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Citric Acid/Kreb's/TCA Cycle - Coggle Diagram
Citric Acid/Kreb's/TCA Cycle
What is citric acid cycle?/ Overview
Occurs in cells with mitochondria under aerobic conditions
Within the mitochondrial matrix
Central role in cell metabolism
Both catabolic and anabolic functions
Amphibolic pathway
Catabolic role
Breakdown of Acetyl-CoA to CO\(_2\) and H\(_2\)O
With generation of ATP and reduced electron carriers NADH + FADH\(_2\)
Anabolic role
Generation of precursors for biosynthesis
Fuelled from carbohydrates, fatty acids + amino acids
All involved in production of Acetyl-CoA
Important substrate for TCA cycle
Other roles in specific cells
M\(\phi\) + dendritic cells undergo metabolic shifts when responding to pro-inflammatory stimuli
'Rewiring' of TCA cyle
Glycolysis increases
Oxidative phosphorylation increases
TCA intermediates accumulate + diverted to support immune cell function
Overall an irreversible pathway
Due to step 1
2 phases
Introduction + oxidation of 2 carbons to carbon dioxide
Regeneration of oxaloacetate
Redox coenzymes
3 dehydrogenation reactions use NAD\(^+\) as redox coenzyme
1 reaction uses FAD as redox coenzyme (step 6)
FAD more powerful oxidant than NAD\(^+\) + bound covalently to enzyme complex
Acetyl-CoA
Origins of Acetyl-CoA
Amino acids
Pyruvate from glucose
Acetate from ethanol
Ketone body
Fatty acids
Fates of Actyl CoA
Ketone bodies
TCA cycle
Anabolic role
Fatty acids + cholesterol
Overall equation
Acetyl-CoA + 2H\(_2\)O + 3NAD\(^+\) + FAD + GDP + P\(_i\)
2CO\(_2\) + 3NADH + FADH\(_2\) + CoA-SH + GTP
Then
GTP + ADP
ATP + GDP
Most of the ATP produced occurs in oxidative phosphorylation
2 x for each glucose molecule
2 x Acetyl-CoA from each glucose
ATP yield
During oxidative phosphorylation
Electrons from NADH + FADH\(_2\) are transferred stepwise toward molecular oxygen
Coenzymes become oxidised again
Proton gradient generated across inner mitochondrial membrane
ATP synthesis occurs through chemiosmotic coupling
2.5 ATP per NADH reoxidised
1.5 ATP per FADH\(_2\) reoxidised
Total yield of 1 acetyl-CoA is 10ATP
NAD+ and FAD+
NAD+
Co-enzyme of dehydrogenases
Receives 2e- and 1H+
Forms NADH + H+
Nicotinamide ring
FAD+
Prosthetic group of flavoproteins
Receives 2e- + 1H+
Forms FADH\(_2\)
Isoalloxazine ring
Steps of TCA cycle
1
Oxaloacetate + acetyl CoA
Condensation (+H\(_2\)O)
Citrate + CoA + H\(^+\)
Citrate continues in cycle
Catalysed by
Citrate synthase
2a
2b
3
4
5
6
7
2 more items...
Succinate + enzyme-bound FAD
1 more item...
Succinyl CoA + P\(_i\) + GDP
Substrate-level phosphorylation
2 more items...
\(\alpha\)-ketoglutarate + NAD\(^+\) + CoA
Oxidative decarboxylation
Catalysed by
1 more item...
Succinyl CoA + CO\(_2\) + NADH
1 more item...
Prosthetic groups
3 more items...
Reversible
Isocitrate
Decarboxylation
Oxidation
\(\alpha\)-ketoglutarate + CO\(_2\) + NADH
1 more item...
