Krebs cycle.

Citric acid cycle

Overview of the citric acid cycle

The citric acid cycle (CAC) – also known as the TCA cycle (tricarboxylic acid cycle) or theKrebs cycle– is a series of chemical reactions used by all aerobic organisms to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and proteins into adenosine triphosphate(ATP) and carbon dioxide. In addition, the cycle provides precursors of certain amino acids, as well as the reducing agent NADH, that are used in numerous other 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. The overall yield of energy-containing compounds from the TCA cycle is three NADH, one FAD(2H), and one GTP.

EVOLUTION

It is believed that components of the citric acid cycle were derived from anaerobic bacteria, and that the TCA cycle itself 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.

StepsEdit

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 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.^[16]

The citric acid cycle is continuously supplied with new carbon in the form of acetyl-CoA, entering at step 0 below.^[17]

	Substrates	Products	Enzyme	Reaction type	Comment
0 / 10	Oxaloacetate + Acetyl CoA + H2O	Citrate + CoA-SH	Citrate synthase	Aldol condensation	irreversible, extends the 4C oxaloacetate to a 6C molecule
1	Citrate	cis-Aconitate + H2O	Aconitase	Dehydration	reversible isomerisation
2	cis-Aconitate + H2O	Isocitrate		Hydration
3	Isocitrate + NAD+	Oxalosuccinate+ NADH + H +	Isocitrate dehydrogenase	Oxidation	generates NADH(equivalent of 2.5 ATP)
4	Oxalosuccinate	α-Ketoglutarate+ CO2		Decarboxylation	rate-limiting, irreversible stage, generates a 5C molecule
5	α-Ketoglutarate+ NAD+ + CoA-SH	Succinyl-CoA + NADH + H+ + CO2	α-Ketoglutarate dehydrogenase	Oxidative decarboxylation	irreversible stage, generates NADH (equivalent of 2.5 ATP), regenerates the 4C chain (CoA excluded)
6	Succinyl-CoA + GDP + Pi	Succinate + CoA-SH + GTP	Succinyl-CoA synthetase	substrate-level phosphorylation	or ADP→ATPinstead of GDP→GTP,[16]generates 1 ATP or equivalent. Condensation reaction of GDP + Pi and hydrolysis of Succinyl-CoAinvolve the H2O needed for balanced equation.
7	Succinate + ubiquinone (Q)	Fumarate + ubiquinol (QH2)	Succinate dehydrogenase	Oxidation	uses FAD as a prosthetic group(FAD→FADH2in the first step of the reaction) in the enzyme.[16] These two electrons are later transferred to QH2 during Complex II of the ETC, where they generate the equivalent of 1.5 ATP
8	Fumarate + H2O	L-Malate	Fumarase	Hydration	Hydration of C-C double bond
9	L-Malate + NAD+	Oxaloacetate + NADH + H+	Malate dehydrogenase	Oxidation	reversible (in fact, equilibrium favors malate), generates NADH(equivalent of 2.5 ATP)
10 / 0	Oxaloacetate + Acetyl CoA + H2O	Citrate + CoA-SH	Citrate synthase	Aldol condensation	This is the same as step 0 and restarts the cycle. The reaction is irreversible and extends the 4C oxaloacetate to a 6C molecule

Mitochondria in animals, including humans, possess two succinyl-CoA synthetases: one that produces GTP from GDP, and another that produces ATP from ADP.^[18] Plants have the type that produces ATP (ADP-forming succinyl-CoA synthetase).^[17] Several of the enzymes in the cycle may be loosely associated in a multienzyme protein complexwithin the mitochondrial matrix.^[19]

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)
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