Citric acid cycle

Over view citric cycle

The citric acid cycle (CAC) – also known as thetricarboxylic acid (TCA) cycle or the Krebs
cycle is a series of chemical reactions used by all aerobic organisms to release stored energy
through the oxidationof acetyl-CoA derived from carbohydrates, fats, andproteins into carbon
dioxide and chemical energy in the form of adenosine triphosphate (ATP). In addition, the cycle
provides precursors of certain amino acids, as well as the reducing agent NADH, that are used
in numerous other biochemical reactions. Its central importance to many biochemical pathways
suggests that it was one of the earliest established components of cellular metabolism and may
have originated abiogenically.Even though it is branded as a 'cycle', it is not necessary for
metabolites to follow only one specific route; at least three segments of the citric acid cycle have
been recognized .
The name of this metabolic pathway is derived from the citric acid (a type of tricarboxylic acid,
often called citrate, as the ionized form predominates at biological pH[ that is consumed and
then regenerated by this sequence of reactions to complete the cycle. The cycle consumes
acetate (in the form of acetyl-CoA) and water, reduces NAD+ to NADH, and produces carbon
dioxide as a waste byproduct. The NADH generated by the citric acid cycle is fed into
the oxidative phosphorylation (electron transport) pathway. The net result of these two closely
linked pathways is the oxidation of nutrients to produce usable chemical energy in the form of
ATP.
 In eukaryotic cells, the citric acid cycle occurs in the matrix of the mitochondrion. In prokaryotic
cells, such as bacteria, which lack mitochondria, the citric acid cycle reaction sequence is
performed in the cytosol with the proton gradient for ATP production being across the cell's
surface (plasma membrane) rather than the inner membrane of the mitochondrion.

Contents

 Discovery
 Evolution
 Overview
 Steps
 Products
 Efficiency
 Variation
 Regulation
 Major metabolic pathways converging on the citric acid cycle
 Citric acid cycle intermediates serve as substrates for biosynthetic processes
 Interactive pathway map
 Glucose feeds the TCA cycle via circulating lactate
 References
 External links

Discover
Several of the components and reactions of the citric acid cycle were established in the 1930s
by the research of Albert Szent-Gyorgyi, who received the Nobel Prize in Physiology or
Medicine in 1937 specifically for his discoveries pertaining to fumeric acid, a key component of
the cycle. He was able to make this discovery successful with the help of pigeon breast muscle.
Because this tissue maintains its oxidative capacity well after breaking down in the "Litanies"
mill and releasing in aqueous solutions breast muscle of the pigeon was very well qualified for
the study of oxidative reactions. The citric acid cycle itself was finally identified in 1937 by Hans
Adolf Krebs and William Arthur Johnson while at the University, for which the former received
the Nobel Prize for Physiology or Medicine in 1953, and for whom the cycle is sometimes
named (Krebs cycle).

Evolution
Components of the citric acid cycle were derived from anaerobic bacteria, and the TCA cycle it
may have evolved more than once. Theoretically, several alternatives to the TCA cycle exist;
however, the TCA cycle appears to be the most efficient. If several TCA alternatives had
evolved independently, they all appear to have converged to the TCA cycle.
Overview

Structural diagram of acetyl-CoA: The portion in blue, on the left, is the acetyl group; the portion
in black is coenzyme A.

The citric acid cycle is a key metabolic pathway that connects carbohydrate, fat, and protein
metabolism. The reactions of the cycle are carried out by eight enzymes that completely oxidize
acetate, in the form of acetyl-CoA, into two molecules each of carbon dioxide and water.
Through catabolism of sugars, fats, and proteins, the two-carbon organic product acetyl-CoA (a
form of acetate) is produced which enters the citric acid cycle. The reactions of the cycle also
convert three equivalents of nicotinamide adenine dinucleotide (NAD+) into three equivalents of
reduced NAD+ (NADH), one equivalent of flavin adenine dinucleotide (FAD) into one equivalent
of FADH2, and one equivalent each of guanosine diphosphate (GDP) and
inorganic phosphate (Pi) into one equivalent of guanosine triphosphate (GTP). The NADH and
FADH2 generated by the citric acid cycle are, in turn, used by the oxidative
phosphorylation pathway to generate energy-rich ATP.
One of the primary sources of acetyl-CoA is from the breakdown of sugars by glycolysis which
yield 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)SCoAacetyl-CoA + NADH + CO2
The product of this reaction, acetyl-CoA, is the starting point for the citric acid cycle. Acetyl-CoA
may also be obtained from the oxidation of fatty acids. 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 might not be lost,
 since many citric acid 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.
 In addition, electrons from the succinate oxidation step are transferred first to
the FAD cofactor of succinate dehydrogenase, reducing it to FADH2, and eventually
to ubiquinone (Q) in the mitochondrial membrane, reducing it to ubiquinol (QH2) which is
a substrate of the electron transfer chain at the level of Complex III.
 For every NADH and FADH2 that are produced in the citric acid cycle, 2.5 and 1.5 ATP
molecules are generated in oxidative phosphorylation, respectively.
 At the end of each cycle, the four-carbon oxaloacetate has been regenerated, and the
cycle continues.

