L11: TCA Cycle and Oxidative Phosphorylation Flashcards
anaerobic glycolysis
- low energy production
- pyruvate -> lactate
TCA cycle and oxidative phosphorylation
- high energy production
- pyruvate -> acetyl CoA -> TCA cycle
acetyl CoA as key molecule
- multiple fuel sources:
- glucose
- amino acids
- ketones
- pyruvate
- fatty acids
- acetate
- ethanol
coenzyme A
- used in energy production and fatty acid synthesis
- sulfur containing molecule that is usually coupled to a 2C acetyl group or acyl group
- has high energy transfer potential
TCA cycle occurs where
- mitochondrial matrix
ETC and ATP synthase are located where
- inner mitochondrial membrane
pyruvate -> acetyl CoA catalyzed by
- pyruvate dehydrogenase complex
pyruvate dehydrogenase complex
- consists of 3 distinct enzymes and 5 coenzymes
PDC cofactors
- thiamine pyrophospahte (B1)
- lipoic acid (inhibited by arsenic)
- FAD (B2; riboflavin)
PDC coenzyme substrates
- CoA (B5; pantothenic acid)
- NAD+ (B3; niacin)
where is pyruvate transported for the PDC
- mitochondrial matrix
Leigh disease symptoms
- severe neurological disorder
- muscle weakness
- difficulty breathing
Leigh disease results
- damage to the brainstem, cerebellum, and basal ganglia
Leigh disease cause
- deficiencies in PDC
- lactic acidosis
- deficit in mitochondrial energy production - disruptive to brain function
First step of TCA
- oxaloacete -> citrate
- addition of acetyl-CoA from PDC
- via citrate synthesis
second step of TCA
- citrate to isocitrate
- via aconitase
third step of TCA
- isocitrate to alpha-ketoglutarate
- via isocitrate dehydrogenase
- generates NADH H+ and CO2
fourth step of TCA
- alpha ketoglutarate -> succinyl CoA
- via alpha ketoglutarate dehydrogenase
- produce NADH, H+, and CO2
- add back CoASH
fifth step of TCA
- succinyl CoA -> succinate
- via succinate thiokinase
- will generate GTP and get rid of CoASH
sixth step of TCA
- fumarate -> malate
- via fumarase
seventh step of TCA
- malate to oxaloacetate
- via malate dehydrogenase
- will generate NADH and H+
amino acid precursors
- oxaloacetate
- alpha-ketoglutarate
neurotransmitter precursors
- glutamate -> GABA
- derived from alpha ketoglutarate
porphyrin precursors
- heme
- derived from succinyl-CoA
fatty acid precursors
- derived from citrate
glucose precursors
- derived from malate
anaplerotic reactions
- if TCA intermediates are removed from the cycle, oxaloacetate must be provided by alternative means
alternative means of getting oxaloacetate
- replenished by conversion from pyruvate via pyruvate carboxylase
- uses ATP
- can enter via amino acid degradation at
- pyruvate
- glutamate -> succinate
- succinyl CoA
- fumarate
- oxaloacetate
- odd chain fatty acids and branch chain amino acids enter as succinyl coA through a propionyl CoA intermediate
control points of TCA
- citrate synthase
- isocitrate dehydrogenase
- alpha ketoglutarate dehydrogenase
- malate dehydrogenase
citrate synthase nhibited by
- citrate
citrate synthase activated by
- oxaloacetate
isocitrate dehydrogenase activated by
- ADP
- Ca2+
isocitrate dehydrogenase inhibited by
- ATP
- NADH
when energy status is high with citrate
- citrate accumulates and halts glycolysis and shunts acetyl CoA towards fatty acid synthesis
alpha ketoglutarate dehydrogenase activated by
- Ca2+
alpha ketoglutrate dehydrogenase inhibited by
- NADH
- succinyl CoA
- ATP
when energy status is high with alpha ketoglutarate
- alpha ketoglutarate accumulates and is used in generating amino acids and nucleotide bases
malate dehydrogenase inhibited by
- NADH
PDC regulation in resting muscle
- energy status high and energy demands are low
- products like NADH, acetyl CoA, and ATP activate PDKinase to phosphorylate PDC
- inactivates PDC
PDC regulation in exercising muscle
- muscle contracting consumes ATP; energy status low
- ADP and pyruvate inhibit PDKinase
- Ca2+ levels rise to be used in muscle contraction
- activates PDPhosphatase
- removes phosphate from PDC, and activates it
- activates PDPhosphatase
ETC process
- Complex I (NADH dehydrogenase)
- Complex II (succinate dehydrogenase)
- Coenzyme Q
- Complex III (cyt c b-c1 complex)
- Cyt C
- Complex IV (cyt c oxidase)
where does FADH2 drop electrons off?
- succinate dehydrogenase at Complex II
- doesn’t pump protons itself
- donates electrons to CoQ and then complex II
ETC
- electron transferring flavoprotein
- accepts electrons from fatty acid oxidation and transfers them to CoQ
glycerol-3-phosphate dehydrogenase
- shuttle component for reoxidizing NADH
proton motive force
- pumping protons out of the matrix creates a:
- pH gradient
- charge gradient
- pushes proteins to re-enter the matrix
- power ATP synthesis via ATP synthase
F0 of ATP synthase?
- in inner mitochondrial membrane
- proton channel
F1 of ATP synthase
- in matrix
- catalytic subunit (binding site for ADP and ATP)
can ATP synthase form ATP in absence of proton gradient?
- yes!
- but proton flow causes a conformational change that results in release of ATP from the enzyme
products from Glycolysis
- 2 ATP
- 2 NADH (*1.5) = 3 ATP
products from PDC
- 2 NADH (*2.5) = 5 ATP
products from TCA cycle
- 6 NADH (*2.5) = 15 ATP
- 2 FADH2 (*1.5) = 3 ATP
- 2 ATP
total GTP from glycolysis
- 30 ATP
yield on glycolysis
- 30%
- rest released as heat and ion transport
why does the NADH from glycolysis yield less ATP?
- it has to be transported/shuttled into the inner mitochondrial membrane and that requires some energy
why does FADH2 yield less ATP
- because it enters the ETC has a further spot down the chain.
