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Khadijah Hanim Abdul Rahman
School of Bioprocess Eng, UniMAP
Sem 1, 2012/2013
Week 14: 10/12/2011
The citric acid cycle (also known as the
tricarboxylic acid cycle, the TCA cycle, or
the Krebs cycle) is a series of chemical
reactions of central importance in all living
cells that utilize oxygen as part of cellular
In aerobic organisms, the citric acid
cycle is part of a metabolic pathway
involved in the chemical conversion of
carbohydrates, fats and proteins into
carbon dioxide and water to generate a
form of usable energy.
The citric acid cycle also provides
precursors for many compounds such
as certain amino acids, and some of its
reactions are therefore important even
in cells performing fermentation.
 Facultative
anaerobes and obligate
aerobes that use O2 to generate energy,
employ the following biochemical
- TCA cycle
- Electron transport pathway
- oxidation phosphorylation
 In eukaryotes- occur in mitochondrion
cycle- metabolic pathway, 2 carbons
fragments derived from organic fuel
molecules are oxidized to form CO2 and the
coenzymes NAD+ and FAD are reduced to
form NADH and FADH2.
 The electron transport chain (ETC)mechanism in which electrons are
transferred from reduced coenzymes to an
acceptor, O2.
 In oxidative phosphorylation- energy
released by ETC is captured in a form of a
proton gradient that drives the synthesis of
ATP, the energy currency of living
In living organisms, both energycapturing and energy releasing
processes consist primarily of redox
 In redox reactions electrons move
between an electron donor and an
electron acceptor.
cycle- series of biochemical
reactions aerobic organisms use to
release chemical energy stored in the 2carbon acetyl group in acetyl-CoA.
 Acetyl-CoA composed of an acetyl group
derived from the breakdown of
carbohydrates, lipids and some amino
acid that is linked to the acyl carrier
molecule Coenzyme A.
 Acetyl-CoA is synthesized from pyruvate
 Acetyl-CoA- also the product of fatty acid
catabolism and certain reactions in amino
acid metabolism.
 Its main function is to convey the carbon
atoms within the acetyl group to the citric
acid cycle to be oxidized for energy
 In TCA cycle- the carbon atoms are oxidized
to CO2 and the high-energy electrons are
transferred to NAD+ and FAD to form the
reduced coenzymes NADH and FADH2.
 In
the first reaction- a 2-carbon acetyl group
condenses with a 4-carbon molecules
(oxaloacetate) to form a 6-carbon molecule
 During the subsequent 7 reactions, in which
2 CO2 molecules are produced and 4 pairs
of electrons are removed from carbon
compounds, citrate is reconverted to
 In one step in the cycle, substrate-level
phosphorylation, high-energy molecule
GTP is produced.
 The
net reaction for TCA cycle as follows:
Acetyl-CoA + 3NAD+ + FAD + GDP + Pi +
2H2O  2CO2 + 3NADH + FADH2 +
CoASH + GTP + 3H+
In addition to its role in energy production,
TCA cycle plays important role. Its cycle
intermediates are substrates in variety of
biosynthetic reactions.
 Pyruvate
is transported out from cytosol into
the mitochondrial matrix where it converted
to acetyl-CoA
 Pyruvate  acetyl-CoA- in a series of
reactions catalyzed by pyruvate
dehydrogenase complex enzyme
 The net reaction, an oxidative
decarboxylation as follows:
Pyruvate + NAD+ + CoASH  Acetyl-CoA
+ NADH + CO2 + H2O + H+
 The
pyruvate dehydogenase enzyme
complex contains 3 enzymes activities:
- Pyruvate dehydrogenase
- Dihydrolipoyl transacetylase
- Dihydrolipoyl dehydrogenase
 TPP (Thiamine pyrophosphate), FAD,
NAD+ and lipoic acid are the required
co-enzymes for acetyl-CoA synthesis
from pyruvate.
 The
main function of acetyl-CoA is to
convey the carbon atoms within the
acetyl group to the citric acid cycle to be
oxidized for energy production.
in each turn of the cycle,
acetyl-CoA from the
glycolytic pathway/fatty
acid catabolism enters
and 2 fully oxidized
carbon molecules leave
as CO2.
 3 molecules of NAD+ and
1 molecule of FAD are
 1 molecule of GTP
(interconvertible with
ATP) is generated in a
TCA cycle is composed of eight
reactions that occur in 2 stages:
1) The 2-carbon of acetyl group of acetylCoA enters the cycle by reacting with a
4-carbon compound oxaloacetate. 2
molecule of CO2 are subsequenly
2) Oxaloacetate is regenerated so it can
react with another acetyl-CoA
cycle begins with the condensation
of acetyl-CoA with oxaloacetate to form
citrate which contains a tertiary alcohol is
reversibly converted to isocitrate by an enzyme
 During isomerization reaction, an intermediatecis-aconitate is formed by dehydration.
 The carbon-carbon double bond of cisaconitate is rehydrated to form isocitrate.
isocitrate dehydrogenase catalyzes oxidative decarboxylation of
isocitrate to form α-ketoglutarate:
There are two different forms of isocitrate dehydrogenase, one
requiring NAD+ as electron acceptor and the other requiring
The overall reactions catalyzed by the two isozymes are otherwise
The NAD-dependent enzyme is found in the mitochondrial matrix
and serves in the citric acid cycle to produce a-ketoglutarate.
The NADP-dependent isozyme is found in both the mitochondrial
matrix and the cytosol. It may function primarily in the generation
of NADPH, which is essential for reductive anabolic reactions.
 The
conversion of α-ketoglutarate to
succinyl-CoA is catalyzed by the enzyme
activities in the dehydrogenase complex:
α-ketoglutarate dehydrogenase.
 The
cleavage of the high-energy
thioester bond of succinyl-CoA to form
succinate, catalyzed by succinate
thiokinase is coupled in mammals to the
substrate-level phosphorylation of GDP.
 Succinate
dehydrogenase catalyzes the
oxidation of succinate to form fumarate:
 Succinate
dehydrogenase is a
flavoprotein using FAD to drive the
oxidation of succinate to fumarate.
 Fumarate
is converted to L-malate in a
reversible stereospecific hydration
reaction catalyzed by fumarase:
 Finally, oxaloacetate
is regenerated with
the oxidation of L-malate:
 The
citric acid cycle begins with the
condensation of acetyl-CoA molecule
with oxaloacetate to form citrate, which is
eventually reconverted to oxaloacetate.
 During this process,
- 2 molecules of CO2
- 3 molecules of NADH
- 1 molecule of FADH2
- 1 molecule of GTP
Many of the enzymes in the TCA cycle are
regulated by negative feedback from ATP when
the energy charge of the cell is high.
 Such enzymes include the pyruvate
dehydrogenase complex that synthesizes the
acetyl-CoA needed for the first reaction of the
TCA cycle.
 Also the enzymes citrate synthase, isocitrate
dehydrogenase and alpha-ketoglutarate
dehydrogenase, that regulate the first three steps
of the TCA cycle, are inhibited by high
concentrations of ATP.
 This regulation ensures that the TCA cycle will
not oxidise excessive amounts of pyruvate and
acetyl-CoA when ATP in the cell is plentiful. This
type of negative regulation by ATP is by an
allosteric mechanism
 Several
enzymes are also negatively
regulated when the level of reducing
equivalents in a cell are high (high ratio
of NADH/NAD+).
 This mechanism for regulation is due to
substrate inhibition by NADH of the
enzymes that use NAD+ as a substrate.
 This includes both the entry point
enzymes pyruvate dehydrogenase and
citrate synthase.