Reaction 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). 

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. 

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. 

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

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 ... 

Pyruvate, from glycolysis of glucose, is carboxylated to oxaloacetate or oxidized to acetyl-CoA. These metabolites enter the Krebs cycle, are metabolized to a-ketoglutarate and oxaloacetate, then transaminated to aspartate or glutamate. Asn, Gin, and Pro are synthesized from Asp or Glu. The cycle replenishes intermediates via the anaplerotic reactions (e.g., car-boxylation of pyruvate to form oxaloacetate). 

Anaplerotic reaction. An enzyme-catalyzed reaction that replenishes the intermediates in a cyclic pathway. 

Answer Oxaloacetate might be withdrawn for aspartate synthesis or for gluconeogenesis. Oxaloacetate is replenished by the anaplerotic reactions catalyzed by PEP carboxykinase, PEP carboxylase, malic enzyme, or pyruvate carboxylase (see Fig. 16-15, p. 632). 

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 ... 

PC requires biotin for activity. Biotin is bound to the enzyme via a peptide-like linkage involving e-NH2 groups of certain lysine residues. This type of biotin complex is biocytin (see Chapter 6). Another compound necessary for PC activity is acetyl-CoA, a positive effector. PC is activated as cellular levels of acetyl-CoA increase, as when extensive lipolysis takes place. Acetyl-CoA is produced in large amounts from fatty acids via the /8-oxidation reaction (see Chapter 19). PC can also be considered an anaplerotic reaction, those reactions that replenish crucial intermediates for metabolic pathways. In this case, oxaloacetate, an important intermediate in the Krebs cycle, is replenished by a reaction catalyzed by PC. 

Anaplerotic reactions replace substances present in catalytic amounts, which are indispensable for the operation of biochemical cycles. Which is an anaplerotic reaction ... 

Ornithine is required to maintain the urea cycle. Conversion of glutamate to ornithine via glutamate semialdehyde is therefore an anaplerotic reaction. Melatonin is a compound synthesized from serotonin. It has a function in the circadian rhythm activity and has nothing to do with intracellular protein degradation. 

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 ). 

With the exception of N5-methyl-THF, the THF derivatives are directly synthesized from a C unit in the appropriate oxidation state, and THF. The major anaplerotic reaction is that catalyzed by serine hydroxymethyltransferase (Sec. 15.1). 

The metabolic flux distributions around the intermediate pyruvate for different strains and environmental conditions are summarised in Fig. 12. This part of the metabolism has been shown to be an important node for the interconversion between glycolytic C3 metabolites and C4 metabolites of the tricarboxylic acid (TCA) cycle. The different anaplerotic reactions are of special importance for the production of recombinant proteins as they provide precursors, such as oxaloace-tate, for amino acid biosynthesis. Due to that, the flux distribution is noticeably affected by both the cultivation conditions and the carbon source used which indicates flexible adaptation to the environmental situation. The flux from pyruvate to oxaloacetate through the reaction catalysed by pyruvate carboxylase was found to be the main anaplerotic pathway in B. megaterium. 

Pyruvate Carboxylase Pyruvate carboxylase catalyzes the car-boxylation of pyruvate to oxaloacetate - both the first committed step of gluconeogenesis from pyruvate and also an important anaplerotic reaction, permitting repletion of tricarboxylic acid cycle intermediates and hence fatty acid synthesis. The mammalian enzyme is activated aUosterically by acetyl CoA, which accumulates when there is a need for increased activity of pyruvate carboxylase to synthesize oxaloacetate to permit increased citric acid cycle activity or for gluconeogenesis (Attwood, 1995 Jitrapakdee and Wallace, 1999). 

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