Steps
Two carbon atoms are oxidized to CO2, the energy from these reactions is transferred to
other metabolic processes through GTP (or ATP), and as electrons in NADH and QH2. The
NADH generated in the citric acid cycle may later be oxidized (donate its electrons) to drive
ATP synthesis in a type of process called oxidative phosphorylation.[6] FADH2 is covalently
attached to succinate dehydrogenase, an enzyme which functions both in the CAC and the
mitochondrialelectron 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.
The citric acid cycle is continuously supplied with new carbon in the form of acetyl-CoA,
entering at step 0 below.

Reaction
Substrates Products Enzyme Comment
type

Oxaloacetat
0
e+ Aldol irreversible,
/ Citrate + Citrate
Acetyl condensatio extends the 4C oxaloacetate to a 6C
1 CoA-SH synthase
CoA + n molecule
0
H2O

cis-
1 Citrate Aconitate + Dehydration
H2O
Aconitase reversible isomerisation
cis-
2 Aconitate + Isocitrate Hydration
H2O
 Oxalosuccin
Isocitrate + generates NADH (equivalent of 2.5
3 ate+ Oxidation
NAD+ ATP)
NADH + H +
Isocitrate
dehydrogen
α- ase
Oxalosucci Ketoglutarat Decarboxyla rate-limiting, irreversible stage,
4
nate e+ tion generates a 5C molecule
CO2

α- Succinyl- α- irreversible stage,

Ketoglutara CoA + Ketoglutara Oxidative generates NADH (equivalent of 2.5
5 te + NADH + te decarboxylat ATP),
NAD+ + H+ + dehydrogen ion regenerates the 4C chain (CoA
CoA-SH CO2 ase excluded)

or ADP→ATP instead of
GDP→GTP,[15]
substrate- generates 1 ATP or equivalent
Succinyl- Succinate + Succinyl-
level
6 CoA + CoA-SH + CoA
phosphorylat
GDP + Pi GTP synthetase Condensation
ion
reaction of GDP + Pi andhydrolysis o
f Succinyl-CoA involve the H2O
needed for balanced equation.

uses FAD as a prosthetic

group(FAD→FADH2 in the first step
Succinate + Fumarate + Succinate of the reaction) in the
7 ubiquinone ubiquinol (Q dehydrogen Oxidation enzyme.[15]These two electrons are
(Q) H2) ase later transferred to QH2during
Complex II of the ETC, where they
generate the equivalent of 1.5 ATP
Fumarate +
8 L-Malate Fumarase Hydration Hydration of C-C double bond
H2O
reversible (in fact, equilibrium
Oxaloacetat Malate
L-Malate + favors malate),
9 e+ dehydroge Oxidation
NAD+ generates NADH (equivalent of 2.5
NADH + H+ nase
ATP)
Oxaloaceta
1 This is the same as step 0 and
te + Aldol
0 Citrate + Citrate restarts the cycle. The reaction is
Acetyl condensatio
/ CoA-SH synthase irreversible and extends the 4C
CoA + n
0 oxaloacetate to a 6C molecule
H2O
Mitochondria in animals, including humans, possess two succinyl-CoA synthetases: one that
produces GTP from GDP, and another that produces ATP from ADP. Plants have the type
that produces ATP (ADP-forming succinyl-CoA synthetase). Several of the enzymes in the
cycle may be loosely associated in a multienzyme protein complex within the mitochondrial
matrix.
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).

