Highlights Lecture #30 Spring 2017

1. The glyoxylate cycle is related to the citric acid cycle and is found only in bacteria and plants, not animals. It uses the same enzymes as the citric acid cycle except it has two additional ones. These include isocitrate lyase (cleaves isocitrate to yield glyoxylate and succinate) and malate synthase (combines acetyl-CoA with glyoxylate to make malate). After the succinate and malate are both converted to oxaloacetate, there are two oxaloacetates at the end of the cycle, instead of one in the citric acid cycle.

2. Thus, the glyoxylate cycle can produce oxaloacetate for gluconeogenesis from acetyl-CoA, but the citric acid cycle can’t. As a result, bacteria and plants can make glucose from acetyl-CoA in net amounts, but animals can’t.

Highlights Electron Transport/Oxidative Phosphorylation

1. Electron transport (ETS) occurs in the inner membrane of the mitochondrion.

2. In ETS, electrons from NADH move to complex I and from FADH2, they move into complex II. Losing electrons like this converts them to NAD+ and FAD.

3. Electrons move through the complexes as follows

Complex I – Coenzyme Q – Complex III – Cytochrome C – Complex IV – Oxygen. When oxygen gains electrons, it creates water.

4. Electrons from complex II are passed to Coenzyme II and then they take the same pathway.

5. As electrons flow through complexes I, III, and IV, protons are “pumped” out of the mitochondrion. This ‘charges’ the battery.

6. Note that electrons starting with NADH pump more protons that electrons starting with Complex Q. This ultimately (in oxidative phosphorylation) results in production of more ATPs per NADH than per FADH2.

7. Coenzyme Q acts as a “traffic cop”, accepting electrons in pairs and passing them on individually.

8. As electrons flow through complexes I, III, and IV, protons are “pumped” out of the mitochondrion.

9. Note that electrons starting with NADH pump more protons that electrons starting with Complex II. This ultimately (in oxidative phosphorylation) results in production of more ATPs per NADH than per FADH2.

10. Oxidative phosphorylation occurs when protons move BACK into the mitochondrion (after being pumped out) through a complex commonly called Complex V. Complex V has the mushroom-like shape, as shown in class. This complex ROTATEs as protons pass through it. Rotation of the complex creates ATP.

11. Complex V has three sets of subunits in the F1 domain that make the ATP. They do this by flipping between states labeled L, T, and O. Flipping is controlled by the ‘rotor’ described in class that is attached to the rotating F0 subunit. Rotation is caused by movement of protons through the complex. L is the state that binds ADP and Pi. T is the state that compresses them together to make ATP. O is the state that releases the ATP.

12. Note that making ATP requires ADP. If there is no ADP, ATP Synthase CANNOT rotate and NO PROTONS CAN PASS THROUGH, since the inner mitochondrial membrane is impermeable to protons unless it has been altered. As a consequence, electron transport will stop when oxidative phosphorylation is stopped as described. This is an important aspect of metabolic control. In metabolic control, the inner mitochondrial membrane must remain impermeable to protons. When this occurs, the electron transport won’t run unless oxidative phosphorylation is occurring and oxidative phosphorylation won’t occur unless there is a proton gradient. When electron transport is not running, oxygen consumption decreases. When it is running, oxygen consumption increases.

13. At rest, your body’s stores of ATP are high and ADP are low. Under these conditions, oxidative phosphorylation is not occurring much, so the proton gradient remains high, thus stopping electron transport. When electron transport stops, NADH accumumlates, stopping the citric acid cycle.

14. When you exercise, your ATP levels fall and ADP levels rise. Thus, oxidative phosphorylation starts and the proton gradient falls. This starts electron transport, which causes NAD and FAD concentrations to rise, thus starting the citric acid cycle.

15. A compound called 2,4 DNP (2,4 dinitrophenol) was used as a “miracle” diet drug about a century ago with disastrous consequences. It acted to poke a hole in the mitochondrial inner membrane, allowing protons to leak back into the matrix without passing through complex V. As a result, when 2,4 DNP is present, electrons move through the electron transport system, but NO ATP is made. Consequently, cells burn everything they can to try to make ATP, but they can’t. Oxygen consumption goes way up and the body temperature goes way up, but no ATP is made by oxidative phosphorylation. Death was a frequent result of 2,4DNP use.

16. Uncoupling of mitochondria occurs when anything permeabilizes the inner wall of the mitochondrion to protons. Then the linkage between electron transport and oxidative phosphorylation is broken. The opposite of uncoupling is tight coupling.

17. Electron transport inhibitors block movement of electrons through the complexes. Ones described in class (and the complexes they block) include rotenone (Complex I), Amytal (I), Antimycin A (III), Azide (IV), Carbon Monoxide (IV), and Cyanide (IV).

18. You should be able to predict what happens at the molecular/metabolic level in various metabolic scenarios involving respiratory/metabolic control such as I described in class.

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