GLUCONEOGENESIS gluco neo genesis de novo synthesis of

GLUCONEOGENESIS gluco neo genesis de novo synthesis of glucose

Definition : Gluconeogenesis is the synthesis of glucose from noncarbohydrates

Precursors of Gluconeogenesis • Non carbohydrates: 1. 2. 3. 4. Lactate Glycerol Glucogenic amino acids Propionate (3 carbon fatty acid)

Importance of gluconeogenesis • Some tissues, such as the brain and the RBCs are completely dependant on glucose for energy. When the dietary carbohydrates are not enough and after stores are finished, the blood glucose level is maintained by gluconeogenesis.

When does it take place? • During fasting and starvation • Low carbohydrate diet (high fat) • During heavy exercise

Site of Gluconeogenesis • It primarily occurs in the liver. • It can also occur in the kidneys (contribute 10%) It occurs in the mitochondria and cytosol of liver and kidney cells.

Properties of Gluconeogenesis • It occurs in the mitochondria and cytosol of liver and kidney cells. • It consumes ATP ( it is anabolic). • The pathway is basically the reverse of glycolysis with a few exceptions.

glucose Glycolysis Gluconeogenesis pyruvate lactate

Gluconeogenesis and Glycolysis The irreversible reactions in glycolysis are - reaction 1 - reaction 3 - reaction 10 The other 7 reactions are reversible.

Step 1 Step 3 glycolysis gluconeogenesis Step 10

The irreversible reactions in glycolysis are catalyzed by: o Hexokinase - reaction 1. o Phosphofructokinase - reaction 3. o Pyruvate Kinase - reaction 10.

1 3 2 2 3 1

glucose Glycolysis Gluconeogenesis pyruvate lactate

Precursors of Gluconeogenesis • glucose is synthesized from: 1. 2. 3. 4. Lactate Glycerol Glucogenic amino acids Propionate (3 carbon fatty acid)

1) Lactate is converted to pyruvate

• Pyruvate enters the mitochondria

The reversal of pyruvate to phosphoenolpyruvate • The reaction of pyruvate kinase is reversed by two separate reactions, taking place inside the mitochondrion and the cytosol.

Reversing step 10 of glycolysis requires 2 enzymes for a 2 -step reaction, consuming ATP and GTP: Pyruvate carboxylase requires biotin ( vitamin B 7). This is a mitochondrial enzyme.

Reversal of PEP → Pyruvate Cytosol Mitochondria

In order to cross the mitochondrial membrane oxaloacetate must 1. be reduced to malate 2. go through the malate shuttle 3. be oxidized to oxaloacetate

In the mitochondrial matrix • Pyruvate in the mitochondria will be converted to oxaloacetate, by pyruvate carboxylase. • Oxaloacetate is converted to malate • Malate is then transported back to the cytosol

In the cytosol • Malate is converted to oxaloacetate. • Oxaloacetate is converted to PEP by phosphoenolpyruvate carboxykinase

1 3 2 2 3 1

Second difference

Conversion of F-1, 6 -BP to F-6 -P • Enzyme: Fructose-1, 6 -Bis. Phosphatase • No ATP used

Third difference

Conversion of G-6 -P to Glucose • Enzyme: Glucose-6 -Phosphatase • No ATP used

Enzymatic differences between glycolysis and gluconeogenesis a) Regulatory enzymes Glycolysis Gluconeogenesis 1. Hexokinase Glucose 6 -phosphatase 3. Phosphofructokinase Fructose 1, 6 - bisphosphatase 10. Pyruvate kinase Pyruvate carboxylase Phosphoenolpyruvate carboxykinase ______________________________ b) The remaining enzymes are shared by both pathways

regulated fructose bisphosphatase regulated

Energy difference between glycolysis and gluconeogenesis ******************* * Total Energy Cost = 6 high energy bonds used per glucose synthesized. four more than produced in glycolysis. These four are needed to convert pyruvate to PEP. *******************

2) Conversion of glycerol to glucose • Glycerol derived from the breakdown of fats is converted to dihydroxyacetone phosphate (DHAP):

3) Glucogenic amino acids: • Are amino acids that can convert to glucose. • Some or all of the carbon atoms of these amino acids are broken down to -pyruvate or - intermediates of the TCA.

19 Amino Acids are Glucogenic, 14 are Purely Glucogenic Pyruvate Amino acid catabolism Citrate Isocitrate a-ketoglutarate Succinyl-Co. A Succinate Fumarate Malate TCA Intermediates TCA oxaloacetate

TCA intermediates are glucogenic: form glucose through oxaloacetate

• • 1. 2. 3. 4. 4)Propionate is converted to succinyl Co. A This process requires biotin and vitamin B 12 Propionate+ Co. A→ Propionyl Co. A + CO 2 ---biotin ---→ D methylmalonyl Co. A→L methylmalonyl Co. A ---- vitamin B 12 → Succinyl Co. A

Reactions 2 and 4 2. Propionyl Co. A carboxylase requires biotin 4. Methylmalonyl Co. A isomerase requires vitamin B 12

The Cori Cycle & The Glucose–Alanine Cycle

The Cori Cycle • It is the process by which lactate produced by muscles during strenuous anaerobic exercise is converted back to glucose through gluconeogenesis, and then returned to the tissues

The Cori Cycle STEPS 1. Lactate produced in muscle is transported to the liver. 2. Lactate is converted to pyruvate by Lactate Dehydrogenase

The Cori Cycle 3. Pyruvate is used as a substrate for gluconeogenesis 4. Glucose is returned to the muscles through the blood stream

The Cori Cycle • Lactate – RBC – muscle

The Glucose–Alanine Cycle • Alanine serves as a "shuttle" for pyruvate from the muscles to the liver. • Pyruvate produced by glycolysis in muscles is transaminated to alanine. • Alanine is transported to the liver, where it is re-converted to pyruvate and used for gluconeogenesis

Significance of these two cycles • Remove lactate in muscle and RBCs • Increase blood glucose level using amino acids in special situations

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