Cell Biochem Biophys (2014) 68:475–478
DOI 10.1007/s12013-013-9750-1
REVIEW PAPER
Citric Acid Cycle and Role of its Intermediates in Metabolism
Muhammad Akram
Published online: 26 September 2013
Ó Springer Science+Business Media New York 2013
Abstract The citric acid cycle is the final common oxi-
dative pathway for carbohydrates, fats and amino acids. It
is the most important metabolic pathway for the energy
supply to the body. TCA is the most important central
pathway connecting almost all the individual metabolic
pathways. In this review article, introduction, regulation
and energetics of TCA cycle have been discussed. The
present study was carried out to review literature on TCA
cycle.
Keywords TCA cycle
Energetics of TCA cycle

Regulation of TCA cycle
Amphibolic role of TCA
cycle
Introduction
The citric acid cycle was proposed by Hans Adolf Krebs in
1937. The citric acid cycle is the primary metabolic pathway
for all the aerobic processes in an animal tissue. It is a series
of reactions that are important for the cells: C2 units or
acetyl-CoA that is derived from fats, carbohydrates and
lipids [12]. TCA cycle utilizes (indirectly) about 2/3 of the
total oxygen consumed by the body and generates about 2/3
of the total energy. The citric acid cycle is the final common
pathway for the oxidation of carbohydrate, protein and lip-
ids. TCA plays an important role in gluconeogenesis,
transamination, deamination and lipogenesis. Oxidation of
acetyl-CoA by TCA cycle accounts for 2/3rd of total oxygen
M. Akram (&)
Department of Eastern Medicine and Surgery, Faculty of
Medical and Health Sciences, The University of Poonch,
Azad Jammu and Kashmir, Pakistan
e-mail: makram_0451@hotmail.com; makram0451@gmail.com
consumption and ATP production. Acetyl-CoA is obtained
from amino acids like leucine, tyrosine, isoleucine, lysine,
phenylalanine and tryptophan, triacylglycerol, carbohy-
drates and ketone bodies. In aerobic organisms the TCA is
amphibolic pathway, one that participates both in the cata-
bolic and anabolic processes [3]. Through its role in the
oxidative catabolism of carbohydrates, fatty acids and
amino acids, the cycle provides precursors for many bio-
synthetic pathways. Unlike the other metabolic pathways/
cycle, very few genetic abnormalities of TCA cycle are
known. This may be due to the vital importance of this
metabolic cycle for the survival of life. It has been observed
that stimulation of Krebs cycle activity in the presence of
ACTH may lead to increased production of steroid precur-
sor(s) of corticosterone which in turn creates an increased
demand for reducing equivalents for their conversion into
corticosterone.
History
Albert Szent-Györgyi and Hans Adolf Krebs [11] estab-
lished reactions and components of TCA in 1930.
Location of TCA cycle
The enzymes of TCA cycle are located in mitochondrial
matrix [8].
Enzymes of TCA Cycle [17]
Citrate synthase
Aconitase
Isocitrate dehydrogenase
Ketoglutarate dehydrogenase
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Succinyl-CoA synthase alpha-ketoglutarate is converted to succinyl-CoA by alpha-

Succinate dehydrogenase ketoglutarate dehydrogenase (Guffon et al. 1993).
Fumarase
Malate dehydrogenase Step 5: Substrate-Level Phosphorylation

Succinyl-CoA is converted to succinate by succinic thio-

kinase. In this reaction GDP is converted to GTP
Sources of Acetyl-CoA
Step 6: Flavin-Dependent Dehydrogenation
Acetyl-CoA is obtained from various sources including
carbohydrates in which glucose is broken down to pyruvic
Succinate is converted to fumaric acid by succinate dehy-
acid and pyruvic acid is decarboxylated to acetyl-CoA.
drogenase [5]. In this reaction, FAD is converted to
Pyruvic acid is a three-carbon compound and acetyl-CoA is
FADH2.
a two-carbon compound. Acetyl-CoA (two-carbon com-
pound) is the starting point for the TCA cycle. Breakdown
Step 7: Hydration of a Carbon–Carbon Double Bond
of acetyl-CoA is the catabolic role of TCA cycle. Jones
et al. [9] have reported the sources of acetyl-CoA for
Hydration of the C=C double bond occurs that is catalyzed
entering the tricarboxylic acid cycle as determined by
by Fumarate Hydratase (also known as Fumarase) and
analysis of succinate 13C isotopomers.
malate is formed [2].

