Raven - Ch. 7, How Cells Harvest Energy

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7.1 Overview 7.2 Glycolysis: Splitting Glucose 7.3 The Oxidation of Pyruvate to Produce Acetyl-CoA 7.4 The Krebs Cycle 7.5 The Electron Transport Chain and Chemiosmosis 7.6 Energy Yield of Aerobic Respiration 7.7 Regulation of Aerobic Respiration 7.8 Oxidation Without O₂ 7.9 Catabolism of Proteins and Fats 7.10 Evolution of Metabolism

Cellular respiration is the complete oxidation of glucose.

Aerobic respiration uses oxygen as the final electron acceptor for redox reactions. Anaerobic respiration utilizes inorganic molecules as acceptors, and fermentation uses organic molecules.

Electron carriers play a critical role in energy metabolism.

Electron carriers can be reversibly oxidized and reduced. For example, NAD⁺ is reduced to NADH by acquiring two electrons; NADH supplies these electrons to other molecules to reduce them.

Metabolism harvests energy in stages.

Mitochondria of eukaryotic cells move electrons in steps via the electron transport chain to capture energy efficiently.

ATP plays a central role in metabolism.

The ultimate goal of cellular respiration is synthesis of ATP, which is used to power most of the cell's activities.

Cells make ATP by two fundamentally different mechanisms.

Substrate-level phosphorylation transfers a phosphate directly to ADP.
Oxidative phosphorylation generates ATP via the enzyme ATP synthase, powered by a proton gradient.

Overview of Respiration

Cells oxidize organic compounds to drive metabolism.

Glycolysis: Splitting Glucose

Glycolysis converts glucose into two 3-carbon molecules of pyruvate. Each molecule of glucose yields two net ATP molecules.

Priming changes glucose into an easily cleaved form.

Priming reactions add two phosphates to glucose; this is cleaved into two 3-carbon molecules of glyceraldehyde 3-phosphate (G3P).

ATP is synthesized by substrate-level phosphorylation.

Oxidation of G3P transfers electrons to NAD⁺, yielding NADH. After four more reactions, the final product is two molecules of pyruvate. Glycolysis produces 2 net ATP, 2 NADH, and 2 pyruvate.

NADH must be recycled into NAD⁺ to continue respiration.

In the presence of oxygen, NADH passes electrons to the electron transport chain. In the absence of oxygen, NADH passes the electrons to an organic molecule such as acetaldehyde (fermentation).

The Oxidation of Pyruvate to Produce Acetyl-CoA

Pyruvate is oxidized to yield 1 CO₂, 1 NADH, and 1 acetyl-CoA. Acetyl-CoA enters the Krebs cycle as 2-carbon acetyl units.

The Krebs cycle extracts electrons and synthesizes one ATP.

The first reaction is an irreversible condensation that produces citrate; it is inhibited when ATP is plentiful. The second and third reactions rearrange citrate to isocitrate. The fourth and fifth reactions are oxidations; in each reaction, one NAD⁺ is reduced to NADH. The sixth reaction is a substrate-level phosphorylation producing GTP, and from that ATP. The seventh reaction is another oxidation that reduces FAD to FADH₂. Reactions eight and nine regenerate oxaloacetate, including one final oxidation that reduces NAD⁺ to NADH.

Glucose becomes CO₂ and potential energy.

As a glucose molecule is broken down to CO₂, some of its energy is preserved in 4 ATPs,10 NADH, and 2 FADH₂.

The Krebs Cycle

Following the electrons in the reactions reveals the direction of transfer.

The Electron Transport Chain and Chemiosmosis

The gradient forms as electrons move through electron carriers.
Chemiosmosis utilizes the electrochemical gradient to produce ATP.

The electron transport chain produces a proton gradient.

In the inner mitochondrial membrane, NADH is oxidized to NAD⁺ by NADH dehydrogenase. Electrons move through ubiquinone and the bc₁ complex to cytochrome oxidase, where they join with H⁺ and O₂ to form H₂O. This results in three protons being pumped into the intermembrane space. For FADH₂, electrons are passed directly to ubiquinone. Thus only two protons are pumped into the intermembrane space.

ATP synthase is a molecular rotary motor.

Protons diffuse back into the mitochondrial matrix via the ATP synthase channel. The enzyme uses this energy to synthesize ATP.

Energy Yield of Aerobic Respiration

The theoretical yield for eukaryotes is 36 molecules of ATP per glucose molecule.
The actual yield for eukaryotes is 30 molecules of ATP per glucose molecule.

Regulation of Aerobic Respiration

Glucose catabolism is controlled by the concentration of ATP molecules and intermediates in the Krebs cycle.

