Citrate anaplerotic reactions

Substrate availability for certain reactions can be optimized by anaplerotic ( topping-up ) reactions. For example, citrate synthase is a key control point of the TCA cycle. The co-substrates of citrate synthase are acetyl-CoA and oxaloacetate (OAA) and clearly, restriction in the availability of either substrate will decrease the rate of the citrate synthase reaction. Suppose, for example, a situation arises when acetyl-CoA concentration is significantly higher than that of OAA, the concentration of the latter can be topped-up and the concentration of acetyl-CoA simultaneously reduced by diverting some of the pyruvate away from acetyl-CoA synthesis (via pyruvate dehydrogenase) to OAA synthesis (via pyruvate carboxylase) as shown in Figure 3.1. The net effect is to balance the relative concentrations of the two co-substrates and thus to promote citrate synthase activity. 

Answer Oxaloacetate depletion would tend to inhibit the citric acid cycle. Oxaloacetate is present at relatively low concentrations in mitochondria, and removing it for gluconeogenesis would tend to shift the equilibrium for the citrate synthase reaction toward oxaloacetate. However, anaplerotic reactions (see Fig. 16-15) counter this effect by replacing oxaloacetate. 

Answer Anaplerotic reactions replenish intermediates in the citric acid cycle. Net synthesis of a-ketoglutarate from pyruvate occurs by the sequential actions of (1) pyruvate carboxylase (which makes extra molecules of oxaloacetate), (2) pyruvate dehydrogenase, and the citric acid cycle enzymes (3) citrate synthase, (4) aconitase, and (5) isocitrate dehydrogenase ... 

The cycle oxidizes acetyl-CoA, and to perform this task, it must convert acetyl-CoA to citrate. For this to be achieved, oxaloacetate must be available. If the removal of intermediates results in a decrease in the amount of oxaloacetate for this purpose, acetyl-CoA cannot be removed and will accumulate. This will inhibit the pyruvate dehydrogenase complex and activate pyruvate carboxylase, leading to the conversion of pyruvate to oxaloacetate. This product is now available to condense with the acetyl-CoA to produce citrate, which will restore the status quo. Reactions like that of pyruvate carboxylase that provide molecules for the replacement of intermediates of the citric acid cycle are known as anaplerotic reactions (Greek, meaning to fill up ana = up + plerotikos from pleroun = to make full ). 

This important anaplerotic reaction provides a means of replenishing L-malate in the citric acid cycle (Figure 14.18) and it also plays an important role in the citrate shuttle (Figure 18.31). 

See also Citric Acid Cycle, Anaplerotic Reaction, Citrate Shuttle... 

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