Substrate Availability and Pyruvate

The TCA cycle is largely controlled by substrate availability and the entry of pyruvate through the pyruvate dehydrogenase complex. A free energy diagram of the TCA cycle would show a large drop at the three decarboxylation steps. This drop is due to the release of CO 2 and the large entropy change associated with this release. Pyruvate dehydrogenase is inhibited by its products — acetyl‐CoA and NADH as well as ATP (the end‐product of energy metabolism) — and activated by AMP. Isocitrate dehydrogenase and alpha‐ketoglutarate dehydrogenase are likewise inhibited by NADH. Isocitrate dehydrogenase is also activated by ADP, and alpha‐ketoglutarate dehydrogenase is inhibited by its product, succinyl‐CoA. There is only one apparent control point at the 4‐carbon level: malate dehydrogenase is inhibited by NADH.

Because the TCA cycle is central to many pathways of metabolism, there must always be a large supply of the intermediates. For example, oxaloacetate is the direct precursor of the amino acid aspartate, with the alpha‐keto group being replaced by an amino group. Likewise, alpha‐ketoglutarate is the direct precursor to glutamate. These two amino acids are important, not only for protein synthesis, but even more so for maintaining nitrogen balance and eliminating toxic ammonia. Therefore, there are a variety of pathways that serve to regenerate TCA cycle intermediates if the supply falls low. For example, the breakdown of amino acids leads to TCA cycle intermediates. If the supply of intermediates falls low, for example, during even short periods of starvation, muscle can be broken down and the carbon skeletons of the amino acids used to build up the supply of 4‐carbon dicarboxylic acids. Oxaloacetate and malate can be synthesized from pyruvate by carboxylation using bicarbonate, the aqueous form of CO 2:

Collectively, these reactions are sometimes termed anapleurotic reactions. The term is less important than the concept: There needs to be a ready supply of TCA cycle intermediates to keep the system primed for a variety of biochemical reactions.