The citric acid cycle, also known as the Krebs cycle or TCA cycle, is a series of chemical reactions that generate energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and proteins. The cycle occurs in the matrix of mitochondria in eukaryotic cells and in the cytosol of prokaryotic cells. It involves 8 steps to oxidize acetyl-CoA completely, producing carbon dioxide, GTP, and the electron carriers NADH and FADH2 to be used in the electron transport chain to generate ATP. The cycle is an important source of energy and precursor molecules for biosynthesis in cells.

1. Citric Acid Cycle, Krebs
Cycle, or TCA Cycle
Dr. Atindra Kumar Pandey
Ph.D., PGDCBP

2. Krebs cycle
Krebs cycle or Citric acid cycle (CAC) – also known as the TCA cycle
(tricarboxylic acid cycle)– is a series of chemical reactions to generate energy
through the oxidation of acetyl-CoA derived from carbohydrates, fats, and
proteins.
The tricarboxylic acid (TCA) cycle, also known as the Krebs or citric acid cycle, is
the main source of energy for cells and an important part of aerobic respiration.
In eukaryotic cells, the citric acid cycle occurs in the matrix of the
mitochondrion.
 In prokaryotic cells, it occurs in the cytosol.
First, pyruvic acid is broken down into Acetyl-Co-enzyme A convert Citric acid
CO2 is produced
Citric acid cycle is often considered the ‘hub’ of cellular metabolism.

3. History
Discovered by Hans Krebs in 1937
He received the Nobel Prize in physiology or
medicine in 1953 for his discovery

4. Steps:
1. Synthesis : citrate synthesis
2. Isomerisation
3. Oxidative decarboxylation
4. Oxidative decarboxylation
5. GTP Synthesis
6. Redox reaction
7. Hydration
8. Redox reaction

5. The TCA Cycle
The TCA cycle is a central pathway that provides a unifying point for many metabolites,
which feed into it at various points. It takes place over eight different steps:
• Step 1: Acetyl CoA (two carbon molecule) joins with oxaloacetate (4 carbon molecule) to
form citrate (6 carbon molecule).
• Step 2: Citrate is converted to isocitrate (an isomer of citrate)
• Step 3: Isocitrate is oxidised to alpha-ketoglutarate (a five carbon molecule) which results
in the release of carbon dioxide. One NADH molecule is formed.
• The enzyme responsible for catalysing this step is isocitrate dehydrogenase. This is a
rate limiting step, as isocitrate dehydrogenase is an allosterically controlled enzyme.
• Step 4: Alpha-ketoglutarate is oxidised to form a 4 carbon molecule. This binds to
coenzyme A, forming succinyl CoA. A second molecule of NADH is produced, alongside a
second molecule of carbon dioxide.
• Step 5: Succinyl CoA is then converted to succinate (4 carbon molecule) and
one GTP molecule is produced.
• Step 6: Succinate is converted into fumarate (4 carbon molecule) and a molecule
of FADH₂ is produced.
• Step 7: Fumarate is converted to malate (another 4 carbon molecule).
• Step 8: Malate is then converted into oxaloacetate. The third molecule of NADH is also
produced.

7. The overall reaction for the citric acid cycle is as follows:
acetyl-CoA + 3 NAD+ + FAD + GDP + P + 2H2O
CoA-SH + 3NADH + FADH2 + 3H+ + GTP + 2CO2.
Note:
each NADH produce 3 ATP
each FADH2 produce 2 ATP
Overall reaction for the citric acid cycle

9. Inhibitors of TCA Cycle
Fluorocitric acid : It inhibits aconitase (non-competitive inhibition)
• Flurocitrate is a metabolite of fluoroacetic acid and is
very toxic because it is not processable using aconitase in the citrate
cycle.
Malonic acid: Inhibition of succinate dehydrogenase by malonic acid
produces an "excitotoxic" lesion. As such, malonate is cytotoxic by
blocking the TCA cycle and cellular respiration. (non-competitive
inhibition)
Arsenic and Mercury inhibits: inhibits pyruvate dehydrogenase (PDH)
and α-ketoglutarate dehydrogenase complex,
• which requires the activity of the sulfhydryl group associated with the
dihydrolipoamide moiety of the enzyme complex. (competitive inhibition)

11. Significance of Krebs cycle
• The citric acid cycle is the final common oxidative pathway for
carbohydrates, fats and amino acids. It is the most important
metabolic pathway for the energy supply to the body.
• It explains the process of breaking of pyruvate into CO2 and water. It
is major pathway of generation of ATP. (ii) More energy is released
(24 ATP) in this process, as compared to glycolysis.
• in the TCA cycle and oxidative pAcetyl CoA produces 12 ATP
molecules accounting for 3 NADH (9 ATP), 1 FADH2 (2 ATP) and 1
GTP (1 ATP) hosphorylation in the electron transport system.
• The two main purposes of the citric acid cycle are: A) Synthesis
(Catabolic) of citrate and gluconeogenesis. B) degradation of
acetyl-CoA to produce energy and to supply precursors for
anabolism.