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Biochem > Gluconeogenesis > Flashcards

Gluconeogenesis Flashcards

1
Q

What is gluconeogenesis

A

The formation of new glucose from non-carbohydrate sources

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2
Q

What is the purpose of gluconeogenesis?

A

To provide glucose for export to other tissues when glycogen stores are exhausted ad when no dietary glucose is available

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3
Q

Where does gluconeogenesis occur?

A

In the liver and kidneys (to a lesser extent)

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4
Q

What hormones regulate gluconeogenesis?

A
  • Glucagon
  • Insulin
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5
Q

What are some glucogenic precursors that can be utilized in gluconeogenesis?

A
  • Pyruvate
  • Lactate
  • Amino acids (alanine)
  • Glycerol
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6
Q

Is gluconeogenesis glycolysis in reverse?

A

No!
- There are three irreversible steps in glycolysis (due to high -ΔG)
- These steps must be bypassed in gluconeogenesis

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7
Q

What is the starting material for gluconeogenesis?

A

Any compound that can be converted to either pyruvate or oxaloacetate

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8
Q

Of the 10 reactions of gluconeogenesis, how many are the reverse of glycolysis?

A

7

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9
Q

What are the three reactions that must be bypassed in gluconeogenesis?

A
  1. Conversion of phosphoenolpyruvate to pyruvate by pyruvate kinase
  2. The phosphorylation of fructose 6-phosphate to fructose 1,6-bisphosphate by phosphofructokinase-1 (PFK-1)
  3. Conversion of glucose to glucose 6-phosphate by hexokinase
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10
Q

Describe the first bypass reaction in gluconeogenesis

A
  1. Conversion of phosphoenolpyruvate (PEP) to pyruvate by pyruvate kinase
  • Last step of glycolysis
  • 2 steps

Step 1: Pyruvate → Oxaloacetate
- Occurs in the mitochondria
- Pyruvate is transported into the mitochondria via the malate shuttle
- Reaction is catalyzed by pyruvate carboxylase (2 active sites)
- Biotin (coenzyme) has long arms that can access both sites 1 and 2
- Site 1 - HCO3- uses energy from hydrolysis to form CO2 which is covalently added to biotin
- Site 2 - Biotin donates CO2 to pyruvate
Pyruvate + HCO3- + ATP → Oxaloacetate + ADP +Pi

Step 2: Oxaloacetate → Phosphoenolpyruvate (PEP)
- Occurs in the cytosol
- Utilize malate shuttle
- Catalyzed by PEP carboxykinase
Oxaloacetate + GTP ⇌ PEP + CO2 + GDP

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11
Q

Why does the second part of the first bypass reaction need to utilize the malate shuttle?

A
  • The second step in the first bypass reaction takes place in the cytosol BUT Oxaloacetate CANNOT freely transport across the mitochondria membrane
  • Oxaloacetate gets converted to malate which can freely cross the mitochondria membrane by the malate transporter
  • Malate gets reconverted to oxaloacetate in the cytosol of the mitochondria
  • Catalyzed by malate dehydrogenase
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12
Q

What is the significance of the malate shuttle?

A
  • NADH is low in the cytosol compared to in the mitochondria
  • The malate shuttle transports NADH from the mitochondria to the cytosol so that it can be used in subsequent gluconeogenesis reactions (conversion of 1,3-bisphosphoglycerate to glyceraldehyde 3-phosphate)

Mitochondria: Oxaloacetate NADH + H+ ⇌ Malate + NAD+
Cytosol: Malate + NAD+ → Oxaloacetate + NADH + H+

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13
Q

The first bypass reaction in which pyruvate → PEP described above is predominant when pyruvate is the glucogenic precursor BUT, lactate can also be used as a glucogenic precursor. How does the by pass reaction differ when lactate is the precursor?

A
  • Lactate is able to bypass the malate shuttle
  • Oxaloacetate is directly converted to PEP by using a mitochondrial version of PEP carboxykinase
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14
Q

Describe the second and third bypass reaction in gluconeogenesis

A
  1. The phosphorylation of fructose 6-phosphate to fructose 1,6-bisphosphate by phosphofructokinase-1 (PFK-1)
  2. Conversion of glucose 6-phosphate to glucose by hexokinase

These are both hydrolysis reactions that utilizes water

  • Step 2 = catalyzed by fructose 1,6-bisphosphatase (FBPase-1)
    Fructose 1,6-phosphate + H2O → Fructose 6-phosphate +Pi
  • Step 3 = catalyzed by Glucose 6-phosphatase
    Glucose 6-phosphate + H2O → glucose + Pi
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15
Q

Gluconeogenesis is very energetically expensive. So, why does the cell carry out this reaction?

