Anaplerotic

It is worth noting that the reaction catalyzed by PEP carboxykinase (Eigure 20.25) could also function as an anaplerotic reaction, were it not for the particular properties of the enzyme. COg binds weakly to PEP carboxykinase, whereas oxaloacetate binds very tightly K, = 2 X 10 Af), and, as a result, the enzyme favors formation of PEP from oxaloacetate. 

Methylmalonyl-CoA mutase 5 -deoxyadenosylco-balamin is part of dimethylbenzimidazolecobamide coenzyme, a constituent of methylmalonyl-CoA mutase. This mutase catalyses the isomerization of methylmalonyl-CoA to succinyl-CoA (anaplerotic reaction of the citric acid cycle). 

Nonphotosynthetic COi fixation via phosphoenolpyruvate carboxylase (PEPC) can contribute a substantial proportion of carbon (>30%) for the biosynthesis of carboxylates in roots of P-deficient plants (Fig. 5) (11,82,101,111-113). Thus, PEPC-mediated COi fixation may be interpreted as an anaplerotic carbon... 

Pyruvate makes oxaloacetate and malate through the anaplerotic reactions. 

The reactions that convert pyruvate to intermediates of the TCA cycle are called the anaplerotic reactions. Pyruvate, which can be made only from glucose or some of the amino acids, can be converted to oxaloacetate by the enzyme pyruvate carboxylase or to malate by malic enzyme. 

Pyruvate carboxylation in astrocytes is the major anaplerotic pathway in brain 544... 

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. 

The intermediates of the tricarboxylic acid cycle are present in the mitochondria only in very small quantities. After the oxidation of acetyl-CoA to CO2, they are constantly regenerated, and their concentrations therefore remain constant, averaged over time. Anabolic pathways, which remove intermediates of the cycle (e.g., gluconeogenesis) would quickly use up the small quantities present in the mitochondria if metabolites did not reenter the cycle at other sites to replace the compounds consumed. Processes that replenish the cycle in this way are called anaplerotic reactions. 

The degradation of most amino acids is anaplerotic, because it produces either intermediates of the cycle or pyruvate glucogenic amino acids see p. 180). Gluconeogenesis is in fact largely sustained by the degradation of amino acids. A particularly important anaplerotic step in animal metabolism leads from pyruvate to oxaloacetic acid. This ATP-dependent reaction is catalyzed by pyruvate... 

By contrast, acetyl CoA does not have anaplerotic effects in animal metabolism. Its carbon skeleton is completely oxidized to CO2 and is therefore no longer available for biosynthesis. Since fatty acid degradation only supplies acetyl CoA, animals are unable to convert fatty acids into glucose. During periods of hunger, it is therefore not the fat reserves that are initially drawn on, but proteins. In contrast to fatty acids, the amino acids released are able to maintain the blood glucose level (see p. 308). 

Using the so-called glyoxylic acid cycle, plants and bacteria are able to convert acetyl-CoA into succinate, which then enters the tricarboxylic acid cycle. For these organisms, fat degradation therefore functions as an anaplerotic process. In plants, this pathway is located in special organelles, the glyoxysomes. 

I—lA Catabolic pathway I Anabolic pathway I % Anaplerotic reaction... 

With two exceptions (lysine and leucine see below), all of the proteinogenic amino acids are also glucogenic. Quantitatively, they represent the most important precursors for gluconeogenesis. At the same time, they also have an anaplerotic effect—1. e., they replenish the tricarboxylic acid cycle in order to feed the anabolic reactions that originate in it (see p. 138). 

Roe CR, Sweetman L, Roe DS, David F, Brunengraber H (2002) Treatment of cardiomyopathy and rhabdomyolysis in long-chain fat oxidation disorders using an anaplerotic odd-chain triglyceride. J Clin Invest 110 259-269... 

As noted earlier, although the citric acid cycle is central to energy-yielding metabolism its role is not limited to energy conservation. Four- and five-carbon intermediates of the cycle serve as precursors for a wide variety of products. To replace intermediates removed for this purpose, cells employ anaplerotic (replenishing) reactions, which are described below. 

Anaplerotic Reactions Replenish Citric Acid Cycle Intermediates... 

As intermediates of the citric acid cycle are removed to serve as biosynthetic precursors, they are replenished by anaplerotic reactions (Fig. 16-15 Table 16-2). Under normal circumstances, the reactions by which cycle intermediates are siphoned off into other pathways and those by which they are replenished are in dynamic balance, so that the concentrations of the citric acid cycle intermediates remain almost constant. 

Table 16-2 shows the most common anaplerotic reactions, all of which, in various tissues and organisms, convert either pyruvate or phosphoenolpyruvate to ox-aloacetate or malate. The most important anaplerotic reaction in mammalian liver and kidney is the reversible carboxylation of pyruvate by C02 to form oxaloacetate, catalyzed by pyruvate carboxylase. When the citric acid cycle is deficient in oxaloacetate or any other intermediates, pyruvate is carboxylated to produce more oxaloacetate. The enzymatic addition of a carboxyl group to pyruvate requires energy, which is supplied by ATP—the free energy required to attach a carboxyl group to pyruvate is about equal to the free energy available from ATP. 

The other anaplerotic reactions shown in Table 16-2 are also regulated to keep the level of intermediates high enough to support the activity of the citric acid cycle. Phosphoenolpyruvate (PEP) carboxylase, for example, is activated by the glycolytic intermediate fructose 1,6-bisphosphate, which accumulates when the citric acid cycle operates too slowly to process the pyruvate generated by glycolysis. 

Intermediates of the citric acid cycle are drawn off as precursors in many biosynthetic pathways. Shown in red are four anaplerotic reactions that replenish depleted cycle intermediates (see Table 16-2). 

When intermediates are shunted from the citric acid cycle to other pathways, they are replenished by several anaplerotic reactions, which produce four-carbon intermediates by carboxylation of three-carbon compounds these reactions are catalyzed by pyruvate carboxylase, PEP carboxykinase, PEP carboxylase, and malic enzyme. Enzymes that catalyze carboxylations commonly employ biotin to activate C02 and... 

As noted in the discussion of anaplerotic reactions (Table 16-2), phosphoenolpyruvate can be synthesized from oxaloacetate in the reversible reaction catalyzed by PEP carboxykinase ... 

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