Products
Products of the first turn of the cycle are one GTP (or ATP), three NADH, and two CO 2.
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++ FAD + GDP NADH + FADH2 + 3
+ Pi + 2 H2O H+ + GTP + 2 CO2

Combining the reactions occurring during

Pyruvate ion + 4 → 4 NADH +
the pyruvate oxidation with those occurring during the
NAD++ FAD + GDP FADH2+ 4 H+ + GTP
citric acid cycle, the following overall pyruvate
+ Pi + 2 H2O + 3 CO2
oxidation reaction is obtained:

Combining the above reaction with the ones occurring → 10 NADH +

Glucose + 10 NAD+ +
in the course ofglycolysis, the following overall 2FADH2 + 10 H+ + 2
2FAD + 2 ADP + 2
glucose oxidation reaction (excluding reactions in the ATP + 2 GTP + 6
GDP + 4 Pi + 2 H2O
respiratory chain) is obtained: CO2

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 molecules obtained after complete oxidation of one glucose in
glycolysis, citric acid cycle, andoxidative phosphorylation is estimated to be between 30 and
38.

Efficiency
The theoretical maximum yield of ATP through oxidation of one molecule of glucose in
glycolysis, citric acid cycle, andoxidative phosphorylation is 38 (assuming 3 molar
equivalents of ATP per equivalent NADH and 2 ATP per FADH2). In eukaryotes, two
equivalents of NADH are generated in glycolysis, which takes place in the cytoplasm.
Transport of these two equivalents into the mitochondria consumes two equivalents of ATP,
thus reducing the net production of ATP to 36. Furthermore, inefficiencies in oxidative
phosphorylation due to leakage of protons across the mitochondrial membrane and slippage
of the ATP synthase/proton pump commonly reduces the ATP yield from NADH and
FADH2 to less than the theoretical maximum yield. The observed yields are, therefore,
closer to ~2.5 ATP per NADH and ~1.5 ATP per FADH2, further reducing the total net
production of ATP to approximately 30.An assessment of the total ATP yield with newly
revised proton-to-ATP ratios provides an estimate of 29.85 ATP per glucose molecule.

Variation
While the citric acid cycle is in general highly conserved, there is significant variability in the
enzymes found in different tax (note that the diagrams on this page are specific to the
mammalian pathway variant).
Some differences exist between eukaryotes and prokaryotes. The conversion of D-threo-
isocitrate to 2-oxoglutarate is catalyzed in eukaryotes by the NAD+-dependent EC 1.1.1.41,
while prokaryotes employ the NADP+-dependent EC 1.1.1.42. Similarly, the conversion of
(S)-malate to oxaloacetate is catalyzed in eukaryotes by the NAD+-dependentEC 1.1.1.37,
while most prokaryotes utilize a quinone-dependent enzyme, EC 1.1.5.4.
A step with significant variability is the conversion of succinyl-CoA to succinate. Most
organisms utilize EC 6.2.1.5, succinate–CoA ligase (ADP-forming) (despite its name, the
enzyme operates in the pathway in the direction of ATP formation). In mammals a GTP-
forming enzyme, succinate–CoA ligase (GDP-forming) (EC 6.2.1.4) also operates. The level
of utilization of each isoform is tissue dependent. In some acetate-producing bacteria, such
as Acetobacter aceti, an entirely different enzyme catalyzes this conversion – EC 2.8.3.18,
succinyl-CoA:acetate CoA-transferase. This specialized enzyme links the TCA cycle with
acetate metabolism in these organism Some bacteria, such asHelicobacter pylori, employ
yet another enzyme for this conversion – succinyl-CoA:acetoacetate CoA-transferase.
Some variability also exists at the previous step – the conversion of 2-oxoglutarate to
succinyl-CoA. While most organisms utilize the ubiquitous NAD+-dependent 2-oxoglutarate
dehydrogenase, some bacteria utilize a ferredoxin-dependent 2-oxoglutarate synthase (EC
1.2.7.3). Other organisms, including obligately autotrophic and methanotrophic bacteria and
archaea, bypass succinyl-CoA entirely, and convert 2-oxoglutarate to succinate via
succinate semialdehyde, using EC 4.1.1.71, 2-oxoglutarate decarboxylase, and EC
1.2.1.79, succinate-semialdehyde dehydrogenase.

