1. Citric Acid Cycle

2. Electron Transport and Oxidative phosphorylation
Gylcolysis
Electron Transport and
Oxidative phosphorylation
TCA Cycle

3. (aka Citric Acid Cycle, Krebs Cycle)
The TCA Cycle
(aka Citric Acid Cycle, Krebs Cycle)
Pyruvate (actually acetate) from glycolysis is degraded to CO2
Some ATP is produced
More NADH is made
NADH goes on to make more ATP in electron transport and oxidative phosphorylation

5. Entry into the TCA Cycle
Pyruvate is translocated from the cytosol to the mitochondria
Pyruvate is oxidatively decarboxylated to form acetyl-CoA
Pyruvate dehydrogenase uses TPP, CoASH, lipoic acid, FAD and NAD+
Acetyl-CoA then enters TCA cycle thru citrate synthase

6. Pyruvate Dehydrogenase Complex
Composed of three enzymes:
pyruvate dehydrogenase (E1) (cofactor = TPP)
Dihydrolipoamide acetyltransferase (E2) (cofactor = Lipoamide, CoA)
Dihydrolipoamide dehydrogenase (E3) (cofactor = FAD, NAD+)

7. Pyruvate Dehydrogenase

9. Citrate Synthase
Only step in TCA cycle that involves the formation of a C-C bond

11. Aconitase Isomerization of Citrate to Isocitrate
Citrate is a poor substrate for oxidation
So aconitase isomerizes citrate to yield isocitrate which has a secondary -OH, which can be oxidized
Aconitase uses an iron-sulfur cluster to position citrate (binds –OH and carboxyl of central carbon)

13. Isocitrate Dehydrogenase
Oxidative decarboxylation of isocitrate to yield  -ketoglutarate
Classic NAD+ chemistry (hydride removal) followed by a decarboxylation
Isocitrate dehydrogenase is a link to the electron transport pathway because it makes NADH
Rxn is metabolically irreversible

15.  -Ketoglutarate Dehydrogenase
A second oxidative decarboxylation
This enzyme is nearly identical to pyruvate dehydrogenase - structurally and mechanistically
Five coenzymes used - TPP, CoASH, Lipoic acid, NAD+, FAD

17. Succinyl-CoA Synthetase
A substrate-level phosphorylation
A nucleoside triphosphate is made (ATP in plants/bacteria and GTP in animals)
Its synthesis is driven by hydrolysis of a CoA ester

19. Succinate Dehydrogenase
An oxidation involving FAD
Mechanism involves hydride removal by FAD and a deprotonation
This enzyme is actually part of the electron transport pathway in the inner mitochondrial membrane
The electrons transferred from succinate to FAD (to form FADH2) are passed directly to ubiquinone (UQ) in the electron transport pathway
Enzyme inhibited by malonate

21. Fumarase Hydration across the double bond
trans-addition of the elements of water across the double bond
Stereospecific reaction

23. Malate Dehydrogenase An NAD+-dependent oxidation
The carbon that gets oxidized is the one that received the -OH in the previous reaction
This reaction is energetically expensive
Go' = +30 kJ/mol

25. Reduced Coenzymes Fuel ATP Production
Acetyl-CoA + 3 NAD+ + Q + GDP + Pi +2 H20  HS-CoA + 3NADH + QH2 + GTP + 2 CO2 + 2 H+
Isocitrate Dehydrogenase 1 NADH=2.5 ATP
a-ketoglutarate dehydrogenase 1 NADH=2.5 ATP
Succinyl-CoA synthetase GTP=1 ATP
Sunccinate dehydrogenase 1 QH2=1.5 ATP
Malate Dehydrogenase 1 NADH=2.5 ATP
Total of 10 ATPs gained from oxidation of 1 Acetyl-CoA

27. Regulation of TCA Cycle

29. TCA Cycle provides intermediates for many biosynthetic processes

30. The Anaplerotic Reactions
The "filling up" reactions
PEP carboxylase - converts PEP to oxaloacetate
Pyruvate carboxylase - converts pyruvate to oxaloacetate
Malic enzyme converts pyruvate into malate