Oxidation Without O₂

In the absence of oxygen other final electron acceptors can be used for respiration.
Methanogens use carbon dioxide.
Sulfur bacteria use sulfate.
Fermentation uses organic compounds.

Fermentation uses organic compounds as electron acceptors.

Fermentation is the regeneration of NAD⁺ by oxidation of NADH and reduction of an organic molecule. In yeast, pyruvate is decarboxylated, then reduced to ethanol. In animals, pyruvate is reduced directly to lactate.

Catabolism of Proteins and Fats

Catabolism of proteins removes amino groups.
A small number of key intermediates connect metabolic pathways.

Acetyl-CoA has many roles.

With high ATP, acetyl-CoA is converted into fatty acids.

Evolution of Metabolism

Major milestones are recognized in the evolution of metabolism; the order of events is hypothetical.
The earliest life forms degraded carbon-based molecules present in the environment.
The evolution of glycolysis also occurred early.
Anoxygenic photosynthesis allowed the capture of light energy.
Oxygen-forming photosynthesis used a different source of hydrogen.
Nitrogen fixation provided new organic nitrogen.
Aerobic respiration utilized oxygen.


The loss of a hydrogen atom.

Aerobic Respiration

When the final, electron-accepting step in oxidative phosphorylation is oxygen.

Anaerobic Respiration

When the final, electron-accepting step in oxidative phosphorylation is a nonorganic molecule other than oxygen.


When the final, electron-accepting step in oxidative phosphorylation is an organic molecule.

Substrate-Level Phosphorylation

When ATP is formed by transferring a phosphate group directly to ADP from a phosphate-bearing intermediate or substrate.


The breakdown of glucose into two pyruvates; an example of substrate-level phosphorylation.

Oxidative Phosphorylation

The synthesis of ATP using the enzyme ATP Synthase, which uses energy from a proton (H⁺) gradient to power production. The gradient is formed by high-energy electrons from the oxidation of glucose passing down an electron transport chain, which are at the end, with their energy depleted, donated to oxygen - hence oxidative phosphorylation.

The two main steps of Glycolysis

Glucose priming
Cleavage and rearrangement

Glucose Priming, reactants/products

Three reactions prime glucose so that it can be more easily cleaved into 2 pyruvates. This step uses 2 ATP.

Cleavage and rearrangement, reactants/products

The 6-carbon product of glucose priming is split, with one product being G3P and another being converted to G3P in another step. Each G3P then donates 2 e⁻s and 1 H⁺ to oxidize NAD⁺, and then later produces two ATPs.



Glucose reactants/products

1 glucose molecule → 2 pyruvates
2 NAD⁺ → 2 NADH
2 ATP → 2 ADP
4 ADP → 4 ATP
→ 2 H₂O
Total: 2 NADH, 2 ATP, 2 H₂O

Purpose of steps after Glycolysis

Release energy from pyruvates
Replace NAD⁺
Transfer NADH to ATP

Hydrolysis of 1 molecule of ATP produces ? energy

ΔG = -7.3 kcal/mol

Evolution of Glycolysis

Second half older; production of G3P newer.

Where Glycolysis Occurs

In the cytoplasm; works for all organisms.

Pyruvate Oxidation

- Between Glycolysis and Krebs
- Releases CO₂
- Reduces NAD⁺ to NADH
- Remaining compound attached to coenzyme A; entire unit called acetyl-CoA.

Multienzyme complex

A unit containing multiple enzymes; pyruvate oxidation is catalyzed by one within the mitochondria. Contains pyruvate dehydrogenase, one of the largest enzymes known.

Pyruvate Oxidation Rxn

pyruvate + NAD⁺ + CoA →
acetyl-CoA + NADH + CO₂ + H⁺

Does the Krebs cycle produce ATP?

Not directly - it produces cofactors that help to make ATP.

Three segments of Krebs

A: Acetyl-CoA plus oxaloacetate. Produces 6-carbon citrate molecule.
B: Citrate rearrangement and decarboxylation. Reduces citrate to 5, then 4 carbons. Produces 2 NADH and 1 GTP.
C: Regeneration of oxaloacetate. Produces 1 NADH, 1 FADH₂.

Nine reactions of Krebs

1. Condensation
2,3. Isomerization
4. First Oxidation
5. Second Oxidation
6. Substrate-Level Phosphorylation
7. Third Oxidation
8,9. Regeneration of Oxaloacetate, Fourth Oxidation

1. Condensation

Citrate formed from Acetyl-CoA and oxaloacetate. Inhibited by high levels of ATP, at which point Acetyle-CoA goes into fat synthesis.

