The Citric Acid Cycle is the major metabolism cycle in our body to generate the energy required for biological processes.

1. ‫حيوية‬ ‫كيمياء‬
-
2
‫محاضرة‬ ،
-
2
Aerobic cells
use a
metabolic
wheel – the
citric acid
cycle – to
generate
energy by
acetyl CoA
oxidation
The Citric Acid Cycle
Aerobic cells use a metabolic wheel – the
citric acid cycle – to generate energy by
acetyl CoA oxidation

2. Glucose
Glucose-6-
phosphate
Pyruvate
Glycogen Ribose, NADPH
Pentose phosphate
pathway
Synthesis of
glycogen
Degradation of
glycogen
Glycolysis Gluconeogenesis
Lactate
Ethanol
Acetyl Co A
Fatty Acids Amino Acids
The citric acid
cycle is the final
common pathway
for the
oxidation of fuel
molecules —
amino acids,
fatty acids, and
carbohydrates.
Most fuel
molecules
enter the
cycle as
acetyl
coenzyme A.

3. An Overview of the Citric Acid Cycle
A four-carbon oxaloacetate condenses with a
two-carbon acetyl unit to yield a six-carbon
citrate.
An isomer of citrate is oxidatively
decarboxylated and five-carbon -
ketoglutarate is formed.
-ketoglutarate is oxidatively
decarboxylated to yield a four-carbon
succinate.
Oxaloacetate is then regenerated from
succinate.
Two carbon atoms (acetyl CoA) enter the
cycle and two carbon atoms leave the cycle
in the form of two molecules of carbon
dioxide.
Three hydride ions (six electrons) are
transferred to three molecules of NAD+, one
pair of hydrogen atoms (two electrons) is
transferred to one molecule of FAD.
The function of the citric acid
cycle is the harvesting of high-
energy electrons from acetyl CoA.

4. 1. Citrate Synthase
• Citrate formed from acetyl CoA and oxaloacetate
• Only cycle reaction with C-C bond formation
• Addition of C2 unit (acetyl) to the keto double bond
of C4 acid, oxaloacetate, to produce C6 compound,
citrate
citrate synthase

5. 2. Aconitase
• Elimination of H2O from citrate to form C=C bond of cis-aconitate
• Stereospecific addition of H2O to cis-aconitate to form isocitrate
• Aconitase is inhibited by fluoroacetate (a compound that is used as a
rat poison). Fluoroacetate is converted to fluoroacetyl CoA, which
condenses with oxaloacetate to form fluorocitrate — a potent inhibitor
of aconitase — resulting in citrate accumulation.
aconitase aconitase

6. 3. Isocitrate Dehydrogenase
• Oxidative decarboxylation of isocitrate to
a-ketoglutarate (a metabolically irreversible reaction)
• One of four oxidation-reduction reactions of the cycle
• Hydride ion from the C-2 of isocitrate is transferred to
NAD+ to form NADH
• Oxalosuccinate is decarboxylated to a-ketoglutarate
isocitrate dehydrogenase
isocitrate dehydrogenase

7. 4. The -Ketoglutarate Dehydrogenase Complex
• Similar to pyruvate dehydrogenase complex
• Same coenzymes, identical mechanisms
E1 - a-ketoglutarate dehydrogenase (with TPP)
E2 – dihydrolipoyl succinyltransferase (with flexible
lipoamide prosthetic group)
E3 - dihydrolipoyl dehydrogenase (with FAD)
-ketoglutarate
dehydrogenase

8. 5. Succinyl-CoA Synthetase
• Free energy in thioester bond of succinyl CoA is
conserved as GTP or ATP in higher animals (or ATP
in plants, some bacteria)
• Substrate level phosphorylation reaction
HS-
+
GTP + ADP GDP + ATP
Succinyl-CoA
Synthetase

9. • Complex of several polypeptides, an FAD prosthetic group and
iron-sulfur clusters
• Embedded in the inner mitochondrial membrane
• Electrons are transferred from succinate to FAD and then to
ubiquinone (Q) in electron transport chain
• Dehydrogenation is stereospecific; only the trans isomer is
formed
6. The Succinate Dehydrogenase Complex
Succinate
Dehydrogenase

10. 7. Fumarase
• Stereospecific trans addition of water to the
double bond of fumarate to form L-malate
• Only the L isomer of malate is formed
Fumarase

11. 8. Malate Dehydrogenase
Malate
Dehydrogenase
Malate is oxidized to form oxaloacetate.

