TCA Cycle

TCA Cycle
By
Mohamed Hussien Amer
Amaal Abdellatif Alsharmolsy
Introduction
The cycle is named after Sir Hans Krebs, who discovered the sequence
of chemical reactions in the 1930s.
It’s a complete oxidation of pyruvate to CO2 & water through a series
of reactions.
It's known as the tricarboxylic acid (TCA) cycle or Krebs cycle.
The 2nd stage of respiration
The Krebs cycle plays a central role in energy production by generating
high-energy molecules (such as NADH and FADH2) that carry electrons to
the electron transport chain, the final step of cellular respiration, where
ATP is synthesized.
Location: Matrix of mitochondria
Properties
a) It consists of 9 enzyme catalyzed steps
b) It begins with the condensation 2C acetyl-CoA with the 4C oxaloacetate to
form 6C citrate.
c) The cycle includes 4 oxidations, which yield 3 NADH + 1 FADH2 + 2CO2.
d) 1 ATP is formed by substrate-level phosphorylation.
e) Finally, oxaloacetate regenerated, which allows the cycle to continue.
f) The cycle must turn twice to metabolize one hexose sugar.
g) All the oxidative enzymes of the kreb's cycle are located in the matrix,
Except Succinate dehydrogenase.
Step 1: Pyruvate oxidation
 It is an oxidative energy yielding process.
 Pyruvate is produced in cytosol then enter the
mitochondrion in exchange for hydroxyl ion "OH".
 When Pyruvate reaches the mitochondrial matrix, it
oxidized & decarboxylated by pyruvate
dehydrogenase complex.
 So, 2 carbon molecules are produced called
acetate.
 Acetate reacts with Coenzyme A producing acetyl-
CoA.
Step 1: Pyruvate oxidation
• Note: The pyruvate dehydrogenase complex is a multimolecular aggregate of three

1)enzymes.
Pyruvate dehydrogenase 2)
3) Dihydrolipoyl
(E1, also called a Dihydrolipoyltransacetylase
dehydrogenase (E3).
decarboxylase). (E2).
• This complex contains 2 tightly bound regulatory enzymes:

1) protein kinase
2) phosphoprotein phosphatase
• Coenzymes: The pyruvate dehydrogenase complex contains 5 coenzymes that act as

carriers or oxidants for the intermediates of the reactions.
• E1 requires thiamine pyrophosphate (vitamin B1 ), E2 requires lipoic acid and
coenzyme A, and E3 requires FAD and NAD+.
Step 2: Synthesis of citrate
Citrate is synthesized by condensation of acetyl CoA and oxaloacetate.
This complex which contains 6C molecule is catalysed by citrate synthase.
Note: Citrate synthase is allosterically activated by Ca2+ and ADP, and
inhibited by ATP, NADH, succinyl CoA, and fatty acyl CoA derivatives.
Step 3: Isomerization of citrate
Citrate is isomerized to cis-Aconitate which automatically converted into
isocitrate by aconitase.
Step 4: Oxidation and decarboxylation of
isocitrate
• Isocitrate is oxidized & release the first CO2, forming 5C molecule α-ketoglutarate.
• NAD is reduced into NADH.

• This step catalyzed by isocitrate dehydrogenase complex.
Step 5: Oxidative decarboxylation of α-
ketoglutarate
• α-ketoglutarate is oxidized & release the second CO2, forming 4C
molecule that join with Coenzyme A, forming the succinyl CoA "unstable"
• NAD is reduced into NADH.
• Enzyme: α-ketoglutarate dehydrogenase
Step 6: Cleavage of succinyl CoA
The high-energy thioester bond of succinyl CoA is broken by succinate thiokinase,
“also known as succinyl CoA synthetase” to form succinate.
The phosphorylation of GDP to GTP is connected to this process. The nucleoside
diphosphate kinase process allows GTP and ATP to be energetically converted to
each other.
The generation of GTP by succinate thiokinase is another example of substrate-level
phosphorylation.
Step 7: Oxidation of succinate
• Succinate oxidized, forming 4C molecule called fumarate.
• 2 H atoms transferred to FAD producing FADH2
• Enzyme: Succinate dehydrogenase
• Succinate dehydrogenase embedded in the inner membrane of the
mitochondria
 Note: FAD, rather than NAD+,

is the electron acceptor
because the reducing power of
succinate is not sufficient to
reduce NAD+.
Step 8: Hydration of fumarate
• Water is added to fumarate, converting it into 4C molecule called malate.
This reaction is freely reversible reaction catalyzed by fumarase (also
called fumarate hydratase).
Note: Fumarate is also produced by the urea cycle, in purine synthesis,
and during catabolism of the amino acids, phenylalanine and tyrosine
Step 9: Oxidation of malate
• Oxaloacetate "Starting 4C compound' is regenerated by oxidation of
malate.
• NAD is reduced into NADH “The third and final of the cycle”
• Enzyme: malate dehydrogenase
Thank You

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TCA Cycle

• Note: The pyruvate dehydrogenase complex is a multimolecular aggregate of three

• This complex contains 2 tightly bound regulatory enzymes:

• Coenzymes: The pyruvate dehydrogenase complex contains 5 coenzymes that act as

• NAD is reduced into NADH.

 Note: FAD, rather than NAD+,

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