Gluconeogenesis Flashcards
What is glucose synthesis needed for
- Constant supply of glycolytic substrate
- Export from liver to maintain blood glucose
- Synthesis of pentoses (ribose, deoxyribose etc)
- Synthesis of amino sugars (example glucosamine, used in proteoglycans)
- Synthesis of acidic sugars (example: uronic acid, used in proteoglycans)
How is NAD+ regenerated after glycolysis
- Pyruvate + NADH + H+ –> NAD+ + Lactate
2. Lactate dehydrogenase
Why is gluconeogenesis needed
- The liver’s capacity to store glycogen is not enough to supply the brain
- So gluconeogenesis must provide glucose when fasting
What are the two amino acids that can’t be converted to oxaloacetate in animals
- Lysine and leucine
- Their breakdown yields only acetyl-CoA
- No pathway for net conversion of acetyl-CoA to oxaloacetate
What must first happen to precursors before they can undergo gluconeogenesis
- Must be converted to oxaloacetate
What are some noncarbohydrate precursors
- lactate
- pyruvate
- citric acid cycle intermediates
- Carbon skeleton of most amino acids
Can fatty acids be used in gluconeogenesis
- In animals no as degraded to acetyl-CoA
- In plants- contain pathway to convert acetyl-CoA to oxaloacetate- glyoxylate cycle
- So lipids can be used as plant cells only carbon source
What three enzymes that are used in glycolysis must be replaced in gluconeogenesis
- Hexokinase
- phosphofructokinase PFK
- pyruvate kinase
- They all catalyse reactions with large negative free energy changes in direction of glycolysis so need to be replaced so is thermodynamically favourable
What is the first step in glucneogenesis
- Pyruvate is converted to oxaloacetate then phosphoenolpyruvate
How is the energy provided for pyruvate converted to phosphoenolpyruvate
- The formation of phosphoenolpyruvate PEP is endergonic so requires free energy input
- First convert pyruvate to oxaloacetate- high level intermediate
- The exergonic decarboxylation of oxaloacetate provides free energy necessary for PEP synthesis
What are the two enzymes required to convert pyruvate to phosphoenolpyruvate
- Pyruvate carboxylase- catalyses the ATP driven formation of oxaloacetate from pyruvate and HCO3-
- PEP carboxykinase (PEPCK)- converts oxaloacetate to PEP in a reaction that uses GTP as a phosphorylating agent
Describe the structure of pyruvate carboxylase
- It has 4-sub units, tetrameric structure
- Mg2+ and biotin dependent
- Each subunit has an identical biotin prosthetic group
- 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
Describe the formation of oxaloacetate from pyruvate
- Biotin is carboxylated by HCO3- (CO2 goes in) and ATP is hydrolysed
- The resulting carboxyl group is activated relative to bicarbonate and can therefore be transferred without further free energy input
- Activated carboxyl group is transferred from carboxybiotin to pyruvate to form oxaloacetate
What can regulate pyruvate carboxylase
- Acetyl-CoA
- oxaloacetate synthesis is an anaplerotic reaction that increases citric acid cycle activity
- Accumulation of citric acid substrate acetyl-CoA signals the need for more oxaloacetate
- Acetyl-CoA is a powerful allosteric activator of pyruvate carboxylase- basically inactive without
- If citric acid cycle is inhibited by high levels of ATP and NADH then oxaloacetate undergoes gluconeogenesis
Describe the function of PEP carboxykinase
- Catalyses the GTP-driven decarboxylation of oxaloacetate to form PEP and GDP
- The CO2 used to make oxaloacetate is eliminated