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KREB's Cycle PDF

The Krebs cycle, also known as the citric acid cycle or TCA cycle, is a series of chemical reactions used by all aerobic organisms to generate energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and proteins. The cycle was discovered by Hans Krebs in 1937, for which he received the 1953 Nobel Prize in Physiology or Medicine. The cycle consists of eight steps that oxidize acetate from acetyl-CoA into two molecules of carbon dioxide. Energy released is used to produce three molecules of NADH and one molecule of FADH2 to be used in the electron transport chain to produce ATP. The cycle is named for its early intermediate product, citric acid.

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325 views30 pages

KREB's Cycle PDF

The Krebs cycle, also known as the citric acid cycle or TCA cycle, is a series of chemical reactions used by all aerobic organisms to generate energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and proteins. The cycle was discovered by Hans Krebs in 1937, for which he received the 1953 Nobel Prize in Physiology or Medicine. The cycle consists of eight steps that oxidize acetate from acetyl-CoA into two molecules of carbon dioxide. Energy released is used to produce three molecules of NADH and one molecule of FADH2 to be used in the electron transport chain to produce ATP. The cycle is named for its early intermediate product, citric acid.

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Ritwik Chakraborty
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KREB’S CYCLE

 The name KREB’S CYCLE has been given to this cycle after the name of the discoverer
HANS KREBS.
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.

 The name TCA CYCLE was given as the first product of this cycle i.e Citric Acid
contains three carboxylic group. Hence the name

TRICABOXYLIC ACID CYCLE


 The name CITRIC ACID CYCLE was given as the first product of this cycle is Citric Acid
Oxidative Decarboxylation of Pyruvate
In presence of O2, lactate produced by Glycolysis is reoxidised to Pyruvate by lactate
dehydrogenase and NAD+ in the cytosol. A specific pyruvate carrier of the inner
mitochondrial membrane then tranport pyruvate from the cytosol to mitochondrial matrix
along with H+.

Monocarboxylate transporters (MCTs)


In the mitochondrial matrix, pyruvate is oxidatively decarboxylated to Acetyl-CoA by a
multienzyme system (Pyruvate dehydrogenase complex).
Pyruvate dehydrogenase Complex:
The PYRUVATE DEHYDROGENASE COMPLEX is a multimolecular aggregate of three
enzymes:

1. Pyruvate decarboxylase
2. Dihydrolipoyl transacetylase
3. Dihydrolipoyl dehydrogenase
Each catalyses a part of the overall reaction
REACTION SEQUENCES
In this cycle, an acetyl (C2) unit from acetyl CoA condenses with oxaloacetate (C4) to form
citrate (C6) which is systematically oxidised and decarboxylated by mitochondrial enzymes
to regenerate oxaloacetate finally.
Thus each turn of the cycle changes a C2 unit into CO2 and H2O
1. Synthesis of Citrate from Acetyl CoA & Oxaloacetate
• The condensation of acetyl CoA & oxaloacetate is catalysed by a condensing enzyme,
citrate synthase, linking methyl ‘C’ of acetyl CoA with ketonyl ‘C’ of oxaloacetate to
release Citrate and CoA, accompanied by loss of heat.
2a. Isomerization of Citrate

• Aconitase[bearing a covalently bound Fe4S4 cluster] isomerizes citrate to iso-citrate.


• It first dehydrates citrate to cis-aconitase by removing H and OH groups from
methylene ‘C’ and ketonyl ‘C’ of oxaloacetate
2b. Isomerization of Citrate

• Now,The enzyme hydrates cis- aconitase to isocitrate by adding H and OH group in a


reverse order to those carbons.
• Aconitase contains an iron-sulphur centre, which acts both in the binding of the
substrate at the active site and in catalysis of addition or removal of H2O
3a. Oxidation & decarboxylation of isocitrate

Isocitrate undergoes dehydrogenation in the presence of isocitrate dehydrogenase to
form a- keto glutarate (C5) in mitochondria.

First, It oxidises isocitrate to oxalosuccinate, using NAD+ as acceptor of hydride(H-) ion
from isocitrate.