A
  • There are many tissues (ex: brain) that rely heavily on glucose
  • Irreversibility of gluconeogenesis ensures that gluconeogenesis and glycolysis do NOT occur simultaneously
    (Doing both at the same time is very wasteful!)
  • Prevents the excretion (complete waste) of pyruvate
  • Many molecules feed into gluconeogenesis
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16
Q

How and why do we prevent gluconeogenesis and glycolysis from running at the same time?

A

PFK-1 and FBPase-1 reciprocally regulate glycolysis and gluconeogenesis to prevent both pathways from running at the same time (which is wasteful)
PFK-1 catalyzes the reaction that commits glucose 6-phosphate to glycolysis

17
Q

Describe the reciprocal regulation of PFK-1 and FBPase-1

A
  • Both enzymes catalyze the reaction that converts Fructose 6-phosphate to Fructose 1,6-bisphosphate (reverse in gluconeogenesis)
  • When ATP (or citrate) = high, PFK-1 is inhibited (ATP production is higher than consumption)
  • ADP or AMP will relieve this inhibition (activate PFK-1) (ATP consumption is higher than ATP production)
  • AMP inhibits FBPase-1
18
Q

What is responsible for the reciprocal regulation of PFK-1 and FBPase-1?

A
  • Fructose 2,6-bisphosphate
19
Q

How does Fructose 2,6-bisphosphate allosterically regulate PFK-1 and FBPase-1

A
  • PFK-1 = allosterically activated by Fructose 2,6-bisphosphate (reduced affinity for inhibitors citrate / ATP)
  • FBPase-1 (second bypass step / gluconeogenesis equivalent of PFK-1) = allosterically inhibited by Fructose 2,6-bisphosphate

In other words….
- If Fructose 2,6-bisphosphate is present: PFK-1 activity is high and FBPase-1 activity = low

20
Q

Where does Fructose 2,6-bisphosphate come from?

A

Fructose 6-phosphate

21
Q

What catalyzes the reaction that creates fructose 6-phosphate?

A

PFK-2

22
Q

What regulates the breakdown of fructose 6-phosphate?

A

FBPase-2

23
Q

How are PFK-2 and FBPase-2 regulated?

A
  • Phosphorylation
  • PFK-2 and FBPase-2 are the same protein molecule. When the enzyme is phosphorylated FBPase-2 is active. When the enzyme is NOT phosphorylated PFK-2 is active.
  • cAMP-dependent protein kinase phosphorylates enzyme activating FBPase-2
  • Phospho-protein phosphatase removes phosphoryl group from enzyme activating PFK-2
24
Q

What role does glucagon play in the regulation of fructose 6-phosphate?

A
  • Stimulates adenylyl cyclase to synthesize cAMP which in turn activates cAMP-dependent protein kinase
  • Lowers cellular levels of fructose 2,6-bisphosphate (FBPase-2)
  • Inhibits glycolysis and stimulates gluconeogenesis
25
Q

What role does insulin play in the regulation of fructose 6-phosphate?

A
  • Stimulates the activity of phosphorus-protein phosphatase
  • Increases cellular levels of fructose 2,6-bisphosphate (PFK-2)
  • Inhibits gluconeogenosis
26
Q

How else can PFK-2 and FBPase-2 be regulated?

A
  • Xylulose 5-phosphate
  • Dephosphorylates PFK-2 / FBPase-2 enzyme activating PFK-2 / inhibiting FBPase-2 inhibiting gluconeogenesis and stimulating glycolysis
27
Q

How does the spatial separation of glycolysis and gluconeogenesis prevent both processes from occurring at the same time?

A
  • Glucose 6-phosphatase (last bypass reaction) is exclusively found on the ER membrane of the liver and kidneys
  • The active site of glucose 6-phosphatase faces the ER lumen
  • Glucose 6-phosphate = converted to glucose in the ER lumen
  • Glucose is then transported to the cytosol (very briefly) before it is transported back out of the cytosol and into the bloodstream
    Because glucose is NOT in the cytosol for a long period of time it cannot enter glycolysis

Biochem (22 decks)

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