12. Stoichiometry of the Citric Acid Cycle
 Two carbon atoms enter
the cycle in the form of
acetyl CoA.
 Two carbon atoms leave the
cycle in the form of CO2 .
 Four pairs of hydrogen
atoms leave the cycle in four
oxidation reactions (three
molecules of NAD+ one
molecule of FAD are
reduced).
 One molecule of GTP,
is formed.
 Two molecules of water are
consumed.
 11 ATP (3 ATP per NADH, and 2
ATP per FADH2) are produced
during oxidative phosphorylation.
 1 ATP is directly formed in the
citric acid cycle from GTP.
 1 acetyl CoA generates
approximately 12 molecules of
ATP.

13. • Integration of metabolism. The citric acid cycle is
amphibolic (both catabolic and anabolic).
Functions of the Citric Acid Cycle
The cycle is involved in
the aerobic catabolism
of carbohydrates, lipids
and amino acids.
Intermediates of the
cycle are starting points
for many anabolic
reactions.
• Yields energy in the form of GTP (ATP).
• Yields reducing power in the form of NADH2 and
FADH2.

14. Regulation of the Citric Acid Cycle
Three enzymes have regulatory properties
- citrate synthase (is allosterically inhibited by NADH, ATP,
succinyl CoA, citrate – feedback inhibition)
- isocitrate dehydrogenase
(allosteric effectors: (+) ADP; (-) NADH, ATP
--ketoglutarate dehydrogenase complex (inhibition by ATP,
succinyl CoA and NADH

15. NADH, ATP, succinyl
CoA, citrate
-
Regulation of the citric acid cycle

16. Krebs Cycle is a Source of Biosynthetic Precursors
Phosphoenol-
pyruvate
Glucose
The citric acid cycle
provides
intermediates for
biosyntheses

17. There are three major pathways of
glucose metabolism
1. Glycolysis
2. Kreb's Cycle (Citric Acid Cycle)
3. Electron Transport Chain
anaerobic
aerobic
aerobic

18. Three major pathways of glucose metabolism
during cellular respiration:
‫الخلوي‬ ‫التنفس‬ ‫أثناء‬ ‫الجلوكوز‬ ‫الستقالب‬ ‫رئيسية‬ ‫مسارات‬ ‫ثالثة‬
:

19. Equation for Cellular Respiration:
oxidation & reduction
• REDOX reactions in respiration
– release energy as breakdown of organic molecules
• break C-C bonds
• C6H12O6  CO2 = the fuel has been oxidized
• O2  H2O = oxygen has been reduced
C6H12O6 6O2 6CO2 6H2O 36ATP

+ + +
oxidation
reduction or 38

20. 3. Electron Transport Chain:
Oxidative Phosphorylation: process in which ATP is formed as a result
of the transfer of electrons from NADH or FADH2 to O2 by a series of
electron carriers.

22. NAD
dehydrogenase
Coenzyme
Q
Coenzyme c
Bc complex
Cytochrome c
oxidase complex
ATP synthase
FADH
NADH
ADP

23. NAD
dehydrogenase
Coenzyme
Q
Coenzyme c
Bc complex
Cytochrome c oxidase
complex
ATP synthase
FADH
NADH
H2O
ADP

24. NAD
dehydrogenase
Coenzyme
Q
Coenzyme c
Bc complex
Cytochrome c
oxidase complex
ATP synthase
FADH
NADH
H2O
ADP

25. Breakdown of One Glucose Molecule
Calculations from each:
NADH= 2 or 3 ATP can be made
FADH2= 2 ATP can be made
1. Glycolysis – Produces:
2 ATP 2 NADH
2. Krebs Cycle - Produces:
2 ATP 8 NADH 2 FADH2
Total: 4 ATP 10 NADH 2 FADH2
3. ETC - Produces: x 3 x 2
30 ATP 4 ATP = 34 ATP
Total: 4 ATP + 34 ATP = 38 ATP
Theoretical Yield
(‫النظري‬ ‫)العائد‬
This is the theoretical maximum yield of ATP per glucose molecule oxidized by aerobic respiration.

26. -Net yield of 38 ATP per glucose molecule
- 6 H2O are formed when the electrons unite with O2* at the
end of electron transport chain.
* We breath because we need oxygen as the final electron
acceptor! The resulting ATP is able to leave the mitochondria
by the ATP transport protein in the membrane. It goes to
wherever it is needed in the cell.
Without
oxygen to
serve as the
final electron
acceptor, the
process
shuts down.

27. 2 NADH
2 ATP net
2 ATP
2 NADH
6 NADH
8 NADH
Cellular Respiration Summary
2 FADH2
2 FADH2
6 CO2
2 ATP net 34 ATP possible
- Each NADH
produces 3 ATP
- Each FADH2
produces 2 ATP