Lecture 10: Cellular Respiration

Aerobic Metabolism of Glucose Traps Nearly 20 Times More Energy than Anaerobic Metabolism

• Anaerobic (without oxygen) metabolism (glycolysis) yields 2 net ATPs per glucose
  • 4 ATPs are produced but 2 ATPs are used to prime the reactions
  • 2 NADHs also produced, but if there is no oxygen the hydrogens are donated to pyruvate to produce lactate
• In aerobic (with oxygen) respiration of glucose 36 ATPs are made per glucose molecule, increasing the trapped energy 18 times
• Higher forms of life require the extra energy made available by respiration

Aerobic Metabolism Takes Place in Mitochondria

• Mitochondria oxidize glucose much more completely than in glycolysis
• Have enzymes for these processes:
  • Decarboxylation of pyruvic acid to acetylCoA
  • Krebs cycle, which oxidizes the acetyl CoA to CO2 and traps energy in the bonds of NADH, FADH2 and ATP
  • Electron transport chain, which converts NADH and FADH2 bond energy to ATP bond energy
• Mitochondria found in almost all eukaryotic cells
• Very abundant in active tissues such as muscle and liver

Acetyl CoA Has a Central Position in Metabolism

• Pyruvic acid is transported into the mitochondria by a facilitated transport system
  • Goes into innermost compartment, the matrix
• The pyruvic dehydrogenase enzyme removes a CO2 from pyruvic acid and produces NADH
  • remember that 2 pyruvates are produced from each glucose
  • the pyruvates are converted to 2 NADHs and 2 acetylCoAs in this reaction
  • the first 2 of the 6 glucose carbons are oxidized to CO2

• Fatty acids and some amino acids are also broken down to acetylCoA and then enter the Krebs Cycle

Completely Oxidizing a Glucose Requires 2 Spins of the Krebs Cycle

• The Krebs cycle is a cyclic set of 8 reactions that oxidize the remaining 2 carbons in AcetylCoA to CO2 and generates NADH, FADH2 and ATP
• For an overview see diagram in lecture 9 and figures on p. 169, 170 and 173 of text
  
  
  
• In each spin of the cycle and acetylCoA combines with oxaloacetic acid to form citric acid
  • 2 carbons (acetylCoA) + 4 carbons (oxaloacetic) = 6 carbons (citric)
• In each spin the 2 acetyl carbons from acetylCoA are oxidized to CO2
• In different parts of the cycle NADH, FADH2 and ATP are generated:
• In the conversion of succinyl CoA to succinate the compound formed is actually GTP (guanosine triphosphate) instead of ATP, but the GTP is rapidly converted to ATP, so I have shown it this way for simplicity
  • This is a substrate level phosphorylation, like those in glycolysis (the electron transport chain is not involved)
• For 2 spins of the cycle the yield of high energy compounds is:
  • 2 ATPs
  • 6 NADHs
  • 2 FADH2s
• The NADHs and FADH2s will be redeemed for ATPs using the electron transport chain

The Electron Transport Chain Uses a Hydrogen Gradient to Make ATP

• A hydrogen atom is equivalent to a hydrogen ion plus an electron
  • H = H+ + e-
• In the FAD reactions 2 hydrogen molecules are removed and added to FAD
• In NAD reactions 2 hydrogens are removed and one is added to the NAD+; the other is split and NAD+ gets the electron leaving a hydrogen ion which goes into solution
• In the electron transport chain the hydrogen atoms are split and recombined several times
• The simplified diagram below shows gives an overview of electron transport chain operations
• Note that there are 2 mitochondrial compartments formed by the 2 bilayer membranes
  • Intermembrane space (yellow): pH 7
  • Matrix (dark blue): pH 8
• The light blue circles represent the electron transport chain (ETC), which is imbedded in the membrane between the 2 compartments (the inner mitochondrial membrane)
• The ETC actually has 3 major electron carrier complexes (text, p. 172)
• Also imbedded in this membrane is the enzyme ATP synthase (pink)

• The Krebs cycle takes place in the matrix, producing NADH and FADH2 (not shown)
• The NADH (and the FADH2) transfers its hydrogens to the ETC, where they are split into H+ ions and electrons
• The ETC acts as a H+ ion pump, pulling H+s into the intermembrane space
  • This causes intermembrane space pH to drop to 7 and raises matrix pH to 8
  • "Pump" may not be the best term for the hydrogen carrier, since this is not an active transport consuming energy from ATP
• The electrons are conducted laterally through the membrane from one ETC complex to the next, each time donating some of their energy to "pump" H+ ions (for more details see text diagram on p. 172)
• Finally the de-energized electrons are combined with hydrogen ions and oxygen to produce water in the matrix
  • This reaction is catalyzed by cytochrome oxidase
  • The reaction is inhibited by cyanide, which is why cyanide is a poison
• These reactions store energy in a hydrogen gradient: H+ concentration is 10 X higher in the intermembrane space than in the matrix
• H+ diffuses back into the matrix through a channel in ATP synthase, producing an electric current
• The shaft of the ATP synthase complex rotates (counterclockwise if you view it from the matrix) when it conducts an electric current. Click to seen an animated cartoon of ATP synthase in action.
• In ways not understood the energy of rotation is linked to the synthesis of ATP.
• ATP is formed in the inner matrix: it must be transported across 2 membranes to get into the cytosol
• The mechanism of ATP generation was worked out by Peter Mitchell, who received the Nobel Prize for his work. He called the scheme "chemiosmosis", but this seems a misuse of the term "osmosis" to me.

Comparing the Energy Capture of Glycolysis and Respiration

• Most of the energy captured from the Krebs cycle is in the bonds of the coenzymes, NADH and FADH2
• In the electron transport chain the coenzyme energy is "cashed in" for ATP- a little like a currency exchange
• The exchange rate is different for the different coenzymes
  • FADH2 gives 2 ATPs
  • NADH made in the mitochondria gets 3 ATPs
  • NADH made outside the mitochondria (in glycolysis) gets only 2 ATPs (some energy is lost in transporting this NADH into the mitochondria)
• If the glucose is totally oxidized, using glycolysis, decarboxylation and the Krebs cycle, 36 ATPs are generated per glucose, compared to only 2 if glycolysis alone is used
• The great increase of energy generated by the mitochondria makes possible complex multicellular life forms
  
• An accounting summary:

	ATPs	NADHs	FADH2s	ATPs From ETC	Total ATPs
Glycolysis	2	2	0	4	6
Decarboxylation of Pyruvate	0	2	0	6	6
Krebs Cycle	2	6	2	22	24
Total	4	10	2	32	36

• These are maximum amounts. As Campbell points out the actual yields are probably a little lower than this.
• If you burn glucose in 1 step 686 kilocalories are released per mole. We can calculate how much of this energy is trapped in the bonds of ATP. Under standard conditions the hydrolysis of ATP gives 7.3 kcal/mole, but under conditions in the cell the value is around 13 kcal/mole.
  • Energy trapped in ATP = (36 ATP)(13 kcal/ATP) = 468 kcal
  • This is 68% of the energy available from glucose
  • On p. 174 of the text Campbell calculates a figure of 38% energy storage. He uses the 7.3 kcal value for an ATP bond instead of 13, which is more appropriate for the cell. For a discussion of standard and "non-standard" free energies see Bruce Alberts, et al. Molecular Biology of the Cell, 3rd edit., p. 667-670.

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