2,3. Isomerization

Citrate needs to be rearranged so it can react better later; forms isocitrate.

4. First Oxidation

- Reduces an NAD⁺ to NADH
- Loses a carbon as CO₂
- Forms 5-carbon α-ketoglutarate.

5. Second Oxidation

- Loses another carbon as CO₂ w/ help from multienzyme complex
- 4-carbon Succinyl joins CoA to form succinyl-CoA
- - Reduces an NAD⁺ to NADH

6. Substrate-Level Phosphorylation

- Succinyl-CoA breaks apart to form Succinate
- Energy release helps make GTP (→ATP)

7. Third Oxidation

- Succinate oxidized to Fumarate
- Not enough energy to reduce NAD⁺, so FADH₂ made instead.
- FADH₂ can only contribute electrons to the electron transport chain in the membrane

8,9. Regeneration of Oxaloacetate, Fourth Oxidation

- Fulmarate is oxidized to Malate, then to oxaloacetate
- Reduces an NAD⁺ to NADH

Reactants/Products of Krebs

Acetyl-CoA + H₂O →
3 NADH + 1 GTP + 1 FADH₂

Krebs Cycle Location

In the matrix of the mitochondria for eukaryotes.
In the cytoplasm and plasma membrane of prokaryotes.


The folds in the mitochondria that makes its inner membrane's surface area larger.

Mitochontrial Inner Membrane

- Principle site of ATP generation
- >70% protein (a lot for a membrane)
- Impenetrable to ions and small molecules except at transporters

Mitochontrial Outer Membrane

- More typical protein %
- Contains porins


Passive holes in the mitochontrial outer membrane that are made out of β-strands to form a β-barrel.

Mitochontrial Intermembrane Space

- Between inner, outer membranes
- Composition of ions and small molecules is the same as the cytosol's

Mitochondrial Matrix

- Contains Krebs cycle enzymes
- Pyruvate gets brought into the matrix

Pyruvate oxidation and Krebs cycle products and reactants (per molecule of glucose)

- 6 CO₂
- 8 NADH
- 2 FADH₂
- 2 GTP (= 2 ATP)

What still needs to be done at the end of the Krebs cycle

- need to get NADHs back to NAD⁺
- need to get FADH₂ back to FAD
- still need to transfer energy in cofactors to ATP

Why is the Krebs cycle dependent on oxygen?

While it does not require oxygen directly, it is coupled to a third pathway that does require oxygen (electron transport chain).

Location of the Electron Transport Chain

Eukaryotes - inner mitochondrial membrane
Prokaryotes - cytoplasmic membrane

Components of the Electron Transport Chain

Complex 1 (transmembrane)
Complex 2 (integral)
Complex 3 (trans)
Complex 4 (trans)
Ubiquinone (carrier)
Cytochrome C (carrier)

Progression along the ETC

- NADH passes electrons to complex 1.
- Energy from the electrons is used to pump H⁺ out of the matrix.
- FADH₂ is oxidized at complex 2, skips complex 1; electrons from it thus result in less ATP
- Ubiquinone takes electrons from complexes 1 and 2 to complex 3, which pumps more H⁺.
- Cytochrome C carries electrons from complex 3 to complex 4; another H⁺ pumped.
- Cytochrome oxidase complex forms water
O₂ + 4 H⁺ → 2 H₂O : End

Proton Gradient

The result of the ETC's pumping; what drives chemiosmosis.

Energy of Carriers

Carriers are of successively lower energy as energy is lost from the previous carrier in driving the proton pumps.


As a result of the ETC, the mitochondrial matrix is negative compared to the intermembrane space; hydrogens want to go in, and can go through a transmembrane enzyme called ATP synthase. By going through, they drive the production of ATP. Because this drive is similar to osmosis, it is called chemiosmosis.

Oxidative Phosphorylation

The chemiosmosis-driven phosphorylation that creates ATP.

ATP Synthase Structure

A "rotor" within the membrane connected by a narrow stalk to a catalytic head sticking out into the matrix.
Movement of H⁺ through it drives physical rotation, changing conformation of domains on the complex.

Theoretical ATP yield for Eukaryotes

2 from Glycolysis SLP
6 from Glycolysis Chemiosmosis (3×2 NADH)
6 from Pyruvate Oxidation Chemiosmosis (3×2 NADH)
2 from Krebs SLP (2×GTP)
18 from Krebs Chemiosmosis (3×6 NADH)
4 from Krebs Chemiosmosis (2×2 FADH₂)
Total = 38 ATP; true for Proks, but for Euks 2 ATP needed to transport NADH from cytoplasm to matrix → theoretically, 36 ATP produced.

