The citric acid cycle is a key component of the metabolic pathway by which all aerobic

organisms generate energy. Through catabolism of sugars, fats, and proteins, a two-carbon
organic product acetate in the form of acetyl-CoA is produced. Acetyl-CoA along with
two equivalents of water (H2O) is consumed by the citric acid cycle producing two equivalents of
carbon dioxide (CO2) and one equivalent of HS-CoA. In addition, one complete turn of the cycle
converts three equivalents of nicotinamide adenine dinucleotide (NAD+) into three equivalents of
reduced NAD+ (NADH), one equivalent of ubiquinone (Q) into one equivalent of reduced
ubiquinone (QH2), and one equivalent each of guanosine diphosphate (GDP) and
inorganic phosphate (Pi) into one equivalent of guanosine triphosphate (GTP). The NADH and
QH2 generated by the citric acid cycle are in turn used by the oxidative phosphorylation pathway
to generate energy-rich adenosine triphosphate (ATP).

One of the primary sources of acetyl-CoA is sugars that are broken down by glycolysis to
produce pyruvate that in turn is decarboxylated by the enzyme pyruvate dehydrogenase
generating acetyl-CoA according to the following reaction scheme

 CH3C(=O)C(=O)O– (pyruvate) + HSCoA + NAD+ → CH3C(=O)SCoA (acetyl-CoA) +

The product of this reaction, acetyl-CoA, is the starting point for the citric acid cycle. Below is a
schematic outline of the cycle:

 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.
 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.

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.

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.

The regulation of the TCA cycle is largely determined by product inhibition and substrate
availability. If the cycle were permitted to run unchecked, large amounts of metabolic energy
could be wasted in overproduction of reduced coenzyme such as NADH and ATP. The major
eventual substrate of the cycle is ADP which gets converted to ATP. A reduced amount of ADP
causes accumulation of precursor NADH which in turn can inhibit a number of enzymes.[1] 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
alpha-ketoglutarate dehydrogenase 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%.

Calcium is used as a regulator. Mitochondrial matrix calcium levels can reach the tens of
micromolar levels during cellular activation. It activates pyruvate dehydrogenase
phosphatase which in turn activates the pyruvate dehydrogenase complex. Calcium also
activates isocitrate dehydrogenase and α-ketoglutarate dehydrogenase. 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

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 catalysed
by prolyl 4-hydroxylases. Fumarate and succinate have been identified as potent inhibitors of
prolyl hydroxylases, thus leading to the stabilisation of HIF.

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 andglyceraldehyde-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 bridges produces propionyl CoA, which is then converted
into succinyl-CoA and fed into the citric acid cycle.

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.