Catalysed by
Isocitrate dehydrogenase
Reversible
cis-aconitate + H\(_2\)O
Hydration
Isocitrate
Catalysed by
Aconitase
Reversible
Fe-S prosthetic group
Citrate
Dehydration
cis-aconite + H\(_2\)O
Fe-S prosthetic group
Catalysed by
Aconitase
Reversible
Energetics
90% energy conservation overall
228kcal/mol available from Acetyl-CoA
207kcal/mol contained in products of TCA cycle
\(\Delta\)G = \(\Sigma\Delta\)G all reactions
-13kcal/mol
Lost as heat
Reoxidation of NADH + FADH\(_2\) via ETC makes reaction favourable
Irreversible reactions
Low [product] + slow reverse reaction
Drive cycle forward
Reversible reactions
Favour production of citrate + malate
Exit cycle + allow citrate to act as inhibitor
Regulation
Regulation required for ATP homeostasis
Rate of TCA cycle must correspond to rate of ETC
ETC rate regulated by ATP/ADP ratio + rate of ATP usage
ATP utilisation determined by
Phosphorylation state of ATP
i.e. Level of ATP + ADP
Reduction state of NAD\(^+\)
i.e. Ratio of NAD\(^+\)/NADH
Under physiological condiitons
Regulation must be rapid
[ATP] doesn't change significantly
System is sensitive to small changes
Citrate synthase reaction
Oxaloacetate + H\(_2\)O + acetyl-CoA = citrate + CoASH
Increased citrate implies low oxaloacetate
Enzyme switched off + acetyl-CoA diverted e.g. fatty acid synthesis
Low NAD\(^+\)/NADH ratio = low energy change
Oxaloacetate build-up
Enzyme switched on
Isocitrate dehydrogenase reaction
Isocitrate + NAD\(^+\) = \(\alpha\)-ketoglutarate + NADH + H\(^+\) + CO\(_2\)
Rate limiting step of TCA cycle
Increased [ADP] = on
Allosteric modification
Increased [ATP] = off
Increased Ca\(^{2+}\)
Enzyme switched on
Conformational change
More isocitrate binding
Increased [NADH]
Enzyme switched off
\(\alpha\)-ketoglutarate reaction
\(\alpha\)-ketoglutarate + CoASH + NAD\(^+\) = succinyl CoA + NADH + H\(^+\) + CO\(_2\)
Succinyl CoA
Competitive inhibitor of CoASH binding
NADH
Negative allosteric effector
Increase [GTP]
Inhibits enzyme
Increased Ca\({2+}\)
Enzyme switched on
Malate dehydrogenase reaction
Malate + NAD\(^+\) = oxaloacetate + NADH + H\(^+\)
Enzyme influenced by NAD\(^+\)/NADH ratio
Low ratio switches enzyme on
More oxaloacetate
High [NADH]
Favours formation of malate
Oxygen availability
Oxygen needed to regenerate NAD\(^+\)
Lack of oxygen = NADH build-up
Increased [lactate] in heart muscle
Angina
Heart does not normally work anaerobically
Continued
Myocardial infarction
Source of biosynthetic precursors
Provides intermediates for biosyntheses
Citrate
Fatty acids
Sterols
\(\alpha\)-ketoglutarate
Glutamate
Other amino acids
Purines
Succinyl CoA
Porphyrins
Haem
Chlorophyll
Oxaloacetate
Phosphoenol-pyruvate
Glucose
Aspartate
Other amino acids
Purines
Pyrimidines
Anaplerotic reactions
Replenishing pathways/reactions
Removal of intermediates from pathway
Implies need for replenishment
TCA inhibitors
Fluoroacetate toxicity
Isolated from plants
'Suicide' substrate
Parent compound is non-toxic
Metabolism produces toxic product
Fluoroacetyl-CoA + oxaloacetate = fluorocitrate
Catalysed by citrate synthase
Fluorocitrate binds aconitase where fluorine binds Fe\(^{2+}\) ion in active site
Inhibition of TCA and death
Malonate block
Malonate
3 carbon homologue of succinate
Structure similarity allows malonate to bind succinate dehydrogenase
Cannot be metabolised by enzyme
Competitive inhibitor
Inhibition causes block of TCA
Build-up of succinate, citrate + \(\alpha\)-ketoglutarate