pathogens.

Where does the PPP occur in the cell?

In the cytosol.

What is ribose-5-phosphate used for?

Nucleotide biosynthesis (DNA/RNA synthesis).

Which tissues are active in PPP for reductive biosynthesis (as listed in notes)?

Liver, adipose tissue, gonads, adrenal cortex; erythrocytes also rely on PPP.

What is the oxidative decarboxylation step that yields CO2 in PPP?

The 6-phosphogluconate dehydrogenase step produces CO2 and NADPH.

What is produced by G6PD that is essential for starting PPP?

NADPH by reducing NADP+ to NADPH.

What is the fate of ribulose-5-phosphate in PPP?

It can be isomerized to ribose-5-phosphate for nucleotide synthesis or rearranged via non-oxidative steps to glycolytic intermediates.

What is the role of AMP in regulating gluconeogenesis?

AMP inhibits Fructose-1,6-bisphosphatase, promoting gluconeogenesis regulation in energy-poor states.

How does insulin regulate gluconeogenesis via the PFK-2/FBP-2 bifunctional enzyme?

Insulin promotes the dephosphorylated state that increases F-2,6-BP, stimulating glycolysis and inhibiting gluconeogenesis.

How does glucagon regulate gluconeogenesis via cAMP signaling?

Elevated cAMP activates PKA, which promotes gluconeogenesis and inhibits glycolysis.

What is the verse of regulation for PFK-2/FBP-2 during fasting?

Phosphorylation by PKA inactivates PFK-2 and activates FBP-2, lowering F-2,6-BP and promoting gluconeogenesis.

What is the energy cost to synthesize glucose from pyruvate in terms of ATP and NADH?

6 ATP and 2 NADH per glucose generated (equivalent to ~6 ATP).

What is the major source of blood glucose during prolonged fasting?

Gluconeogenesis in liver (and kidney contribution during prolonged fast).

Which glucose metabolic pathway ensures a supply of NADPH and ribose-5-phosphate?

Pentose Phosphate Pathway (hexose monophosphate shunt).

What are the two divisions of the PPP?

Oxidative phase (NADPH production) and non-oxidative phase (transketolase and transaldolase interconversions).

What is the key clinical deficiency discussed in PPP?

G6PD deficiency leading to hemolytic anemia.

Which product of PPP is directly used for nucleic acid biosynthesis?

Ribose-5-phosphate.

Which molecule is an indicator of fatty acid metabolism activity and regulates pyruvate carboxylase?

Acetyl-CoA (positive allosteric activator of pyruvate carboxylase).

What nutrient is required for pyruvate carboxylase activity due to its role as a cofactor?

Biotin.

Which enzymes catalyze the reversible non-oxidative PPP reactions?

Transketolase and Transaldolase.

What cofactor does transketolase require?

Thiamine pyrophosphate (TPP).

Which molecules can be produced from PPP to feed glycolysis?

Fructose-6-phosphate and glyceraldehyde-3-phosphate.

Which cycle is primarily used to supply the liver with lactate for glucose production?

Cori cycle.

Which cycle involves transporting amino groups to the liver for urea synthesis?

Glucose-alanine cycle.

What are the four unique reactions of gluconeogenesis?

Pyruvate carboxylase; phosphoenolpyruvate carboxykinase (PEPCK); fructose-1,6-bisphosphatase; glucose-6-phosphatase.

Which steps in glycolysis are bypassed by gluconeogenesis?

The irreversible steps: hexokinase, phosphofructokinase-1, and pyruvate kinase.

What molecule directly enters gluconeogenesis from lactate?

Pyruvate (via lactate dehydrogenase conversion).

What molecule directly enters gluconeogenesis from glycerol?

DHAP (dihydroxyacetone phosphate) via glycerol-3-phosphate pathway.

Which organ is altruistic in gluconeogenesis and why?

Liver, because it primarily maintains glucose homeostasis during fast.

Which organ is termed selfish in gluconeogenesis and when does it contribute?

Kidney; contributes 10% overnight fast and up to 40% during prolonged fast.

What happens to NAD+ during prolonged alcohol consumption and how does it affect gluconeogenesis?

NAD+ is depleted (NAD+ to NADH), inhibiting gluconeogenesis and promoting lactate buildup.

What is the source of pyruvate for gluconeogenesis under glucogenic conditions?

Lactate, alanine, and some amino acid-derived substrates.

Which step produces oxaloacetate for gluconeogenesis?

Pyruvate carboxylase converts pyruvate to oxaloacetate in mitochondria.

What is the fate of oxaloacetate produced in mitochondria for gluconeogenesis?

Oxaloacetate is transported to cytosol or converted to malate to cross the mitochondrial membrane, then reconverted to OAA for PEP formation.

What is the common result when F-2,6-BP is high?

Inhibition of gluconeogenesis via stimulation of glycolysis.

What results from high AMP levels on gluconeogenesis?

Inhibition of fructose-1,6-bisphosphatase, favoring glycolysis.

Which two regulatory signals coordinate glucose production with dietary intake?

Insulin and glucagon signaling balance gluconeogenesis and glycolysis.

Why is glucose essential as an energy source in certain tissues?

RBCs lack mitochondria; brain, renal medulla, lens, cornea, testes, and exercising muscles rely heavily on glucose.

Do PPP oxidative steps generate ATP?

No; they generate NADPH and CO2.

What is the relationship between PPP and detoxification pathways?

NADPH from PPP supplies reducing power for detoxification and glutathione maintenance.

Which ribonucleotide precursor is produced by PPP for DNA/RNA synthesis?

Ribose-5-phosphate.

What role does NADPH play in phagocytes?

NADPH oxidase uses NADPH to generate ROS for microbial killing.

Name a key clinical correlation of PPP deficiency.

Hemolytic anemia due to G6PD deficiency.

Which disease state is linked to reduced NADPH production in RBCs?

Hemolytic anemia from oxidative stress due to G6PD deficiency.

What is the net ATP cost per glucose made via gluconeogenesis?

Approximately 6 ATP equivalents (with NADH cost included).

What is the major energy source during the fasting state besides gluconeogenesis?

Fatty acid β-oxidation producing acetyl-CoA and NADH that support energy needs.

Which cycle increases the carbon skeletons entering gluconeogenesis via amino acids?

Glucogenic amino acid metabolism to α-keto acids and subsequently to oxaloacetate.

Which organ predominates during overnight fasting for gluconeogenesis?

Liver.

What is the fate of F-2,6-BP during fasting?

Decreases, relieving inhibition of FBPase and promoting gluconeogenesis.

Which tissue is a major site of ribose-5-phosphate production for nucleotide synthesis?

Liver and other tissues via PPP.

What are the two components of PPP that determine its direction?

NADPH demand and ribose-5-phosphate demand (plus ATP needs).

Which step in gluconeogenesis produces NADH consumption in the reverse of glycolysis?

Reduction of 1,3-bisphosphoglycerate to glyceraldehyde-3-phosphate requires NADH.

What is a common consequence of severe gluconeogenic enzyme deficiency?

Hypoglycemia due to impaired glucose production.

Which molecule provides the carbon skeletons entering gluconeogenesis via amino acids?

α-Keto acids from glucogenic amino acids.

What happens to glycerol in lipid metabolism with respect to gluconeogenesis?

Glycerol is converted to DHAP and enters gluconeogenesis.

What is the ER luminal enzyme critical for releasing glucose into blood?

Glucose-6-phosphatase.