Glucose synthesis

Pyruvate kinase possesses allosteric sites for numerous effectors. It is activated by AMP and fructose-1,6-bisphosphate and inhibited by ATP, acetyl-CoA, and alanine. (Note that alanine is the a-amino acid counterpart of the a-keto acid, pyruvate.) Furthermore, liver pyruvate kinase is regulated by covalent modification. Flormones such as glucagon activate a cAMP-dependent protein kinase, which transfers a phosphoryl group from ATP to the enzyme. The phos-phorylated form of pyruvate kinase is more strongly inhibited by ATP and alanine and has a higher for PEP, so that, in the presence of physiological levels of PEP, the enzyme is inactive. Then PEP is used as a substrate for glucose synthesis in the pathway (to be described in Chapter 23), instead... 

Succinyl-CoA derived from propionyl-CoA can enter the TCA cycle. Oxidation of succinate to oxaloacetate provides a substrate for glucose synthesis. Thus, although the acetate units produced in /3-oxidation cannot be utilized in glu-coneogenesis by animals, the occasional propionate produced from oxidation of odd-carbon fatty acids can be used for sugar synthesis. Alternatively, succinate introduced to the TCA cycle from odd-carbon fatty acid oxidation may be oxidized to COg. However, all of the 4-carbon intermediates in the TCA cycle are regenerated in the cycle and thus should be viewed as catalytic species. Net consumption of succinyl-CoA thus does not occur directly in the TCA cycle. Rather, the succinyl-CoA generated from /3-oxidation of odd-carbon fatty acids must be converted to pyruvate and then to acetyl-CoA (which is completely oxidized in the TCA cycle). To follow this latter route, succinyl-CoA entering the TCA cycle must be first converted to malate in the usual way, and then transported from the mitochondrial matrix to the cytosol, where it is oxida-... 

Three nonequilibrium reactions catalyzed by hexoki-nase, phosphofructokinase, and pyruvate kinase prevent simple reversal of glycolysis for glucose synthesis (Chapter 17). They are circumvented as follows ... 

The Jirst indirect route in glucose synthesis involves the formation of phosphoenolpyruvate from pyruvate without the intervention of pyruvate kinase. This route is catalyzed by two enzymes. At first, pyruvate is converted into oxaloacetate. This reaction occurs in the mitochondria as the pyruvate molecules enter them, and is catalyzed by pyruvate carboxylase according to the scheme... 

Noncarbohydrate Sources for Gluconeogenesis. In addition to pyruvate and lactate, which are delivered to the liver and kidneys, other noncarbohydrate compounds serve as substrates for glucose synthesis. In accordance with the gluconeogenesis scheme, it may be anticipated that all materials of noncarbohydrate nature that are... 

Subsequently, dihydroxyacetone phosphate is used in glucose synthesis. 

Figure 6.48 Glucose sparing effect and net glucose synthesis when fatty acids are primary fuel...

As we have seen, normally pyruvate would be the substrate for pyruvate dehydrogenase complex to form acetyl-CoA, but during fasting in the absence of glucose, acetyl -CoA for the TCA cycle is derived from fatty acid (3-oxidation (see Section 7.5.2) so pyruvate is diverted into oxaloacetate by the enzyme pyruvate carboxylase. Thus any amino acids whose carbon skeletons can be converted into pyruvate, OAA or another substrate of the TCA cycle, can be used for glucose synthesis. 

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). 

By interacting with its receptors on the surface of myocytes and hepatocytes, adiponectin activates their AMPK. The activated kinase phosphorylates key metabolic enzymes (see Fig. 23-37, for example), shifting metabolism toward oxidation of fatty acids and away from lipid and glucose synthesis. 

Answer Lysine and leucine are exclusively ketogenic. These amino acids are degraded entirely to acetyl-CoA and acetoacetyl-CoA, and no parts of their carbon skeletons can be used for glucose synthesis. Leucine is especially common in proteins. Its degradation makes a substantial contribution to ketosis under starvation conditions. 

Figure 10-1. Enzymatic pathways for glucose synthesis from amino acids or pyruvate in mammalian Ever. Enclosed in the boxes are the glucogenic amino acids with arrows indicating the points where carbon skeletons from these amino acids enter the pathways of gluconeogenesis or the tricarboxylic acid cycle. Bracketed next to the rate-controlling enzymes for gluconeogenesis are some of the substances that increase (T) or decrease (1) the activity of these enzymes. 3PG, 3-phosphoglycerate.

One is from glucose 1-phosphate and the other is from uridine monophosphate (UMP). The pyrophosphate that is liberated from the terminal phosphates of UTP is hydrolyzed to inorganic phosphate by the enzyme pyrophosphatase. This hydrolysis, which is irreversible, drives the reaction in the direction of UDP-glucose synthesis. 

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