Lecture 30 Summary

The citric acid cycle is a means of complete oxidation of the acetyl group of acetyl CoA to two molecules of carbon dioxide. In the complete oxidation of glucose, by oxygen, to water and carbon dioxide, the cycle works in concert with glycolysis and pyruvate dehydrogenase complex.

Four of the six total CO₂ produced per glucose arise from two turns of the cycle. Although it yields very little energy in the form of high-energy phosphates, the citric acid cycle is tightly linked with oxidative phosphorylation. The steps of the cycle include:

• Citrate synthase : Reaction, energetics, mechanism
• Aconitase: Isomerization of citrate to isocitrate
• Isocitrate dehydrogenase [IDH ]
• Oxidative decarboxylation of α-ketoglutarate yields succinyl CoA.
• Succinyl CoA synthetase : Reaction, energetics, mechanism
• Regeneration of oxaloacetate: Succinate dehydrogenase; fumarase: malate dehydrogenase.

The centrality of the cycle, also known for historical reasons as the tricarboxylic acid cycle or the Krebs cycle, to oxidative intermediary metabolism is notable. It oxidatively processes acetyl CoA derived from fatty acid and amino acid catabolism, in addition to that from glucose and other carbohydrates. The reduced products of the cycle, NADH and FADH₂, are the electron donors for the electron transport chain. The tight linkage between the citric acid cycle and oxidative phosphorylation, called respiratory control, insures that NADH production by the cycle is regulated by the need for energy in the form of ATP. In eukaryotic cells, the citric acid cycle is carried out in mitochondria. Citric acid cycle intermediates in some cases serve as precursors to other metabolic products: Oxaloacetate may be used to generate glucose by gluconeogenesis and succinyl CoA is used in heme biosynthesis.

One turn of the cycle results in the oxidation of a two-carbon unit. The two-carbon units, in the form of acetyl CoA, enter the cycle by combining with oxaloacetate, in a reaction catalyzed by citrate synthase. The cycle continues with isomerization of citrate to isocitrate, followed by two oxidative decarboxylations. The carbon dioxide given off originates from oxaloacetate, so the realease of carbon atoms as CO₂ from the added acetyl group occurs in subsequent turns of the cycle. Hydrolysis of succinyl CoA is linked to phosphorylation of GDP (an example of the so-called substrate-level phosphorylation means of capturing the energy released from catabolic processes in the form of high-energy phosphates). Oxaloacetate is then regenerated from succinate in three steps, a FAD-linked dehydrogenation, addition of water, and a final NAD-linked oxidation of a secondary alcohol to a ketone. A stoichiometric equation can be written for one turn of the cycle:

3 NAD⁺  +  FAD  +  GDP  +  P_i  +  acetyl CoA  →  3 NADH  +  FADH₂  +  GTP   +  CoA  +  2 CO₂

Regulation of the citric acid cycle

Most of the regulation of the citric acid cycle can be accounted for by three main influences: substrate availability, product inhibition, and competitive feedback inhibition. The rate of citrate production is effectively under the control of oxaloacetate levels. NADH, which is a product of several different steps of the citric acid cycle competes with the substrate NAD+. This product inhibition slows the rate of the citric acid cycle when the electron transport chain is unable to reoxidize NADH sufficiently. ATP, a broadly acting allosteric effector, inhibits the same citric acid cycle components subject to product inhibition by NADH, namely isocitrate dehydrogenase (IDH) and α-ketoglutarate dehydrogenase complex, as well as PDH complex. Both α-keto acid dehydrogenase complexes are also inhibited by high levels of their cognate thioester products (acetyl CoA and succinyl CoA). ADP is apparently an allosteric activator of IDH.

Learning objectives

Page updated 07-21-2010

References