Citric acid cycle intermediates

Althoi alanine is the major gluconeogenic amino acid, 18 of the 20 (all but leucine and lysine) are also gluconeogenic. Most of these are converted by individual pathways to citric acid cycle intermediates, then to malate, following the same path from there to glucose. 

Both muscle and liver have aminotransferases, which, unlike deaminases, do not release the amino groups as free ammonium ion. This class of enzymes transfers the amino group from one carbon skeleton (an amino acid) to another (usually a-ketoglutarate, a citric acid cycle intermediate). Pyridoxal phosphate (PLP) derived from vitamin is required to mediate the transfer. 

This enzyme is found in many tissues, where it catalyzes the reversible oxidative deamination of the amino acid glutamate. It produces the citric acid cycle intermediate a-ketoglutarate, which serves as an entry point to the cycle for a group of glucogenic amino adds. Its role in urea synthesis and nitrogen removal is stiU controversial, but has heen induded in Figure 1-17-1 and Table 1-17-1. 

He W, Miao FJ, Lin DC, etal. (2004) Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors. Nature 429 188-193. 

Citric Acid Cycle Intermediates and Many Amino Acids Are Glucogenic... 

Note All these amino acids are precursors of blood glucose or liver glycogen, because they can be converted to pyruvate or citric acid cycle intermediates. Of the 20 common amino acids, only leucine and lysine are unable to furnish carbon for net glucose synthesis. These amino acids are also ketogenic (see Fig. 18-21). 

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. 

The same intermediates of glycolysis and the citric acid cycle that activate isocitrate dehydrogenase are allosteric inhibitors of isocitrate lyase. When energy-yielding metabolism is sufficiently fast to keep the concentrations of glycolytic and citric acid cycle intermediates low, isocitrate dehydrogenase is inactivated, the inhibition of isocitrate lyase is relieved, and isocitrate flows into the glyoxylate pathway, to be used in the biosynthesis of carbohydrates, amino acids, and other cellular components. 

C]Glucose Catabolism An actively respiring bacterial culture is briefly incubated with [1-14C] glucose, and the glycolytic and citric acid cycle intermediates are isolated. Where is the 14C in each of the intermediates listed below Consider only the initial incorporation of 14C, in the first pass of labeled glucose through the pathways. 

The toxic effect of fluoroacetate was studied in an experiment using intact isolated rat heart. After the heart was perfused with 0.22 mM fluoroacetate, the measured rate of glucose uptake and glycolysis decreased, and glucose 6-phosphate and fructose 6-phosphate accumulated. Examination of the citric acid cycle intermediates revealed that their concentrations were below normal, except for citrate, with a concentration 10 times higher than normal. 

Synthesis of L-Malate in Wine Making The tartness of some wines is due to high concentrations of L-malate. Write a sequence of reactions showing how yeast cells synthesize L-malate from glucose under anaerobic conditions in the presence of dissolved C02 (HCO3 ). Note that the overall reaction for this fermentation cannot involve the consumption of nicotinamide coenzymes or citric acid cycle intermediates. 

Gluconeogenesis citric acid cycle intermediates---> glucose... 

Carboxylation of pyruvate to oxaloacetate (OAA) by pyruvate carboxylase is a biotin-dependent reaction (see Figure 8.24). This reaction is important because it replenishes the citric acid cycle intermediates, and provides substrate for gluconeogenesis (see p. 116). 

Zhao et al. (36) found that some citric acid metabolites are decreased in acute ischemia and acute myocardial disease. The citric acid plays an important role in oxidative phosphorylation and ATP production in the cardiomyo-cytes in which levels of citric acid cycle intermediates are supplied by glycolysis and (1-oxidation of fatty acids. 

Citrate. PFK is also inhibited by citrate, the first product of the citric acid cycle proper (see Topic LI). A high level of citrate signals that there is a plentiful supply of citric acid cycle intermediates already and hence no additional breakdown of glucose via glycolysis is needed. 

Oxaloacetate, the product of the pyruvate carboxylase reaction, functions both as an important citric acid cycle intermediate in the oxidation of acetyl CoA and as a precursor for gluconeogenesis. The activity of pyruvate carboxylase depends on the presence of acetyl CoA so that more oxaloacetate is made when acetyl CoA levels rise. 

Thus pyruvate carboxylase generates oxaloacetate for gluconeogenesis but also must maintain oxaloacetate levels for citric acid cycle function. For the latter reason, the activity of pyruvate carboxylase depends absolutely on the presence of acetyl CoA the biotin prosthetic group of the enzyme cannot be carboxy-lated unless acetyl CoA is bound to the enzyme. This allosteric activation by acetyl CoA ensures that more oxaloacetate is made when excess acetyl CoA is present. In this role of maintaining the level of citric acid cycle intermediates, the pyruvate carboxylase reaction is said to be anaplerotic, that is filling up. ... 

Glutamate dehydrogenase catalyzes the reductive amination of the citric acid cycle intermediate a-ketoglutarate (Fig. 3a) (see Topic LI). Although the reaction is reversible, the reductant used in the biosynthetic reaction is NADPH. This enzyme is also involved in the catabolism of amino acids (see Topic M2). 

Net Synthesis of a-Ketoglutarate a-Ketoglutarate plays a central role in the biosynthesis of several amino acids. Write a sequence of enzymatic reactions that could result in the net synthesis of a-ketoglutarate from pyruvate. Your proposed sequence must not involve the net consumption of other citric acid cycle intermediates. Write an equation for the overall reaction and identify the source of each reactant. 

Phytanic Acid Metabolism When phytanic acid uniformly labeled with 14C is fed to a mouse, radioactivity can be detected in malate, a citric acid cycle intermediate, within minutes. Draw a metabolic pathway that could account for this. Which of the carbon atoms in malate would contain 14C label ... 

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