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Gluconeogenesis Flashcards

1
Q

What is glucose synthesis needed for

A
  1. Constant supply of glycolytic substrate
  2. Export from liver to maintain blood glucose
  3. Synthesis of pentoses (ribose, deoxyribose etc)
  4. Synthesis of amino sugars (example glucosamine, used in proteoglycans)
  5. Synthesis of acidic sugars (example: uronic acid, used in proteoglycans)
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2
Q

How is NAD+ regenerated after glycolysis

A
  1. Pyruvate + NADH + H+ –> NAD+ + Lactate

2. Lactate dehydrogenase

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3
Q

Why is gluconeogenesis needed

A
  1. The liver’s capacity to store glycogen is not enough to supply the brain
  2. So gluconeogenesis must provide glucose when fasting
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4
Q

What are the two amino acids that can’t be converted to oxaloacetate in animals

A
  1. Lysine and leucine
  2. Their breakdown yields only acetyl-CoA
  3. No pathway for net conversion of acetyl-CoA to oxaloacetate
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5
Q

What must first happen to precursors before they can undergo gluconeogenesis

A
  1. Must be converted to oxaloacetate
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6
Q

What are some noncarbohydrate precursors

A
  1. lactate
  2. pyruvate
  3. citric acid cycle intermediates
  4. Carbon skeleton of most amino acids
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7
Q

Can fatty acids be used in gluconeogenesis

A
  1. In animals no as degraded to acetyl-CoA
  2. In plants- contain pathway to convert acetyl-CoA to oxaloacetate- glyoxylate cycle
  3. So lipids can be used as plant cells only carbon source
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8
Q

What three enzymes that are used in glycolysis must be replaced in gluconeogenesis

A
  1. Hexokinase
  2. phosphofructokinase PFK
  3. pyruvate kinase
  4. They all catalyse reactions with large negative free energy changes in direction of glycolysis so need to be replaced so is thermodynamically favourable
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9
Q

What is the first step in glucneogenesis

A
  1. Pyruvate is converted to oxaloacetate then phosphoenolpyruvate
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10
Q

How is the energy provided for pyruvate converted to phosphoenolpyruvate

A
  1. The formation of phosphoenolpyruvate PEP is endergonic so requires free energy input
  2. First convert pyruvate to oxaloacetate- high level intermediate
  3. The exergonic decarboxylation of oxaloacetate provides free energy necessary for PEP synthesis
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11
Q

What are the two enzymes required to convert pyruvate to phosphoenolpyruvate

A
  1. Pyruvate carboxylase- catalyses the ATP driven formation of oxaloacetate from pyruvate and HCO3-
  2. PEP carboxykinase (PEPCK)- converts oxaloacetate to PEP in a reaction that uses GTP as a phosphorylating agent
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12
Q

Describe the structure of pyruvate carboxylase

A
  1. It has 4-sub units, tetrameric structure
  2. Mg2+ and biotin dependent
  3. Each subunit has an identical biotin prosthetic group
  4. Biotin is covalently bound to the enzyme by an amide linkage forming biocytin residue- this forms a ring structure at the end of a long flexible arm like in lipoic acid prosthetic group in pyruvate dehydrogenase
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13
Q

Describe the formation of oxaloacetate from pyruvate

A
  1. Biotin is carboxylated by HCO3- (CO2 goes in) and ATP is hydrolysed
  2. The resulting carboxyl group is activated relative to bicarbonate and can therefore be transferred without further free energy input
  3. Activated carboxyl group is transferred from carboxybiotin to pyruvate to form oxaloacetate
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14
Q

What can regulate pyruvate carboxylase

A
  1. Acetyl-CoA
  2. oxaloacetate synthesis is an anaplerotic reaction that increases citric acid cycle activity
  3. Accumulation of citric acid substrate acetyl-CoA signals the need for more oxaloacetate
  4. Acetyl-CoA is a powerful allosteric activator of pyruvate carboxylase- basically inactive without
  5. If citric acid cycle is inhibited by high levels of ATP and NADH then oxaloacetate undergoes gluconeogenesis
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15
Q

Describe the function of PEP carboxykinase

A
  1. Catalyses the GTP-driven decarboxylation of oxaloacetate to form PEP and GDP
  2. The CO2 used to make oxaloacetate is eliminated
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16
Q

What does gluconeogenesis require

A
  1. Metabolite transport between mitochondria and cytosol
17
Q

Why is the transport between mitochondria and cytosol required

A
  1. Generation of oxaloacetate from pyruvate or citric acid intermediates occurs only in mitochondria
  2. Enzymes that convert PEP to glucose are cytosolic
  3. PEPCK location varies
18
Q

How is PEP transported

A
  1. PEP is transported across the mitochondrial membrane by specific membrane transport proteins
  2. But no system for oxaloacetate- first must be converted to either aspartate or malate
19
Q

What is the malate dehydrogenase route

A
  1. Involves mitochondrial oxidation of NADH
  2. Followed by the cytosolic reduction of NAD+
  3. Therefore it also transfers NADH reducing equivalents from mitochondria to cytosol
20
Q

What is the aspartate aminotransferase route

A
  1. Does not involve NADH
  2. As cytosolic NADH is needed for gluconeogenesis, under most conditions route through malate is necessary
  3. If it is lactate- its oxidation to pyruvate generates NADH so either transport method can be used
21
Q

