Regulation:

Regulation of the cycle is governed through substrate availability, inhibition through accumulating products and allosteric review inhibition through subsequent intermediates in the cycle. There are three enzymes in the cycle itself are regulated (α-ketoglutarate dehydrogenase, citrate synthase and isocitrate dehydrogenase) and so is the enzyme that converts pyruvate to acetyl CoA to enter the cycle which is namely pyruvate dehydrogenase:

-  Citrate synthase is inhibited through citrate and also via ATP (the Km for acetyl CoA is increased as the level of ATP rises);

-  isocitrate dehydrogenase is inhibited through NADH and ATP but activated through ADP;

-  through NADH and succinyl CoA α-ketoglutarate dehydrogenase is inhibited;

-  Pyruvate dehydrogenase is inhibited by NADH and acetyl CoA instance example Product inhibition. Moreover, in eukaryotes the enzyme is also controlled through phos- phorylation or dephosphorylation through a phosphatase and pyruvate dehydrogenase kinase. The  kinase  catalyzes  the  phosphorylation of a specific Ser residue in pyruvate dehydrogenase,  using ATP as the phosphate donor and that will inactivates  the enzyme.  Removal of the phosphate group through the phosphatase reactivates the enzyme. At any period of  time,  the  activity  of  pyruvate dehydrogenase is determined  through the relative balance among the kinase and phosphatase  reactions.  Raising the NADH/NAD⁺, acetyl CoA/CoA or ATP or ADP ratio stimulates phosphorylation and therefore inactivates pyruvate dehydrogenase.   Because  pyruvate  builds  up,  it  inhibits  the  kinase  and  thus permits  the  phosphatase  to reactivate  pyruvate  dehydrogenase,  therefore  stimulating pyruvate conversion to acetyl CoA.

Whole, the cycle speeds up when cellular energy stages are low (high ADP concentration, low ATP and NADH) and slows down as ATP (and then NADH₂, succinyl CoA and citrate) accumulates.

Figure:  Regulation points of the citric acid cycle