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The 'citric acid cycle' [also known as the 'tricarboxylic acid (TCA) cycle', the 'Krebs cycle', or 'Szent-Györgyi-Krebs cycle' (after Hans Adolf Krebs and Albert Szent-Györgyi who first determined the chemical intermediates and reaction sequence of the cycle)] is a series of enzyme-catalysed chemical reactions of central importance in all living cells that use oxygen as part of cellular respiration. 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.
It is the third of four metabolic pathways that are involved in carbohydrate catabolism and ATP production, the other three being glycolysis and pyruvate oxidation before it, and electron transport chain after it.
The citric acid cycle also provides precursors for many compounds such as certain amino acids, and some of its reactions are therefore important even in cells performing fermentation.

Contents

Overview

A simplified view of the process

Products

Regulation

Major metabolic pathways converging on the TCA cycle

See also

References

External links

Overview

Two carbons are oxidized to CO₂, and the energy from these reactions is stored in GTP, NADH and FADH₂. NADH and FADH₂ are coenzymes (molecules that enable or enhance enzymes) that store energy and are utilized in oxidative phosphorylation.

Step	Substrate		Enzyme		Reaction type	Reactants/ Coenzymes	Products/ Coenzymes	Comment
1	Oxaloacetate		Citrate synthase		Condensation	Acetyl CoA + H2O	CoA-SH
2	Citrate		Aconitase		Dehydration		H2O
3	''cis''-Aconitate		Aconitase		Hydration	H2O
4	Isocitrate		Isocitrate dehydrogenase		Oxidation	NAD+	NADH + H+
5	Oxalosuccinate		Isocitrate dehydrogenase		Decarboxylation	H+	CO2
6	α-Ketoglutarate		α-Ketoglutarate dehydrogenase		Oxidative decarboxylation	NAD+ + CoA-SH	NADH + H+ + CO2
7	Succinyl-CoA		Succinyl-CoA synthetase		substrate level phosphorylation	GDP + Pi	GTP + CoA-SH	or ADP->ATP
8	Succinate		Succinate dehydrogenase		Oxidation	FAD	FADH2
9	Fumarate		Fumarase		Addition (H2O)	H2O
10	''L''-Malate		Malate dehydrogenase		Oxidation	NAD+	NADH + H+

A simplified view of the process

★ The citric acid cycle begins with Acetyl-CoA transferring its two-carbon acetyl group to the four-carbon acceptor compound, oxaloacetate, forming citrate, a six-carbon compound.

★ The citrate then goes through a series of chemical transformations, losing first one, then a second carboxyl group as CO₂.

★ 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 FAD, forming FADH₂.

★ At the end of each cycle, the four-carbon oxaloacetate has been regenerated, and the cycle continues.

Products

Products of the first turn of the cycle are: ''one GTP, three NADH, one FADH₂, and 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 all cycles, the products are: ''two GTP, six NADH, two FADH₂, and four CO₂''

'Description'	'Reactants'	'Products'
The sum of all reactions in the citric acid cycle is:	Acetyl-CoA + 3 NAD+ + FAD + GDP + Pi + 2 H2O	→ CoA-SH + 3 NADH + 3 H+ + FADH2 + GTP + 2 CO2
Combining the reactions occurring during the pyruvate oxydation with those occurring during the citric acid cycle, we get the following overall pyruvate oxidation reaction before the respiratory chain:	Pyruvic acid + 4 NAD+ + FAD + GDP + Pi + 2 H2O	→ 4 NADH + 4 H+ + FADH2 + GTP + 3 CO2
Combining the above reaction with the ones occurring in the course of glycolysis, we get the following overall glucose oxidation reaction before the respiratory chain:	Glucose + 10 NAD+ + 2 FAD + 2 ADP + 2 GDP + 4 Pi + 2 H2O	→ 10 NADH + 10 H+ + 2 FADH2 + 2 ATP + 2 GTP + 6 CO2

(the above reactions are equilibrated if P_i represents the H₂PO₄^- ion, ADP and GDP the ADP^2- and GDP^2- ions respectively, ATP and GTP the ATP^3- and GTP^3- ions respectively).
Considering the future conversion of GTP to ATP and the maximum 32 ATP produced by the 10 NADH and the 2 FADH₂ (see the theoretical yields for cellular respiration), we see that each glucose molecule is able to produce a maximum of 32 ATP.

Regulation

''Although pyruvate dehydrogenase is not technically a part of the citric acid cycle, its regulation is included here.''
Many of the enzymes in the TCA cycle are regulated by negative feedback from ATP when the energy charge of the cell is high.
Such enzymes include the pyruvate dehydrogenase, citrate synthase, isocitrate dehydrogenase and alpha-ketoglutarate dehydrogenase. These enzymes, which regulate the first three steps of the TCA cycle, are inhibited by high concentrations of ATP. This regulation ensures that the TCA cycle will not oxidise excessive amounts of pyruvate and acetyl-CoA when ATP in the cell is plentiful. This type of negative regulation by ATP is by an allosteric mechanism.
Several enzymes are also negatively regulated when the level of reducing equivalents in a cell are high (high ratio of NADH/NAD+). This mechanism for regulation is due to substrate inhibition by NADH of the enzymes that use NAD+ as a substrate. This includes pyruvate dehydrogenase, citrate synthase, isocitrate dehydrogenase, alpha-ketoglutarate dehydrogenase, and malate dehydrogenase.
Calcium is used as a regulator. It activates pyruvate dehydrogenase, isocitrate dehydrogenase and oxoglutarate dehydrogenase.^[1] 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 makes 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.

Major metabolic pathways converging on the TCA cycle

Most of the body's catabolic pathways converge on the TCA cycle, as the diagram shows. 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 protease enzymes into their constituent amino acids. These amino acids are brought into the cells and can be a source of energy by being funnelled 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. Sometimes beta oxidation can yield propionyl CoA which can result in further glucose production by gluconeogenesis in the liver.
The citric acid cycle is always followed by oxidative phosphorylation. This process extracts the energy (as electrons) from NADH and FADH₂, oxidizing them to NAD⁺ and FAD, respectively, so that the cycle can continue. The citric acid cycle itself does not use oxygen, but oxidative phosphorylation does.
The total energy gained from the complete breakdown of one molecule of glucose by glycolysis, the citric acid cycle and oxidative phosphorylation equals about 36 ATP molecules.
The citric acid cycle is called an amphibolic pathway because it participates in both catabolism and anabolism.

See also

★ Calvin cycle

★ Oxidative decarboxylation

★ Citric acid

★ Glycolysis

★ Pyruvate decarboxylation

★ Oxidative phosphorylation

★ Reverse (Reductive) Krebs cycle

★ Hans Adolf Krebs

References

1. Regulation of mammalian pyruvate dehydrogenase, Denton RM, , , Mol Cell Biochem, 1975


★ Biology, Neil A. Campbell, , , Benjamin Cummings, 2005,

★ Biology, Solomon, E.P., , , Brooks Cole, 2005,

External links

★ An animation of the citric acid cycle at Smith College

★ A video of members of The Ohio State Marching Band enacting the Krebs cycle at YouTube

★ Notes on citric acid cycle at rahulgladwin.com

★ A more detailed tutorial animation at johnkyrk.com

★ A citric-acid cycle self quiz flash applet at University of Pittsburgh

★ The chemical logic behind the citric acid cycle at ufp.pt