Actual ATP yield for Eukaryotes

- Inner mitochondrial membrane "leaky"
- Proton gradient used for other things as well
→ measured values closer to 2.5xNADH, 1.5xFADH₂
- Actual yield ~30 ATP/glucose

Efficiency of catabolism of glucose

Aerobic respiration captures ~32% of a glucose's energy (compared to ~25% for a car engine).

Regulation of Aerobic Respiration - Glycolysis

ATP and citrate are allosteric inhibitors of an enzyme in glycolysis, phosphofructokinase. When ATP is in excess or Krebs is making more citrate than is consumed, glycolysis is slowed.

Regulation of Aerobic Respiration - Pyruvate Oxidation

Pyruvate dehydrogenase, which converts pyruvate to acetyl-CoA, is inhibited by NADH.

Regulation of Aerobic Respiration - Krebs

High levels of ATP will slow several steps in the Krebs catabolic pathway.

Ethanol Fermentation

Glycolysis produces ATP and NADH.
Pyruvates produced lose CO₂ to become acetaldehyde.
Acetaldehyde takes Hs from NADH to become ethanol, and NADHs are oxidized back to NAD⁺.

Lactic Acid Fermentation

Glycolysis produces ATP and NADH.
Lactate dehydrogenase takes Hs from NADH and give it to the pyruvates to form lactate and NAD⁺.


The removal of amines, sp. so that proteins can be catabolised.

Catabolism of proteins removes amino groups

Depending on what amino acids are broken down, different substances present at different stages are made; they then enter glycolysis or Krebs.

Catabolism of fatty acids produces acetyl groups in a process called β oxidation

Fatty acids are oxidized in the matrix of the mitochondria; enzymes remove 2-carbon acetyl groups until the entire fatty acid has been converted into acetyl groups. They are then combined with coenzyme A to form acetyl Co-A.

Respiration of fatty acids vs ATP

Carbon for carbon, fats will yield more energy than carbs, and are lighter to boot, hence their use as storage.

For organisms that do not undergo aerobic respiration, they compensate by...

... having glycolysis proceed much faster, so that they can still produce enough ATP to function.

A small number of key intermediates connect metabolic pathways

- Pyruvate
- Acetyl Co-A
Allows the interconversions of fats/sugars/etc.

Acetyl-CoA has many roles

- Almost all catabolized molecules are turned into acetyl-CoA
- Also used in anabolic metabolism, building fatty acids
- Which role, depends on ATP concentration

Earliest lifeforms degraded carbon-based molecules present in the environment

Believed to have metabolized abiotically produced molecules. Then, began to store energy in bonds of ATP.

Evolution of glycolysis occurred early on

As proteins evolved catalytic functions, became possible to extract more energy from molecules. Must have evolved early on b/c present in all organisms today.

Anoxygenic photosynthesis allowed capture of light energy

Photosynthesis that used H₂S evolved. Uses light to pump protons.

Oxygen-forming photosynthesis uses a different source of hydrogen

Organisms evolved that substituted use of H₂S in photosynthesis for H₂O; produced oxygen gas. Became dominant.

New nitrogen fixation provided new organic nitrogen

Nitrogen fixation = getting nitrogen from N₂ gas; important step in evolution, as nitrogen needed to make proteins.

Aerobic respiration utilized oxygen

Ancient, purple, nonsulfur bacteria evolved to not photosynthesize at all, instead subsisting only off sequestered molecules → mitochondria descendants of those cells, now found in all euk cells.

Why are catabolic and biosynthetic pathways coordinated?

Don't want to spend more energy than necessary (ex. break down only to build up again)

What coordinates the catabolic and biosynthetic pathways?

- the amount of enzymes present (long-term)
- the activity of allosteric enzymes (short-term)

What do different types of allosteric regulators do and what are they called?

- Allosteric regulators bind to non-active sites of enzymes and change the conformation of the active site.
- They can either increase or decrease the activity of the enzyme.
- called a Positive Regulator if it increases activity
- called a Negative Regulator if it decreases activity

Feedback Inhibition

When an allosteric regulator is a product of a later reaction in a pathway.
ex. glycolysis regulated by ATP; if lots of ATP, wasteful to do glycolysis; pathway slowed by rate limiting step.

First Committed Step

The first step in a pathway that could be shut off that won't interfere with the production of other molecules but is as early on as possible to not waste energy.

Limiting Step

A key step in a reaction that if altered could change the entire pathway's speed. A "chokepoint".
ex. feedback inhibition of glycolysis by ATP; phosphofructokinase inhibited.

Some allosteric regulators can turn "up" one reaction and turn "down" a different reaction

i.e. it acts positively on one pathway and negatively on another

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