What happens instead of the PFK and hexokinase reaction

A
  1. Instead of generating ATP by reversing the reaction
  2. Fructose-bisphosphate and Glucose-6-phosphate are hydrolysed- releasing Pi in exergonic processes
  3. This is catalysed by fructose-1,6-bisphosphatase FBPase and glucose-6-phosphatase
22
Q

What is the overall equation for gluconeogenesis

A
  1. 2Pyruvate + 2NADH + 4H+ + 4ATP + 2GTP + 6H2O –> glucose + 2NAD+ + 4ADP + 2GDP + 6Pi
  2. It uses two molecules of each of ATP and GTP per molecule of glucose on top of the ATP that is already consumed by direct reversal of glycolysis
23
Q

Describe why gluconeogenesis needs to be regulated

A
  1. Otherwise futile cycle of glycolysis and gluconeogenesis wasting ATP and GTP
24
Q

How is gluconeogenesis regulated

A
  1. Reciprocally regulated with glycolysis
  2. When blood glucose level is high- liver wants to conserve- glycogen is synthesised and glycolytic pathway and pyruvate dehydrogenase are activated
  3. Glucose is broken down to acetyl-CoA for fatty acid biosynthesis and fat storage
  4. When fasting- liver maintains blood glucose level by stimulating glycogen breakdown and by reversing flux through glycolysis to gluconeogenesis
25
Q

How are the rates of glycolysis and gluconeogenesis controlled

A
  1. Allosteric interactions and covalent modifications
  2. PFK/FBPase- allosteric inhibitors/activators
  3. PK/pyruvate carboxylase and PEPCK- allosteric inhibitors/activators and phosphorylation
  4. hexokinase/glucose-6-phosphatase- allosteric inhibitors/activators and phosphorylation
26
Q

What is one of the most important regulators of glycolysis/gluconeogenesis

A
  1. Concentration of Fructose-2,6-phosphate is one of the most important- activates PFK and inhibits FBPase
  2. Rate of synthesis and breakdown is controlled by phosphofructokinase-2 PFK-2 and fructose bisphosphatase-2 FBPase-2
  3. These enzymes activities are also subject to allosteric inhibition by covalent modification
  4. Low levels of blood-glucose - hormonal activation of gluconeogenesis through regulation of fructose-1,6-phosphate-
  5. increased cAMP- increased enzyme phosphorylation- activate FBPase-2 inactivate PFK-2-
  6. decrease fructose-1,6-bisphosphate-inhibition of PFK and activation of FBPase-
  7. increased gluconeogenesis
27
Q

How is pyruvate kinase inhibited

A
  1. Activation of gluconeogenesis in liver inhibits glycolysis on pyruvate kinase level
  2. Both allosterically by alanine and by phosphorylation
  3. Glycogen breakdown is stimulated by phosphorylation
  4. Both pathways flow towards G6P which is converted to glucose for export to muscle and brain
28
Q

Describe muscle pyruvate kinase

A
  1. Isoenzyme of the liver enzymes
  2. Not subject to same controls
  3. Tissue lacks ability to synthesise glucose via gluconeogenesis.
29
Q

Describe the inhibitors/activators for PFK

A
  1. Allosteric inhibitors- ATP, Citrate
  2. Allosteric activators- AMP, Fructose-2,6-bisphosphate
  3. Phosphorylation- no effect
  4. Protein synthesis- no effect
30
Q

Describe the inhibitors/activators for FBPase

A
  1. Allosteric inhibitors- AMP, Fructose-2,6-bisphosphate
  2. Allosteric activators- None
  3. Phosphorylation- no effect
  4. Protein synthesis- no effect
31
Q

Describe the inhibitors/activators for PK

A
  1. Allosteric inhibitors- Alanine
  2. Allosteric activators- Fructose-1,6-bisphosphate
  3. Phosphorylation- inactivates
  4. Protein synthesis- no effect
32
Q

Describe the inhibitors/activators for pyruvate carboxylase

A
  1. Allosteric inhibitors- none
  2. Allosteric activators- acetyl-CoA
  3. Phosphorylation- no effect
  4. Protein synthesis- no effect
33
Q

Describe the inhibitors/activators for PEPCK

A
  1. Allosteric inhibitors- None
  2. Allosteric activators- none
  3. Phosphorylation- no effect
  4. Protein synthesis- stimulated by glucagon
34
Q

Describe the inhibitors/activators for PFK-2

A
  1. Allosteric inhibitors- Citrate
  2. Allosteric activators- AMP, F6P, Pi
  3. Phosphorylation- inactivates
  4. Protein synthesis- No effect
35
Q

Describe the inhibitors/activators for FBPase-2

A
  1. Allosteric inhibitors- F6P
  2. Allosteric activators- glycerol-3-p
  3. Phosphorylation- activates
  4. Protein synthesis- none
36
Q

What is the cori cycle

A
  1. When ATP demand exceeds oxidative flux short-twitch fibres also produce lactate- which is transferred to the liver
  2. In the liver it is reconverted to pyruvate by lactate dehydrogenase and then to glucose by gluconeogenesis
  3. Liver ATP is used to resynthesise glucose from lactate produced in muscle
  4. The resynthesized glucose is returned to the muscle where it is stored as glycogen and used on demand to generate ATP for muscle contraction
  5. The ATP used by the liver is regenerated by oxidative phosphorylation- takes a while for oxygen level to return to normal- oxygen debt
37
Q

What effect do insulin/ glucagon have

A
  1. Insulin- lowers blood glucose

2. Glucagon- raises blood glucose

BB10235 (16 decks)

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