Fates of Pyruvate

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KEY FATES OF PYRUVATE

1. Acetyl CoA: substrate for citric acid cycle and fatty acid synthesis
2. Oxaloacetate: intermediate in CAC and substrate for gluconeogenesis
3. Lactate: produced by eukaryotes in absence of oxygen
4. Ethanol: produced by yeast and some bacteria (including intestinal flora) in absence of oxygen.

AEROBIC CONDITIONS

1. Cellular respiration: Pyruvate converts to acetyl CoA

• Fed conditions (glucose abundant)
• Occurs in mitochondrial matrix
• Pyruvate dehydrogenase complex
• Irreversible reaction: produces 1 CO2 and 1NADH
• Acetyl CoA enters the citric acid cycle and oxidative phosphorylation
• Final product is ATP

2. Gluconeogenesis: Pyruvate converts to oxaloacetate

• Fasting conditions (glucose in demand)
• Occurs in liver (minor process in kidneys): mitochondrial matrix
• Pyruvate carboxylase
• Irreversible reaction
• Oxaloacetate is substrate for gluconeogenesis and CAC intermediate

ANAEROBIC CONDITIONS

3. Lactic acid fermentation (humans)

• Occurs in exercising muscle and red blood cells: cytosol
• Glycolysis: 1 glucose = 2 pyruvates + 2 ATP + 2 NADH
• Lactate dehydrogenase: 2 pyruvate + 2NADH = 2 lactate + 2 NAD+
• Reversible reaction
• Lactate can enter bloodstream and travel to liver: lactate dehydrogenase catalyzes reverse reaction (lactate to pyruvate)

Clinical correlation: intense exercise can produce lactic acidosis; lactate accumulates in muscle cells and causes intracellular drop in pH

4. Ethanol production (yeast and select bacteria)

• Can occur in inteestinal flora
• Glycolysis: 1 glucose = 2 pyruvates + 2 ATP + 2 NADH
• 2 step rxn: pyruvate to acetaldehyde to ethanol
• Ethanol formation consumes 2 NADH in second step and produces 2 NAD+ for reuse
• Irreversible reaction
• Fermentation in yeast used to make beer and wine

Full-Length Text

• Here we will learn the different fates of pyruvate, which is the product of glycolysis.

• To begin, start a table so we can list 4 key fates of pyruvate.
  • Acetyl CoA, which is a substrate for the citric acid cycle and fatty acid synthesis.
  • Oxaloacetate, which is an intermediate in the citric acid cycle and also a substrate for gluconeogenesis.
  • Lactate, which is produced by eukaryotes in the absence of oxygen.
  • Ethanol, which is produced by yeast and some bacteria (including intestinal flora) in the absence of oxygen.

We will illustrate the location and function of each of these processes.

• To begin, indicate that pyruvate is a three-carbon molecule and that it is formed in the first step of glucose metabolism: glycolysis.
  • Two pyruvates are formed per glucose molecule, but we will only illustrate one for simplicity.

• Show that this occurs in the cytosol.

• Show that we categorize the pyruvate fates based on if they are: aerobic or anaerobic, meaning whether they occur in the presence or absence of oxygen.

• Next, show that in aerobic conditions (the presence of oxygen), pyruvate has two possible fates:

• The first is cellular respiration, which occurs in fed conditions – when glucose is abundant.
• The second is gluconeogenesis, which occurs in fasting conditions – when glucose is in demand.

Begin with cellular respiration, in which the key fate of pyruvate is acetyl CoA.

• Draw a mitochondrion as follows:
  • Outer mitochondrial membrane, which is a phospholipid bilayer.
  • Inner mitochondrial membrane, which comprises invaginations called cristae. It is also a phospholipid bilayer.
  • Label the intermembrane space, which lies between the membranes.
  • Label the matrix, which lies within the inner mitochondrial membrane.

• Show that pyruvate enters the matrix, where it is converted to acetyl CoA.

• Indicate that this is an irreversible reaction, catalyzed by an enzymatic complex called pyruvate dehydrogenase complex.

