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Cell Biochem Biophys (2014) 68:475–478

DOI 10.1007/s12013-013-9750-1


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- consumption and ATP production. Acetyl-CoA is obtained
dative pathway for carbohydrates, fats and amino acids. It from amino acids like leucine, tyrosine, isoleucine, lysine,
is the most important metabolic pathway for the energy phenylalanine and tryptophan, triacylglycerol, carbohy-
supply to the body. TCA is the most important central drates and ketone bodies. In aerobic organisms the TCA is
pathway connecting almost all the individual metabolic amphibolic pathway, one that participates both in the cata-
pathways. In this review article, introduction, regulation bolic and anabolic processes [3]. Through its role in the
and energetics of TCA cycle have been discussed. The oxidative catabolism of carbohydrates, fatty acids and
present study was carried out to review literature on TCA amino acids, the cycle provides precursors for many bio-
cycle. synthetic pathways. Unlike the other metabolic pathways/
cycle, very few genetic abnormalities of TCA cycle are
Keywords TCA cycle  Energetics of TCA cycle  known. This may be due to the vital importance of this
Regulation of TCA cycle  Amphibolic role of TCA metabolic cycle for the survival of life. It has been observed
cycle 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
Introduction demand for reducing equivalents for their conversion into
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 History
of reactions that are important for the cells: C2 units or
acetyl-CoA that is derived from fats, carbohydrates and Albert Szent-Györgyi and Hans Adolf Krebs [11] estab-
lipids [12]. TCA cycle utilizes (indirectly) about 2/3 of the lished reactions and components of TCA in 1930.
total oxygen consumed by the body and generates about 2/3
of the total energy. The citric acid cycle is the final common Location of TCA cycle
pathway for the oxidation of carbohydrate, protein and lip-
ids. TCA plays an important role in gluconeogenesis, The enzymes of TCA cycle are located in mitochondrial
transamination, deamination and lipogenesis. Oxidation of matrix [8].
acetyl-CoA by TCA cycle accounts for 2/3rd of total oxygen
Enzymes of TCA Cycle [17]

M. Akram (&) Citrate synthase

Department of Eastern Medicine and Surgery, Faculty of
Medical and Health Sciences, The University of Poonch,
Azad Jammu and Kashmir, Pakistan Isocitrate dehydrogenase
e-mail: makram_0451@hotmail.com; makram0451@gmail.com Ketoglutarate dehydrogenase

476 Cell Biochem Biophys (2014) 68:475–478

Succinyl-CoA synthase alpha-ketoglutarate is converted to succinyl-CoA by alpha-

Succinate dehydrogenase ketoglutarate dehydrogenase (Guffon et al. 1993).
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
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
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].

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
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.

Cell Biochem Biophys (2014) 68:475–478 477

Arsenite only supplies energy but also provides many intermediates

required for the synthesis of amino acids, glucose, heme,
It inhibits alpha-ketoglutarate dehydrogenase etc. The citric acid cycle is amphibolic, since it has other
metabolic roles in addition to oxidation. It takes place in
Malonate gluconeogenesis, transamination, deamination and the
synthesis of fatty acids.
It inhibits succinate dehydrogenase

Regulation of TCA
Three enzymes namely citrate synthase, isocitrate dehy- 1. Abdel-aleem, S., Nada, M. A., Sayed-Ahmed, M., Hendrickson,
drogenase and alpha-ketoglutarate dehydrogenase regulate S. C., St Louis, J., Walthall, H. P., et al. (1996). Regulation of
citric acid cycle. Wan et al. [16] have reported the regu- fatty acid oxidation by acetyl-CoA generated from glucose uti-
lation of citric acid cycle by calcium. lization in isolated myocytes. Journal of Molecular and Cellular
Cardiology, 28(5), 825–833.
2. Akiba, T., Hiraga, K., & Tuboi, S. (1984). Intracellular distri-
bution of fumarase in various animals. Journal of Biochemistry
Metabolic role of citric acid cycle (Tokyo), 96, 189–195.
3. Baldwin, J. E., & Krebs, H. (1981). The evaluation of metabolic
cycle. Nature, 292, 291–381.
1. Oxidation of acetyl-CoA Glucose and fatty acids form 4. Bowtell, J. L., Marwood, S., Bruce, M., Constantin-Teodosiu, D.,
acetyl-CoA. It is converted to carbon di-oxide and & Greenhaff, P. L. (2007). Tricarboxylic acid cycle intermediate
water. Abdel-aleem et al. [1] stated that fatty acid pool size: Functional importance for oxidative metabolism in
oxidation is regulated by acetyl-CoA generated from exercising human skeletal muscle. Sports Medicine (Auckland, N.
Z.), 37(12), 1071–1088.
glucose oxidation that is evident in a study conducted 5. Briere, J. J., Favier, J., El Ghouzzi, V., Djouadi, F., Benit, P.,
in isolated myocytes. Gimenez, A. P., et al. (2005). Succinate dehydrogenase defi-
2. Integration with amino acids metabolism Many amino ciency in human. Cellular and Molecular Life Sciences, 62,
acids after being deaminated give rise to compounds 2317–2324.
6. Costello, L. C., & Franklin, R. B. (1981). Aconitase activity,
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cycle [14]. Enzyme, 26, 281–287.
3. Integration with lipid metabolism Fatty acids are also 7. Fonnum, F., Johnsen, A., & Hassel, B. (1997). Use of fluoroci-
first oxidized to acetyl-CoA which is then oxidized in trate and fluoroacetate in the study of brain metabolism. Glia,
21(1), 106–113.
the citric acid cycle [4] 8. Hellemond, J. J., Opperdoes, F. R., & Tielens, A. G. (2005). The
extraordinary mitochondrion and unusual citric acid cycle in
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Biosynthetic function 9. Jones, J. G., Sherry, A. D., Jeffrey, F. M., Storey, C. J., & Malloy,
C. R. (1993). Sources of acetyl-CoA entering the tricarboxylic
acid cycle as determined by analysis of succinate 13C isotopo-
Several intermediates of this cycle take part in the forma- mers. Biochemistry, 32(45), 12240–12244.
tion of substances of great physiological importance. Cit- 10. Kamzolova, S. V., Shishkanova, N. V., Morgunov, I. G., & Fi-
rate is provided to the lens of the eye, bone and the seminal nogenova, T. V. (2003). Oxygen requirements for growth and
plasma. Citrate stimulates fatty acids synthesis by activat- citric acid production of Yarrowia lipolytica. FEMS Yeast
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Conclusion the citric acid cycle. Journal of Molecular Evolution, 43,
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Citric acid cycle is one of the main metabolic pathways
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result of glycolysis is completely oxidized via this cycle. 14. Reeds, P. J., Berthold, H. K., Boza, J. J., Burrin, D. G., Jahoor, F.,
Jaksic, T., et al. (1997). Integration of amino acid and carbon
Before pyruvic acid can enter citric acid cycle, it is con-
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