The citric acid cycle is the final common pathway for the oxidation of fuel molecules — amino acids, fatty acids, and carbohydrates.
Hans Adolf Krebs. Biochemist; born in Germany. Worked in Britain. His discovery in 1937 of the ‘Krebs cycle’ of chemical reactions was critical to the understanding of cell metabolism and earned him the 1953 Nobel Prize for Physiology or Medicine.
2. Glucose
Glucose-6-
phosphate
Pyruvate
Glycogen Ribose, NADPH
Pentose phosphate
pathway
Synthesis of
glycogen
Degradation of
glycogen
Glycolysis Gluconeogenesis
LactateEthanol
Acetyl Co AFatty 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. In eukaryotes
the reactions of
the citric acid
cycle take
place inside
mitochondria
Hans Adolf Krebs. Biochemist; born in
Germany. Worked in Britain. His discovery in
1937 of the ‘Krebs cycle’ of chemical reactions
was critical to the understanding of cell
metabolism and earned him the 1953 Nobel Prize
for Physiology or Medicine.Physiology or Medicine.
4. 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 α-
ketoglutarate is formed.
α-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.
5.
6. 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
7. 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 aconitase
8. 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 dehydrogenaseisocitrate dehydrogenase
9. 4. The α-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)
α-ketoglutarate
dehydrogenase
10. 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
11. • 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
12. 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
15. 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.
9 ATP (2.5 ATP per NADH, and 1.5 ATP per FADH2)are produced
during oxidative phosphorylation.
1 ATP is directly formed in the citric acid cycle.
1 acetyl CoA generates approximately 10 molecules of ATP.
16. • 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.
17. Regulation of the Citric Acid Cycle
• Pathway controlled by:
(1) Allosteric modulators
(2) Covalent modification of cycle enzymes
(3) Supply of acetyl CoA (pyruvate dehydrogenase complex)
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. Bacterial ICDH can be
covalently modified by kinase/phosphatase)
−α-ketoglutarate dehydrogenase complex (inhibition by ATP,
succinyl CoA and NADH
18. Krebs Cycle is a Source of Biosynthetic Precursors
Phosphoenol-
pyruvate
Glucose
The citric acid cycle
provides intermediates
for biosyntheses