• Illustrate that this reaction also produces one NADH molecule and one carbon dioxide molecule as waste.
  • Remember, this is actually 2NADH molecules and 2 carbon dioxide molecules per glucose.

• Draw a circle of arrows in the matrix to illustrate the citric acid cycle.

• Show that acetyl CoA can enter the citric acid cycle.

• Next, draw the electron transport chain on the inner mitochondrial membrane.
  • Indicate that the products of the citric acid cycle can enter the electron transport chain.

• Show that the final product is ATP, energy for the cell.
  • Acetyl CoA is also a substrate for fatty acid synthesis, but we will not describe this here.

Next, let's show gluconeogenesis, in which the key fate of pyruvate is oxaloacetate.

• Draw a liver, which stores glucose in the body.

• Draw a section of mitochondrion: the inner membrane and the matrix.

• Show that pyruvate again enters the mitochondrial matrix where it is converted to oxaloacetate.
  • Indicate that this is an irreversible reaction catalyzed by pyruvate carboxylase.

• Write that oxaloacetate is a substrate for gluconeogenesis.

• Write that it is also an intermediate of the citric acid cycle.
  • Thus, indicate that this pathway also replenishes citric acid cycle intermediates.

• This brings us to the final two pathways, which occur in the absence of oxygen:
  • Lactic acid fermentation (lactate production), which occurs in humans.
  • Ethanol production, which occurs in yeast and select bacteria.

Let's start with lactate production.

• Indicate that it occurs in exercising muscle and red blood cells (rbc's).

• To begin, draw an exercising muscle cell.
  • Exercising muscles lack oxygen, which slows down the citric acid cycle and oxidative phosphorylation, and causes NADH to accumulate.

How do these cells produce energy?

• We have already drawn the answer: glycolysis.

Let's redraw glycolysis in the cytosol of the exercising muscle cell. We won't draw it again in the red blood cell, but the same process occurs here.

• Indicate that glycolysis breaks down glucose into two molecules pyruvate.

• Show that it produces 2 NADH's and 2 ATP's via substrate-level phosphorylation.

• Use an arrow to illustrate that pyruvate undergoes lactic acid fermentation in the cytosol.

• Draw the product of this process: 2 lactates (one for each pyruvate).

• Illustrate that 2NADH's are consumed in the production of lactate. NAD+ can then be reused in glycolysis.

• Thus, the net NADH produced in lactic acid fermentation is 0. The net ATP is 2.

• Indicate that this process is catalyzed by lactate dehydrogenase and that it is reversible; it is influenced by the concentration of NADH in the cell.
  • Thus, high NADH favors lactic acid fermentation.

• As a clinical correlation, write that intense exercise can produce lactic acidosis, in which lactate accumulates in muscle cells and causes an intracellular drop in pH.
  • This can produce cramps.

How do we get rid of this excess lactate?

• Show that lactate can exit the muscle and enter the bloodstream.

• Indicate that it travels to the liver, where it is oxidized back to pyruvate by the same enzyme.
  • Pyruvate can then enter gluconeogenesis or the citric acid cycle.

This brings us to our final pathway: ethanol production.

• Draw an intestine to indicate that this can occur in our intestinal flora.

• Show that a glucose molecule is in the cytosol.

• Show that it undergoes glycolysis to produce two pyruvate molecules.

• Again show that 2NADH's and 2ATP's are produced.

• Next, indicate that pyruvate reduces to ethanol in a two-step reaction that also occurs in the cytosol.

• Show that the intermediate in these processes is acetaldehyde.

• Illustrate that two carbon dioxide molecules are lost (1 per pyruvate) to produce this two-carbon intermediate.

• Finally, show that two NADH's are oxidized to produce ethanol in the second step.
  • NAD+ can then be reused in glycolysis.

• Each step requires a different enzyme, which we will not cover here.

• Indicate that this reaction is reversible.

• Draw a pint-glass to indicate that fermentation in yeast is used to make beer and wine.