Regulation
The regulation of the citric acid 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. NADH, a product of all dehydrogenases in the citric acid cycle with the
exception of succinate dehydrogenase, inhibits pyruvate dehydrogenase, isocitrate
dehydrogenase, α-ketoglutarate dehydrogenase, and also citrate synthase. Acetyl-
coAinhibits 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 allostericmechanism that can account for large changes in reaction rate from
an allosteric effector whose concentration changes less than 10%
Calcium is also used as a regulator in the citric acid cycle. Calcium levels in the
mitochondrial matrix can reach up to the tens of micromolar levels during cellular
activation.[31] It activates pyruvate dehydrogenase phosphatase which in turn activates
the pyruvate dehydrogenase complex. Calcium also activates isocitrate
dehydrogenase and α-ketoglutarate dehydrogenase.[32] 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 ofhypoxia-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.

Major metabolic pathways converging on the citric acid cycl

Several catabolic pathways converge on the citric acid cycle. Most of these reactions add
intermediates to the citric acid cycle, and are therefore known as anaplerotic reactions, from
the Greek meaning to "fill up". These increase the amount of acetyl CoA that the cycle is
able to carry, increasing the mitochondrion's capability to carry out respiration if this is
otherwise a limiting factor. Processes that remove intermediates from the cycle are termed
"cataplerotic" reactions.
In this section and in the next, the citric acid cycle intermediates are indicated in italics to
distinguish them from other substrates and end-products.
Pyruvate molecules produced by glycolysis are actively transported across the
inner mitochondrial membrane, and into the matrix. Here they can be oxidized and
combined with coenzyme A to form CO2, acetyl-CoA, and NADH, as in the normal cycle.
However, it is also possible for pyruvate to be carboxylated by pyruvate carboxylase to
form oxaloacetate. This latter reaction "fills up" the amount of oxaloacetate in the citric acid
cycle, and is therefore an anaplerotic reaction, increasing the cycle’s capacity to
metabolize acetyl-CoA when the tissue's energy needs (e.g. in muscle) are suddenly
increased by activity.
In the citric acid cycle all the intermediates (e.g. citrate, iso-citrate, alpha-ketoglutarate,
succinate, fumarate, malate andoxaloacetate) are regenerated during each turn of the cycle.
Adding more of any of these intermediates to the mitochondrion therefore means that that
additional amount is retained within the cycle, increasing all the other intermediates as one
is converted into the other. Hence the addition of any one of them to the cycle has an
anaplerotic effect, and its removal has a cataplerotic effect. These anaplerotic and
cataplerotic reactions will, during the course of the cycle, increase or decrease the amount
of oxaloacetate available to combine with acetyl-CoA to form citric acid. This in turn
increases or decreases the rate of ATP production by the mitochondrion, and thus the
availability of ATP to the cell.
Acetyl-CoA, on the other hand, derived from pyruvate oxidation, or from the beta-
oxidation of fatty acids, is the only fuel to enter the citric acid cycle. With each turn of the
cycle one molecule of acetyl-CoA is consumed for every molecule ofoxaloacetate present in
the mitochondrial matrix, and is never regenerated. It is the oxidation of the acetate portion
ofacetyl-CoA that produces CO2 and water, with the energy thus released captured in the
form of ATP.The three steps of beta-oxidation resemble the steps that occur in the
production of oxaloacetate from succinate in the TCA cycle. Acyl-CoA is oxidized to trans-
Enoyl-CoA while FAD is reduced to FADH2, which is similar to the oxidation of succinate to
fumarate. Following, trans-Enoyl-CoA is hydrated across the double bond to beta-
hydroxyacyl-CoA, just like fumarate is hydrated to malate. Lastly, beta-hydroxyacyl-CoA is
oxidized to beta-ketoacyl-CoA while NAD+ is reduced to NADH, which follows the same
process as the oxidation of malate to oxaloacetate.
In the liver, the carboxylation of cytosolic pyruvate into intra-mitochondrial oxaloacetate is an
early step in thegluconeogenic pathway which converts lactate and de-
aminated alanine into glucose under the influence of high levels
of glucagon and/or epinephrine in the blood Here the addition of oxaloacetate to the
mitochondrion does not have a net anaplerotic effect, as another citric acid cycle
intermediate (malate) is immediately removed from the mitochondrion to be converted into
cytosolic oxaloacetate, which is ultimately converted into glucose, in a process that is almost
the reverse of glycolysis.
In protein catabolism, proteins are broken down by proteases into their constituent amino
acids. Their carbon skeletons (i.e. the de-aminated amino acids) may either enter the citric
acid cycle as intermediates (e.g. alpha-ketoglutaratederived from glutamate or glutamine),
having an anaplerotic effect on the cycle, or, in the case of leucine, isoleucine, lysine,
phenylalanine, tryptophan, and tyrosine, they are converted into acetyl-CoA which can be
burned to CO2 and water, or used to form ketone bodies, which too can only be burned in
tissues other than the liver where they are formed, or excreted via the urine or
breath.] These latter amino acids are therefore termed "ketogenic" amino acids, whereas
those that enter the citric acid cycle as intermediates can only be cataplerotically removed
by entering the gluconeogenic pathway via malate which is transported out of the
mitochondrion to be converted into cytosolic oxaloacetate and ultimately into glucose.
These are the so-called "glucogenic" amino acids. De-aminated alanine, cysteine, glycine,
serine, and threonine are converted to pyruvate and can consequently either enter the citric
acid cycle as oxaloacetate (an anaplerotic reaction) or as acetyl-CoA to be disposed of as
CO2 and water.
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 and skeletal muscle tissue, fatty acids are broken down through a process
known asbeta oxidation, which results in the production of mitochondrial 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 as an anaplerotic intermediate.
The total energy gained from the complete breakdown of one (six-carbon) molecule of
glucose by glycolysis, the formation of 2 acetyl-CoA molecules, their catabolism in the citric
acid cycle, and oxidative phosphorylation equals about 30 ATP molecules, in eukaryotes.
The number of ATP molecules derived from the beta oxidation of a 6 carbon segment of a
fatty acid chain, and the subsequent oxidation of the resulting 3 molecules of acetyl-CoA is
40.

