CHAPTER 17Gluconeogenesis

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.

DHAP can be usedfor 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 areneeded for the three irreversiblereactions of glycolysis:

hexokinasePFK-1pyruvate 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-PO3

2-

- 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 areneeded for the three irreversiblereactions of glycolysis:

hexokinasePFK-1pyruvate 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 substratefor pathways leading to glycogen, starch, and pentose sugar synthesis

- Glucose is an important end product when other tissue needan energy source for glycolysis. This takes place largely in the liver.

Figure 17.3: The conversion of pyruvateTo 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.

GlucosePyruvate

Pyruvate translocase

Figure 17.5

Allosteric activators

Allosteric inhibitors

Allosteric activators

Allosteric inhibitors

Reciprocal regulation in the liver

Allosteric inhibitors

Allosteric inhibitorsAllosteric

activators

Allosteric activators

When glucose is abundant, glycolysis dominates

When glucose is scarce, gluconeogenesis will take over

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-BPwhen glycolysis must be slowed. PFK-2 and FBPase2 (fructose 2,6-bisphophatase)are different enzyme activities found on the SAME protein molecule.

PFK2domain

FBPase2domain

Figure 17.7: synthesis and breakdown of fructose 2,6-bisphosphate

Insulin is secreted by the pancreas

Production of F-2,6-BPincreases

After times of Feasting

Figure 17.7: synthesis and breakdown of fructose 2,6-bisphosphate

Conc. of F-2,6-BPmust decreases

After times of Fasting

Glucagon is secreted by the pancreas

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 musclesvia the bloodstream

Figure 17.10The Cori Cycle

The interaction of glycolysis and gluconeogenesis

Assignment

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