The citric acid cycle — also known as the tricarboxylic acid cycle (TCA cycle), the Krebs

cycle, or the Szent-Györgyi-Krebs cycle[1][2] — is a series of enzyme-catalysed chemical

reactions, which is of central importance in all living cells that use oxygen as part of cellular
respiration. In eukaryotic cells, the citric acid cycle occurs in the matrix of the mitochondrion.
The components and reactions of the citric acid cycle were established by seminal work from
Albert Szent-Györgyi and Hans Krebs.

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. Other relevant reactions in the pathway include those in
glycolysis and pyruvate oxidation before the citric acid cycle, and oxidative phosphorylation
after it. In addition, it provides precursors for many compounds including some amino acids and
is therefore functional even in cells performing fermentation.

Contents
[hide]

 1 A simplified view of the process

 2 Steps
 3 Products
 4 Regulation
 5 Major metabolic pathways converging on the TCA cycle
 6 Interactive pathway map
 7 See also
 8 Notes
 9 External links

[edit] A simplified view of the process

 The citric acid cycle begins with the transfer of a two-carbon acetyl group from acetyl-
CoA to the four-carbon acceptor compound (oxaloacetate) to form a six-carbon
compound (citrate).
 The citrate then goes through a series of chemical transformations, losing two carboxyl
groups as CO2. The carbons lost as CO2 originate from what was oxaloacetate, not
directly from acetyl-CoA. The carbons donated by acetyl-CoA become part of the
oxaloacetate carbon backbone after the first turn of the citric acid cycle. Loss of the
acetyl-CoA-donated carbons as CO2 requires several turns of the citric acid cycle.
However, because of the role of the citric acid cycle in anabolism, they may not be lost,
since many TCA cycle intermediates are also used as precursors for the biosynthesis of
other molecules.[3]
  Most of the energy made available by the oxidative steps of the cycle is transferred as
energy-rich electrons to NAD+, forming NADH. For each acetyl group that enters the
citric acid cycle, three molecules of NADH are produced.
 Electrons are also transferred to the electron acceptor Q, forming QH2.
 At the end of each cycle, the four-carbon oxaloacetate has been regenerated, and the
cycle continues.

[edit] Steps
Two carbon atoms are oxidized to CO2, the energy from these reactions being transferred to other
metabolic processes by GTP (or ATP), and as electrons in NADH and QH2. The NADH generated
in the TCA cycle may later donate its electrons in oxidative phosphorylation to drive ATP
synthesis; FADH2 is covalently attached to succinate dehydrogenase, an enzyme functioning both in
the TCA cycle and the mitochondrial electron transport chain in oxidative phosphorylation.
FADH2, therefore, facilitates transfer of electrons to coenzyme Q, which is the final electron
acceptor of the reaction catalyzed by the Succinate:ubiquinone oxidoreductase complex, also
acting as an intermediate in the electron transport chain.[4]

The citric acid cycle is continuously supplied with new carbon in the form of acetyl-CoA,
entering at step 1 below.[5]

Substrates Products Enzyme Reaction type Comment

rate-limiting stage
Oxaloacetate + (irreversible),
Citrate + Aldol
1 Acetyl CoA + Citrate synthase extends the 4C
CoA-SH condensation
H2O oxaloacetate to a 6C
molecule
cis-Aconitate +
2 Citrate Dehydration
H2O
Aconitase reversible isomerisation
cis-Aconitate +
3 Isocitrate Hydration
H2O
Oxalosuccinate
Isocitrate + generates NADH
4 + Oxidation
NAD+ NADH + H + (equivalent of 2.5 ATP)
Isocitrate
α-Ketoglutarate dehydrogenase
irreversible stage,
5 Oxalosuccinate + Decarboxylation
generates a 5C molecule
CO2
irreversible stage,
α-Ketoglutarate Succinyl-CoA
generates NADH
+ + α-Ketoglutarate Oxidative
6 + + (equivalent of 2.5 ATP),
NAD + NADH + H + dehydrogenase decarboxylation
regenerates the 4C chain
CoA-SH CO2
(CoA excluded)
7 Succinyl-CoA Succinate + Succinyl-CoA substrate-level or ADP→ATP instead of
+ CoA-SH + synthetase phosphorylation GDP→GTP,[4]
GDP + Pi GTP generates 1 ATP or
 equivalent
uses FAD as a prosthetic
group (FAD→FADH2 in
Fumarate + the first step of the
Succinate + Succinate
8 ubiquinol Oxidation reaction) in the enzyme,
ubiquinone (Q) dehydrogenase [4]
(QH2)
generates the equivalent
of 1.5 ATP
Fumarate + H2O addition
9 L-Malate Fumarase
H2O (hydration)
L-Malate + Oxaloacetate + Malate generates NADH
10 Oxidation
NAD+ NADH + H+ dehydrogenase (equivalent of 2.5 ATP)

Mitochondria in animals, including humans, possess two succinyl-CoA synthetases: one that
produces GTP from GDP, and another that produces ATP from ADP.[6] Plants have the type that
produces ATP (ADP-forming succinyl-CoA synthetase).[5] Several of the enzymes in the cycle
may be loosely-associated in a multienzyme protein complex within the mitochondrial matrix.[7]

The GTP that is formed by GDP-forming succinyl-CoA synthetase may be utilized by

nucleoside-diphosphate kinase to form ATP (the catalyzed reaction is GTP + ADP → GDP +
ATP).[4]

[edit] Products
Products of the first turn of the cycle are: one GTP (or ATP), three NADH, one QH2, two CO2.