Citric acid cycle intermediates serve as substrates for biosynthetic

processes
In this subheading, as in the previous one, the TCA intermediates are identified by italics.
Several of the citric acid cycle intermediates are used for the synthesis of important
compounds, which will have significant cataplerotic effects on the cycle.Acetyl-CoA cannot
be transported out of the mitochondrion. To obtain cytosolic acetyl-CoA, citrate is removed
from the citric acid cycle and carried across the inner mitochondrial membrane into the
cytosol. There it is cleaved by ATP citrate lyase into acetyl-CoA and oxaloacetate. The
oxaloacetate is returned to mitochondrion as malate (and then converted back
into oxaloacetate to transfer more acetyl-CoA out of the mitochondrion). The cytosolic
acetyl-CoA is used for fatty acid synthesis and the production of cholesterol. Cholesterol
can, in turn, be used to synthesize the steroid hormones, bile salts, and vitamin D.
The carbon skeletons of many non-essential amino acids are made from citric acid cycle
intermediates. To turn them into amino acids the alpha keto-acids formed from the citric acid
cycle intermediates have to acquire their amino groups from glutamate in
a transamination reaction, in which pyridoxal phosphate is a cofactor. In this reaction the
glutamate is converted into alpha-ketoglutarate, which is a citric acid cycle intermediate. The
intermediates that can provide the carbon skeletons for amino acid synthesis
are oxaloacetate which forms aspartate and asparagine; and alpha-ketoglutarate which
forms glutamine, proline, and arginine.
Of these amino acids, aspartate and glutamine are used, together with carbon and nitrogen
atoms from other sources, to form the purines that are used as the bases in DNA and RNA,
as well as in ATP, AMP, GTP, NAD, FAD and CoA.
The pyrimidines are partly assembled from aspartate (derived from oxaloacetate). The
pyrimidines, thymine, cytosineand uracil, form the complementary bases to the purine bases
in DNA and RNA, and are also components of CTP, UMP,UDP and UTP.
The majority of the carbon atoms in the porphyrins come from the citric acid cycle
intermediate, succinyl-CoA. These molecules are an important component of
the hemoproteins, such as hemoglobin, myoglobin and variouscytochromes.
During gluconeogenesis mitochondrial oxaloacetate is reduced to malate which is then
transported out of the mitochondrion, to be oxidized back to oxaloacetate in the cytosol.
Cytosolic oxaloacetate is then decarboxylated
tophosphoenolpyruvate by phosphoenolpyruvate carboxykinase, which is the rate limiting
step in the conversion of nearly all the gluconeogenic precursors (such as the glucogenic
amino acids and lactate) into glucose by the liver and kidney.
Because the citric acid cycle is involved in both catabolic and anabolic processes, it is
known as an amphibolic pathway.
Interactive pathway map

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TCA Cycle edit

1. Jump up^ The interactive pathway map can be edited at

WikiPathways: "TCACycle_WP78".

