CHAPTER 17 Gluconeogenesis

Gluconeogenesis The Liver and kidney can synthesize glucose from noncarbohydrate precursors such as lactate, alanine and glycerol Under fasting conditions, and when glycogen reserves are low, gluconeogenesis supplies almost all of the body’s glucose 2 Pyruvate + 2 NADH + 4 ATP + 2 GTP + 6 H2O + 2 H+ Glucose + 2 NAD+ + 4 ADP + 2 GDP + 6 Pi Biosynthesis of glucose requires energy in the form of ATP equivalents and NADH

The placement of glycerol (from triglyceride breakdown) into glycolysis or gluconeogenesis. Triose phosphate isomerase DHAP can be used for glycolysis or gluconeogenesis

Figure 17.1: Comparison of Gluconeogenesis and Glycolysis - NOT a complete reversal of glycolysis. Irreversible reactions in glycolysis cannot be utilized for gluconeogenesis - Unique enzymatic reactions are needed for the three irreversible reactions of glycolysis: hexokinase PFK-1 pyruvate kinase All seven near equilibrium reactions of glycolysis proceed in reverse.

Figure 17.2: Carboxylation of pyruvate requires the coenzyme biotin Bicarbonate (HOCO2-) is first phosphorylated using ATP to make HOCO2-PO32- Biotin-enzyme + HOCO2-PO32- makes CO2-biotin-enzyme + Pi CO2-biotin-enzyme + pyruvate makes biotin-enzyme + oxaloacetate biotin

Figure 17.1: Comparison of Gluconeogenesis and glycolysis - NOT a complete reversal of glycolysis. Irreversible reactions in glycolysis cannot be utilized for gluconeogenesis - Unique enzymatic reactions are needed for the three irreversible reactions of glycolysis: hexokinase PFK-1 pyruvate kinase All seven near equilibrium reactions of glycolysis proceed in reverse.

Fructose 1,6-bisphosphatase (F1,6BPase) Catalyzes a metabolically irreversible reaction F1,6BPase is allosterically inhibited by AMP and fructose 2,6-bisphosphate (strong activator of PFK-1)

Glucose 6-phosphatase Catalyzes a metabolically irreversible hydrolysis reaction In most cases, the biosynthesis ends with glucose 6-phosphate where it becomes the active substrate for pathways leading to glycogen, starch, and pentose sugar synthesis Glucose is an important end product when other tissue need an energy source for glycolysis. This takes place largely in the liver.

Figure 17.3: The conversion of pyruvate To oxaloacetate. Pyruvate translocase Pyruvate Glucose Figure 17.3: The conversion of pyruvate To oxaloacetate. The conversion takes place in the mitochondrial matrix. Oxaloacetate is reduced to malate before transport into the cytoplasm. - malate is then oxidized back to oxaloacetate.

Figure 17.5 Reciprocal regulation in the liver Allosteric activators When glucose is abundant, glycolysis dominates When glucose is scarce, gluconeogenesis will take over Allosteric activators Allosteric inhibitors Allosteric inhibitors Allosteric activators Allosteric inhibitors Allosteric activators Allosteric inhibitors Allosteric activators Figure 17.5

Fructose 2,6-bisphosphate is produced by PFK-2 Recall that F-2,6-BP is a powerful activator of PFK (or PFK-1) in glycolysis Phosphofructokinase 2 (PFK-2) synthesizes F-2,6,BP, BUT it also breaks down F-2,6-BP when glycolysis must be slowed. PFK-2 and FBPase2 (fructose 2,6-bisphophatase) are different enzyme activities found on the SAME protein molecule. FBPase2 domain PFK2 domain

Figure 17.7: synthesis and breakdown of fructose 2,6-bisphosphate After times of Feasting Insulin is secreted by the pancreas Production of F-2,6-BP increases

Figure 17.7: synthesis and breakdown of fructose 2,6-bisphosphate After times of Fasting Glucagon is secreted by the pancreas Conc. of F-2,6-BP must decreases

The interaction of glycolysis and gluconeogenesis Lactate metabolism during high anaerobic activity Glycolysis generates large amounts of lactate in active muscle Liver lactate dehydrogenase converts lactate to pyruvate (a substrate for gluconeogenesis) Glucose produced by the liver is delivered back to muscles via the bloodstream Figure 12.2 Cori cycle: glucose catabolism to L-lactate in peripheral tissues, delivery of lactate to the liver, formation of glucose from lactate in the liver, and delivery of glucose back to peripheral tissues. Figure 17.10 The Cori Cycle The interaction of glycolysis and gluconeogenesis

Assignment Read Chapter 17 Read Chapter 18