This is the first oxidative step of TCA cycle.
3b. Oxidation & decarboxylation of isocitrate

Next, the enzyme decarboxylate oxalosuccinate to a - keto glutarate in presence of
Mn2+
4. Conversion of α- ketoglutarate to succinyl-CoA
• The next step is another (second) oxidative decarboxylation, in which a-ketoglutarate is
converted to succinyl-CoA by the action of the α-ketoglutarate dehydrogenase
complex;
• NAD+ serves as electron acceptor.
• This is the second oxidative step of TCA cycle.

TPP

This reaction is identical to the pyruvate dehydrogenase complex reaction.


5. Conversion of Succinyl-CoA to Succinate
 Succinate thiokinase cleaves the high-energy thioester bond of Succinyl CoA to produce
Succinate and CoA.
 In the next step, the energy released in this exergonic reaction drive the endergonic
eaction of phosphorylation of GDP with Pi , forming GTP.
6. Oxidation of Succinate to Fumerate
• The succinate formed from Succinyl-CoA is oxidised to Fumarate by Succinate
dehydrogenase with the help of FAD.
• The dehydrogenation involves direct transfer of hydrogen from substrate to
flavoprotein (FAD) and reducing it to FADH2.
• This is the third oxidative reaction in TCA cycle
7. Hydration of Fumerate to produce Malate

• Fumerase (fumerase hydratase) catalyses the addition of water to fumerate to give


malate.
• The enzyme is highly stereospecific,catalyses only the hydration of trans double bond
of fumerate but does not act on maleate(the cis isomer)
8. Oxidation of Malate to Oxaloacetate

• Malate dehydrogenase oxidises Malate to Oxaloacetate, using NAD+ as the electron


acceptor.
• This is the fourth oxidative reaction of the TCA cycle

Formation of Oxaloacetate completes one turn of TCA Cycle.


Using labeled carbon Oxaloacetate, it has been shown that, CO2 evolved in the reaction
comes from Oxaloacetate derived part of citrate & not from acetate derived part.
Importance:
 The major function of citric acid cycle is to act as the final common pathway
for the oxidation of carbohydrate, protein and lipid.
 This is because glucose, many amino acids and fatty acids are all
metabolized to acetyl CoA or intermediates of the cycle.
 It also play a major role in gluconeogenesis, transamination, deamination
and lipogenesis.
 Several of this process are carried out in many tissues, but liver is the only
tissue in which all occurs to a significant extent.
Figure 1 : Schematic drawing of the citric acid cycle.

Molecule Enzyme Reaction type Reactants/ Products/


Coenzymes Coenzymes

I. Citrate 1. Aconitase Dehydration H2O

II. cis-Aconitate 2. Aconitase Hydration H2O


+ +
III. Isocitrate 3. Isocitrate dehydrogenase Oxidation NAD NADH + H
IV. Oxalosuccinate 4. Isocitrate dehydrogenase Decarboxylation
V. α-Ketoglutarate 5. α-Ketoglutarate Oxidative +
NAD + CoA
+
NADH + H + CO2
dehydrogenase decarboxylation

VI. Succinyl-CoA 6. Succinyl-CoA synthetase Hydrolysis GDP + Pi GTP + CoA-SH

VII. Succinate 7. Succinate dehydrogenase Oxidation FAD FADH2


VIII. Fumarate 8. Fumarase Addition (H2O) H2O
+ +
IX. L-Malate 9. Malate dehydrogenase Oxidation NAD NADH + H
X. Oxaloacetate 10. Citrate synthase Condensation
XI. Acetyl-CoA

The sum of all reactions in the citric acid cycle is:


Acetyl-CoA + 3 NAD+ + FAD + GDP + Pi + 2 H2O ⇒ CoA-SH + 3 NADH + H+ + FADH2 + GTP + 2 CO2 + 3 H+
Reference:
1. Biochemistry by U Satyanarayan
2. Biochemistry by D Das
3. en.wikipedia.org>wiki
4. Slideshare.net
5. Youtube
6. www.ncbi.nlm.nih.gov

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