Chapters #18 & 19: TCA Cycle Flashcards
What happens to pyruvate under aerobic conditions?
Under aerobic conditions, pyruvate enters the mitochondria, where it is converted into acetyl CoA (CoA = coenzyme A).
What is Acetyl CoA?
Acetyl CoA is the fuel for the citric acid cycle, which processes the two-carbon acetyl unit into 2 molecules of CO2 while generating high-energy electrons that can be used to form ATP.
Although acetyl CoA is typically drawn as the shorthand structure (upper right) for convenience, the coenzyme A molecule is quite complex, containing a nucleotide base, pentose sugar, multiple phosphates, a Pantothenate unit derived from vitamin B5, and a β-mercaptoethylamine unit as shown above.
The full chemical structure of acetyl CoA is shown above, with the acetyl group colored in fuchsia. The molecule’s function as a high energy carrier in metabolism is associated with its…
A. amide bonds.
B. negatively charged phosphates.
C. nucleotide component.
D. phosphoanhydride bond.
E. thioester bond.
E. thioester bond.
What is the pyruvate dehydrogenase complex?
- The pyruvate dehydrogenase complex converts pyruvate into acetyl CoA and is located in the mitochondrial matrix.
- Three enzymes and five coenzymes are required for full activity of the complex
- How does pyruvate from the cytoplasm get into the mitochondrial matrix for this reaction? by a specific pyruvate-H+ symport* embedded in the mitochondrial membrane.
What are the three enzymes and five coenzymes needed for the pyruvate dehydrogenase complex
- Three enzymes and five coenzymes are required for full activity of the complex
1.Nicotinamide adenine dinucleotide (NAD+) – made from niacin (vitamin B3)
2.Flavin adenine dinucleotide (FAD) – made from riboflavin (vitamin B2)
3.Thiamine pyrophosphate (TPP) – made from thiamine (vitamin B1)
4.Coenzyme A (CoA) – made from pantothenic acid (vitamin B5)
5.Lipoamide – made from lipoic acid
Describe the regulation of the pyruvate dehydrogenase complex
- The formation of acetyl CoA from pyruvate is an irreversible step in animals.
- Therefore, acetyl CoA cannot be converted into glucose.
Why?
* The carbon atoms of acetyl CoA are thus destined to two fates:
*Oxidation to CO2 (energy)
*Incorporation into lipids (storage)
- Phosphorylation of pyruvate dehydrogenase on the E1 component controls the activity of the complex.
What does a high energy and low energy charge of the pyruvate dehydrogenase complex: regulation look like
In addition to affecting the PDH complex as shown, these metabolites (circled) also regulate PDH activity by either enhancing (metabolites on the left) or inhibiting (metabolites on the right) the activity of PDH kinase. Does this make metabolic sense?
What is the citric acid cycle?
- Part of the aerobic processing of glucose that generates greater than 90% of the energy used by aerobic cells in humans
- A cyclic process that is fairly efficient in terms of energy production
- The final common pathway for the oxidation of fuel molecules (carbohydrates, fatty acids, and amino acids).
- Also a supplier of precursors for building amino acids, nucleotide, and bases.
- “The metabolic hub of the cell”
- Takes place in the matrix of the mitochondria
- Molecules enter as either two-carbon acetyl groups or other components of the cycle.
- The carbon-containing molecules are oxidized, reducing NAD+ & FAD, and producing NADH and FADH2 respectively.
- One high phosphoryl-transfer compound is generated.
- The two-carbon acetyl CoA is essentially oxidized into two molecules of CO2.
The high-energy electrons of NADH and FADH2 are subsequently used to power the synthesis of ATP.
What are the other names of the citric acid cycle?
a.k.a.. the Krebs cycle or the tricarboxylic acid (TCA) cycle
What is the TCA cycle and Energy Production?
- The TCA cycle is a common pathway for metabolism of all fuels: carbohydrate, fat, and protein. Electrons are stripped from these fuels in the process of oxidation, and they are used to make acetyl CoA.
- The TCA cycle produces a bonus molecule of GTP, which counts as a molecule of ATP.
- The electrons/protons from NADH and FADH2 are used to produce ATP through the electron transport chain and oxidative phosphorylation.
The TCA cycle can only occur if the electron transport chain is using up the electrons and protons from NADH and FADH2 to regenerate NAD+ and FAD.
What is the first step of the citric acid cycle?
Oxaloacetate and acetyl CoA are combined into citrate
What’s the point?
* Two-carbon units are brought into the citric acid cycle for oxidation and subsequent ATP production.
* Since this condensation initiates the citric acid cycle, wasteful side reactions such as hydrolysis of acetyl CoA must be prevented. Citrate synthase exhibits sequential, ordered kinetics and induced fit that both prevent side reactions.
Describe steps 6-8 of the citric acid cycle
6-8. Regeneration of oxaloacetate
- Reactions 6-8, proceeding from succinate to fumarate, to malate, to oxaloacetate, is an excellent example of the systematic oxidation of carbon carried out in the process of oxidative phosphorylation.
- The dehydrogenase reactions demonstrate the simultaneous oxidation of a carbon atom coupled to the reduction of a nucleotide cofactor (NAD+ or FAD) the receives the electrons for delivery to the electron transport chain
What is the net reaction of the TCA cycle?
What is the citric acid cycle regulated by?
*As we just discussed, the bridge between glycolysis and the citric acid cycle (pyruvate dehydrogenase complex) is regulated by several molecules.
*In the citric acid cycle itself, there are two primary control points:
* Isocitrate dehydrogenase
* α-ketoglutarate dehydrogenase
*What feature do these reactions have in common?
*Generation of high energy electrons captured by NAD+
*Release of CO2
*negative ΔG°’ values
How does ADP regulate the citric acid cycle?
ADP (energy charge is low) enhances the enzyme’s affinity for substrates.
How does ATP regulate the citric acid cycle?
ATP (energy charge is high) is inhibitory and NADH directly displaces NAD+.
How does succinyl CoA regulate the citric acid cycle?
Succinyl CoA exhibits product inhibition
What is the importance of regulation in the citric acid cycle?
The use of these steps of the citric acid cycle as control points is important in integrating the citric acid cycle with other pathways.
Describe the biosynthetic relationships of the citric acid cycle
he citric acid cycle is not only the major degradative (catabolic) pathway in the cell, it is a major source of materials for biosynthetic (anabolic) pathways: Amphibolic: operates catabolically and anabolically
Describe how intermediates relate to the citric acid cycle and their biosynthetic relationships
Describe the anaplerotic reactions of the TCA cycle
Anaplerotic: reactions that replenish or “fill up” the TCA cycle
How do anaplerotic reactions replenish the TCA cycle?
- Acetyl CoA can be produced from either pyruvate or fatty acids
- Oxaloacetate is produced from pyruvate.
- Why is this issue important?
Oxaloacetate must be replenished for continued operation of the citric acid cycle.
What is the take home message for the TCA cycle?
- Pyruvate Dehydrogenase is a protein complex containing three enzymes and 5 coenzymes.
- Pyruvate Dehydrogenase converts pyruvate into acetyl CoA in the mitochondrial matrix and links glycolysis to the TCA cycle.
- The TCA cycle is an aerobic processing of glucose that generates energy and biomolecule precursors.
- The TCA cycle is tightly regulated to provide appropriate precursors required by other metabolic pathways.
- The TCA cycle is an amphibolic pathways that operates catabolically and anabolically.
