Lecture 15 & 17: Pyruvate Oxidation and the TCA Cycle Flashcards
What is the role of pyruvate metabolism in aerobic energy metabolism? (4 main roles/fates)
Pyruvate (two are made from each glucose that passes through glycolysis) has 4 main roles in energy metabolism in general.
1) Can be reduced in the cytosol to NADH and lactate to regenerate NAD+.
2) Can enter the mitochondria and be converted to Acetyl-CoA to enter the TCA cycle and produce energy.
3) Can be converted to oxaloacetate (in the liver and the brain) to replenish the intermediates of the TCA cycle.
4) Can be converted to Alanine (if you need some).
How does the TCA cycle conserve energy?
It stores it in the products NADH and FADH2 which it sends to the electron transport chain to make ATP.
What is the role of the TCA cycle as an amphibolic hub?
Many of the intermediates/products of the TCA cycle can come from different processes, or be sent to replenish the store of that molecule to aid another process.
What are 5 examples of the amphibolic hub actions of the TCA cycle?
Its products and intermediates include:
1) Citrate -> Functions in Fatty Acid Synthesis
2) Alpha-ketoglutarate -> Functions in amino acid synthesis and as a neurotransmitter
3) Succinyl-CoA ->Heme Synthesis
4) Malate -> Gluconeogenesis
5) Oxaloacetate -> Amino Acid Synthesis
There are 2 main control points for the TCA cycle, what are they and how do they work? (There is also a bonus one if you used the BRS review book, you found it.)
The two main points are:
1) Isocitrate dehydrogenase -
Activated by - NAD (indicating low levels of energy)
Deactivated by NADH (indicating high levels of energy)
2) Citrate synthase - Deactivated by excess citrate (which accumulates as result of isocitrate dehydrogenase turning off and isocitrate that accumulates reverting back to citrate.
Bonus! In the presence of excessive NADH (lots of energy in the cell) Oxaloacetate is turned into Malate, further decreasing the availability of this substrate for the TCA cycle (slows the entire cycle).
Describe the units of the isocitrate dehydrogenase complex and how they work with the reaction. (Including the vitamins/cofactors they need to make it work).
Three subunits to the complex:
E1: pyruvate Dehydrogenase. This enzyme includes Thiamine pyrophosphate (thiamine is vitamin B1). TPP (thiamine pyrophosphate) reacts with pyruvate to make CO2 and hydroxyethyl TPP.
E2: dehydrolipoamide acetyltransferase. This enzyme include lipoic acid, which takes the hydroxyethyl group from TPP and then transfers this group as an acetyl group to coenzyme A. The sulfurs on the lipoate acid are left reduced however.
E3: dehydrolipoamide dehydrogenase. This enzyme includes FAD, which oxides the sulfurs on the lipoic acid and becomes FADH2. This FADH2 then transfers its electron to NAD+ to make NADH.
We learned about 2 diseases and 2 syndromes that are a result (or tied to) the TCA cycle not working properly. Name them and describe what they are.
Dry Beriberi: characterized by peripheral neuropathy of sensory, motor, and reflex functions. Affects distal more than proximal limbs, resulting in stocking glove syndrome (paresthesia), polyneuritis, and symmetrical muscle wasting.
Wet Beriberi: cardiovascular system is affected resulting in congestive heart failure, edema, and dilated cardiomyopathy.
Wernicke-Korsakoff syndrome: Common in alcoholics. causes mental confusion, confabulation (making new memories), and psychomotor slowing, among other symptoms.
Leigh Syndrome: also called infantile subacute necrotizing encephalomyelopathy. Hypotonia, dystonia, ataxia, respiratory distress, weakness and loss of the eyes are common symptoms. Death will occur within a few years. Has many causes originating in defects with the mitochondria or aerobic metabolism pathway. Multiple forms of inheritance exist for different defects. Pyruvate Dehydrogenase Defect is X-linked. Common finding is lactic acidosis as one would expect if the aerobic metabolism pathway was inhibited. Some cases can be treated with Thiamine supplementation
Describe the mechanism of how pyruvate dehydrogenase activity is regulated in response to the metabolic needs of the cell.
Pyruvate dehydrogenase kinase phosphorylates PDC (pyruvate dehydrogenase complex) to inactivate it. This Kinase is inhibited by Pyruvate and ADP (Which means that when a cell needs energy, this inhibitor is turned off). It is induced by AcetylCoA and NADH (whose presence is indicative of plenty of energy). Pyruvate dehydrogenase phosphatase dephosphorylates the PDC to activate it.
What are some important vitamin derived coenzymes and what are they used for?
Niacin
· Used to make the nicotinamide portion of NAD which is used in reactions with isocitrate dehydrogenase, α-ketoglutarate dehydrogenase, and malate dehydrogenase.
Riboflavin
Used in the synthesis of FAD. Serves as a cofactor for, and is also required for (respectively)
• Succinate dehydrogenase
• α-ketoglutarate dehydrogenase
α-ketoglutarate dehydrogenase
· Contains lipoic acid and four other cofactors that are synthesized from vitamins.
• Thiamine - for thiamine pyrophosphate
• Pantothenate for CoASH
• Riboflavin for FAD
· Niacin for NAD+