Because two acetyl-CoA molecules are produced from each glucose molecule, two cycles are
required per glucose molecule. Therefore, at the end of two cycles, the products are: two GTP,
six NADH, two QH2, and four CO2

Description Reactants Products

Acetyl-CoA + 3 → CoA-SH + 3
The sum of all reactions in the citric acid cycle is: NAD+ + Q + GDP + NADH + 3 H+ +
Pi + 2 H2O QH2 + GTP + 2 CO2
Combining the reactions occurring during the
Pyruvate ion + 4 → 4 NADH + 3 H+
pyruvate oxidation with those occurring during the
NAD+ + Q + GDP + + QH2 + GTP + 3
citric acid cycle, the following overall pyruvate
Pi + 2 H2O CO2
oxidation reaction is obtained:
Combining the above reaction with the ones
Glucose + 10 NAD+ + → 10 NADH + 10
occurring in the course of glycolysis, the following
2 Q + 2 ADP + 2 H+ + 2 QH2 + 2 ATP
overall glucose oxidation reaction (excluding
GDP + 4 Pi + 2 H2O + 2 GTP + 6 CO2
reactions in the respiratory chain) is obtained:

The above reactions are balanced if Pi represents the H2PO4- ion, ADP and GDP the ADP2- and
GDP2- ions, respectively, and ATP and GTP the ATP3- and GTP3- ions, respectively.
The total number of ATP obtained after complete oxidation of one glucose in glycolysis, citric
acid cycle, and oxidative phosphorylation is estimated to be between 30 and 38. A recent
assessment of the total ATP yield with the updated proton-to-ATP ratios provides an estimate of
29.85 ATP per glucose molecule.[8]

[edit] Regulation
Although pyruvate dehydrogenase is not technically a part of the citric acid cycle, its regulation
is included here.

The regulation of the TCA cycle is largely determined by substrate availability and product
inhibition. NADH, a product of all dehydrogenases in the TCA cycle with the exception of
succinate dehydrogenase, inhibits pyruvate dehydrogenase, isocitrate dehydrogenase, α-
ketoglutarate dehydrogenase, and also citrate synthase. Acetyl-coA inhibits pyruvate
dehydrogenase, while succinyl-CoA inhibits succinyl-CoA synthetase and citrate synthase.
When tested in vitro with TCA enzymes, ATP inhibits citrate synthase and α-ketoglutarate
dehydrogenase; however, ATP levels do not change more than 10% in vivo between rest and
vigorous exercise. There is no known allosteric mechanism that can account for large changes in
reaction rate from an allosteric effector whose concentration changes less than 10%.[9]

Calcium is used as a regulator. It activates pyruvate dehydrogenase, isocitrate dehydrogenase and

α-ketoglutarate dehydrogenase.[10] This increases the reaction rate of many of the steps in the
cycle, and therefore increases flux throughout the pathway.

Citrate is used for feedback inhibition, as it inhibits phosphofructokinase, an enzyme involved in

glycolysis that catalyses formation of fructose 1,6-bisphosphate,a precursor of pyruvate. This
prevents a constant high rate of flux when there is an accumulation of citrate and a decrease in
substrate for the enzyme.

Recent work has demonstrated an important link between intermediates of the citric acid cycle
and the regulation of hypoxia-inducible factors (HIF). HIF plays a role in the regulation of
oxygen homeostasis, and is a transcription factor that targets angiogenesis, vascular remodeling,
glucose utilization, iron transport and apoptosis. HIF is synthesized consititutively, and
hydroxylation of at least one of two critical proline residues mediates their interaction with the
von Hippel Lindau E3 ubiquitin ligase complex, which targets them for rapid degradation. This
reaction is calalysed by prolyl 4-hydroxylases. Fumarate and succinate have been identified as
potent inhibitors of prolyl hydroxylases, thus leading to the stabilisation of HIF.[11]

[edit] Major metabolic pathways converging on the TCA

cycle
Several catabolic pathways converge on the TCA cycle. Reactions that form intermediates of the
TCA cycle in order to replenish them (especially during the scarcity of the intermediates) are
called anaplerotic reactions.
The citric acid cycle is the third step in carbohydrate catabolism (the breakdown of sugars).
Glycolysis breaks glucose (a six-carbon-molecule) down into pyruvate (a three-carbon
molecule). In eukaryotes, pyruvate moves into the mitochondria. It is converted into acetyl-CoA
by decarboxylation and enters the citric acid cycle.

In protein catabolism, proteins are broken down by proteases into their constituent amino acids.
The carbon backbone of these amino acids can become a source of energy by being converted to
acetyl-CoA and entering into the citric acid cycle.

In fat catabolism, triglycerides are hydrolyzed to break them into fatty acids and glycerol. In the
liver the glycerol can be converted into glucose via dihydroxyacetone phosphate and
glyceraldehyde-3-phosphate by way of gluconeogenesis. In many tissues, especially heart tissue,
fatty acids are broken down through a process known as beta oxidation, which results in acetyl-
CoA, which can be used in the citric acid cycle. Beta oxidation of fatty acids with an odd number
of methylene groups produces propionyl CoA, which is then converted into succinyl-CoA and
fed into the citric acid cycle.[12]

The total energy gained from the complete breakdown of one molecule of glucose by glycolysis,
the citric acid cycle, and oxidative phosphorylation equals about 30 ATP molecules, in
eukaryotes. The citric acid cycle is called an amphibolic pathway because it participates in both
catabolism and anabolism.
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