Lecture 21: Citric Acid Cycle Flashcards
Committed step
First irreversible reaction in a pathway who’s product cannot enter other pathways
Formation of fructose-1,6-bisphosphate
Aerobic oxidation
Mitochondrial conversion of pyruvate to acetyl-CoA and oxidation in TCA cycle
Citric acid cycle
TCA cycle, Krebs cycle
Oxidizes acetyl-CoA to CO2 and reduces NAD and FAD to NADH and FADH
No mitochondria, no TCA
Each round generates 3NADH, one GH2 and one GTP or ATP
Compartmentation
Allows additional regulation of metabolic pathways though regulation of their location/transport
Brings metabolites of one pathway into closer vicinity: faster reaction, less risk of unwanted side reactions
Oxidation of pyruvate to acetyl-CoA
Catalyses by pyruvate dehydrogenase
Requires NAD, TPP, FAD, CoA-SH and lipoic acid
Acetyl-CoA cannot be converted to glucose ever
Coenzyme A
Derivative of ADP: pantothenic acid linked to it via phosphate ester bond
Mercaptoethylamine is attached to pantothenic acid
Thiol group forms thioester bonds
Pyruvate dehydrogenase
Oxidizes pyruvate to acetyl-CoA
Pantothenic acid
Vitamin B5
Acetyl-CoA
Coenzyme A with a thioester bond to acetate
Thioester of coenzyme A and acetic acid
Oxidation in TCA cycle
Precursor for many larger metabolites
Pyruvate dehydrogenase phosphatase
Dephosphorylates PDH and activates PDH
Pyruvate dehydrogenase kinase
Phosphorylates PDH and inactivates PDH
Regulated allosterically:
Inactivated by acetyl CoA and activated by pyruvate and ADP
Step 1 of TCA: Citrate synthase
Condensation of oxaloacetate with acetyl-CoA to citrate, 2CO2 released
Irreversible
Product inhibition through citrate
Feedback inhibition by NADH and succinyl-CoA
Step 2 of TCA: Aconitate
Isomerization of citrate to isocitrate by dehydration-hydration
Step 3 of TCA: Isocitrate dehydrogenase
Oxidative decarboxylation of isocitrate to alpha-ketoglutarate
Irreversible
Redox reaction
Several forms of IDH: in many cancers, one of isoforms is mutated and works backwards
Step 4 of TCA: alpha-ketoglutarate dehydrogenase complex
Oxidative decarboxylation to succinyl-CoA Similar to PDH complex Irreversible reaction Multi enzyme complex Works in similar way as PDH Thiamine as cofactor
Step 5 of TCA: Succinyl-CoA synthetase
Hydrolysis of CoA ester generates succinate and GTP (GTP can easily be converted to ATP)
Reversible
Succinate is a symmetrical molecule
Step 6 of TCA: Succinate dehydrogenase
Reversible, redox
Succinate dehydrogenase generates ubiquinol
Fumarate formation
Reduces FAD to FADH2, deoxidation of FADH2 to Q: QH2
Coenzyme Q
Ubiquinone
Accepts two electrons (H-) in stepwise manner to become ubiquinol
Step 7 of TCA: Fumarase
Catalyzes hydration of fumarate to malate
Reversible
No change in oxidation state
Step 8 of TCA: Malate dehydrogenase
Regenerates oxaloacetate from malate
Reversible reaction, redox
Different isoforms of malate dehydrogenase for mitochondrial and cytosolic enzyme
TCA is mitochondria and uses NAD to make NADH
TCA reducing elements
NADH and FADH2 generated in the citric acid cycle are used to fuel ATP production in mitochondria
1NADH = 2.4 ATP
1FADH2 = 1QH2 = 1.5 ATP
The amount of ATP generates depends on efficiency of oxidative phosphorylation
Citrate accumulation
Inhibits phosphofructokinase
Occurs when too much acetyl-CoA enters the TCA cycle and not enough NADH is used
Regulation of TCA
Allosteric feedback inhibition
Allosteric activation by ADP
Production inhibition
Citric acid cycle intermediates
Important precursors for many amino acids
Can enter gluconeogenesis through oxaloacetate
All citric acid cycle intermediates are glucogenic
More intermediates: more reactions can occur in parallel
Can be replenished