Step 8: A Dehydrogenation Reaction that Regenerates

Stages of Citric Acid Cycle
Oxaloacetate
Step 1: Condensation
Malate is dehydrogenated to produce oxaloacetate by the
enzyme Malate Dehydrogenase. In this reaction NAD is
Acetyl-CoA (two-carbon compound) and oxaloacetate
converted to NADH2. Oxaloacetate formed in this reaction
(four-carbon compound) are converted to citrate (six-car-
reacts with acetyl-CoA to form citrate in order to start
bon compound). This reaction is catalyzed by citrate
another round of the citric acid cycle [15].
synthetase.

Step 2: Isomerization of Citrate

Energetics of TCA Cycle [13]
Citrate is converted to cis-aconitate. This is catalyzed by
3 NADH2 = 9 ATP
aconitase [6]. Cis-aconitate is an intermediate and is further
1 FADH2 = 2 ATP
converted to isocitrate by aconitase. Aconitase is involved
1 GTP = 1 ATP
in both reactions. In which first dehydration and then
Total ATP = 12 ATP
rehydration occur and as a result final product isocitrate is
obtained
Requirement of Oxygen by TCA cycle
Step 3: Generation of CO2 by an NAD? Linked
Enzyme There is no direct participation of oxygen in TCA. How-
ever, the cycle operates only under aerobic conditions [10].
Isocitrate is converted to alpha-ketoglutarate by isocitrate
dehydrogenase. Isocitrate is first dehydrogenated to
Oxalosuccinate which is an unstable compound and is Inhibitors of TCA
readily decarboxylated to alpha-ketoglutarate. In addition
to decarboxylation, this step produces a reduced nicotin- Fluoroacetate
amide adenine dinucleotide (NADH2) cofactor.
It condenses with CoA and form fluoroacetyl-CoA. Fluo-
Step 4: A Second Oxidative Decarboxylation Step roacetyl-CoA condenses with oxaloacetate to form fluo-
rocitrate that inhibits aconitase, as a result citrate start to
This step is performed by a multi-enzyme complex, the accumulate. Fonnum et al. [7] have studied the use of
a-ketoglutarate dehydrogenation complex. In this reaction, fluorocitrate and fluoroacetate in the brain metabolism.

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Arsenite
It inhibits alpha-ketoglutarate dehydrogenase
Malonate
It inhibits succinate dehydrogenase
Regulation of TCA
Three enzymes namely citrate synthase, isocitrate dehy-
drogenase and alpha-ketoglutarate dehydrogenase regulate
citric acid cycle. Wan et al. [16] have reported the regu-
lation of citric acid cycle by calcium.
Metabolic role of citric acid cycle
1. Oxidation of acetyl-CoA Glucose and fatty acids form
acetyl-CoA. It is converted to carbon di-oxide and
water. Abdel-aleem et al. [1] stated that fatty acid
oxidation is regulated by acetyl-CoA generated from
glucose oxidation that is evident in a study conducted
in isolated myocytes.
2. Integration with amino acids metabolism Many amino
acids after being deaminated give rise to compounds
that are also intermediate metabolites in citric acid
cycle [14].
3. Integration with lipid metabolism Fatty acids are also
first oxidized to acetyl-CoA which is then oxidized in
the citric acid cycle [4]
Biosynthetic function
Several intermediates of this cycle take part in the forma-
tion of substances of great physiological importance. Cit-
rate is provided to the lens of the eye, bone and the seminal
plasma. Citrate stimulates fatty acids synthesis by activat-
ing acetyl-CoA carboxylase
Conclusion
Citric acid cycle is one of the main metabolic pathways
that living cells utilize to completely oxidize biofuels to
carbon dioxide and water. The pyruvic acid formed as a
result of glycolysis is completely oxidized via this cycle.
Before pyruvic acid can enter citric acid cycle, it is con-
verted to acetyl-CoA. The acetyl-CoA thus produced is
then completely oxidized in citric acid cycle. This cycle not
477
only supplies energy but also provides many intermediates
required for the synthesis of amino acids, glucose, heme,
etc. The citric acid cycle is amphibolic, since it has other
metabolic roles in addition to oxidation. It takes place in
gluconeogenesis, transamination, deamination and the
synthesis of fatty acids.
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