Glucose feeds the TCA cycle via circulating lactate[edit]

The metabolic role of lactate is well recognized, including as a fuel for tissues and tumors. In the
classical Cori cycle, muscles produce lactate which is then taken up by the liver for
gluconeogenesis. New studies suggest that lactate can be used as a source of carbon for the
TCA cycle.[39]

See also[edit]
 Calvin cycle
 Glyoxylate cycle
 Reverse (reductive) Krebs cycle

References[edit]
1. Jump up^ Lowenstein JM (1969). Methods in Enzymology, Volume 13: Citric Acid
Cycle. Boston: Academic Press. ISBN 0-12-181870-5.
2. Jump up^ Jay J, Weitzman PD (1987). Krebs' citric acid cycle: half a century and
still turning. London: Biochemical Society. p. 25.ISBN 0-904498-22-0.
3. Jump up^ Wagner, Andreas (2014). Arrival of the Fittest (first ed.). New York:
Penguin Group. p. 100. ISBN 9781591846468.
4. Jump up^ Lane, Nick (2009). Life Ascending: The Ten Great Inventions of
Evolution. New York: W.W. Norton & Co. ISBN 0-393-06596-0.
5. Jump up^ Which way does the citric acid cycle turn during hypoxia? The critical
role of α-ketoglutarate dehydrogenase complex. Chinopoulos C. J Neurosci Res.
2013 Aug;91(8):1030-43. doi: 10.1002/jnr.23196. PMID: 23378250
6. ^ Jump up to:a b c Voet D, Voet JG (2004). Biochemistry (3rd ed.). New York: John
Wiley & Sons, Inc. p. 615.
7. Jump up^ "The Nobel Prize in Physiology or Medicine 1937". The Nobel
Foundation. Retrieved 2011-10-26.
8. Jump up^ Chandramana, Sudeep. (2014). Inclusive Growth And Youth
Empowerment: Adevelopment Model For Aspirational India. Journal of Science,
Technology and Management. 7. 52-62.
9. Jump up^ Krebs, HA; Johnson, WA (April 1937). "Metabolism of ketonic acids in
animal tissues". The Biochemical Journal. 31(4): 645–
60. doi:10.1042/bj0310645. PMC 1266984  . PMID 16746382.
10. Jump up^ "The Nobel Prize in Physiology or Medicine 1953". The Nobel
Foundation. Retrieved 2011-10-26.
11. Jump up^ Gest H (1987). "Evolutionary roots of the citric acid cycle in
prokaryotes". Biochem. Soc. Symp. 54: 3–16.PMID 3332996.
12. Jump up^ Meléndez-Hevia E, Waddell TG, Cascante M (September 1996). "The
puzzle of the Krebs citric acid cycle: assembling the pieces of chemically feasible
 reactions, and opportunism in the design of metabolic pathways during evolution". J.
Mol. Evol. 43 (3): 293–303. doi:10.1007/BF02338838. PMID 8703096.
13. Jump up^ Ebenhöh O, Heinrich R (January 2001). "Evolutionary optimization of
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outlined graphically in page 73
39. Jump up^ TY - JOUR AU - Hui, Sheng AU - Ghergurovich, Jonathan M. AU -
Morscher, Raphael J. AU - Jang, Cholsoon AU - Teng, Xin AU - Lu, Wenyun AU -
Esparza, Lourdes A. AU - Reya, Tannishtha AU - Le Zhan, AU - Yanxiang Guo,
Jessie AU - White, Eileen AU - Rabinowitz, Joshua D. TI - Glucose feeds the TCA
cycle via circulating lactate JA - Nature PY - 2017/10/18/online VL - advance online
 publication SP - EP - PB - Macmillan Publishers Limited, part of Springer Nature. All
rights reserved. SN - 1476-4687 UR - https://dx.doi.org/10.1038/nature24057 L3 -
10.1038/nature24057 M3 - Letter L3 -
http://www.nature.com/nature/journal/vaop/ncurrent/abs/nature24057.html#supplem
entary-information ER -

External links[edit]
 An animation of the citric acid cycle at Smith College
 Citric acid cycle variants at MetaCyc
 Pathways connected to the citric acid cycle at Kyoto Encyclopedia of Genes and Genomes
 Introduction at Khan Academy
 metpath: Interactive representation of the citric acid cycle

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Metabolism, catabolism, anabolism

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Citric acid cycle metabolic pathway