Gluconeogenes

Gluconeogene.si.s, Glycogen Metaboli.sm, and the Pento.s< Pho.sphate Padiway... 

COMPARTMENTALIZED PYRUVATE CARBOXYLASE DEPENDS ON METABOLITE CONVERSION AND TRANSPORT The second interesting feature of pyruvate carboxylase is that it is found only in the matrix of the mitochondria. By contrast, the next enzyme in the gluconeogenic pathway, PEP carboxykinase, may be localized in the cytosol or in the mitochondria or both. For example, rabbit liver PEP carboxykinase is predominantly mitochondrial, whereas the rat liver enzyme is strictly cytosolic. In human liver, PEP carboxykinase is found both in the cytosol and in the mitochondria. Pyruvate is transported into the mitochondrial matrix, where it can be converted to acetyl-CoA (for use in the TCA cycle) and then to citrate (for fatty acid synthesis see Figure 25.1). /Uternatively, it may be converted directly to 0/ A by pyruvate carboxylase and used in glu-... 

Metformin restrains hepatic glucose production principally by suppression of gluconeogenesis. The mechanisms involve potentiation of insulin action and decreased hepatic extraction of certain gluconeogenic substrates such as lactate. In addition, metformin reduces the rate of hepatic glycogenolysis and decreases the activity of hepatic glucose-6-phosphatase. Insulin-stimulated glucose uptake and glycogenesis by skeletal muscle is increased by metformin mainly by increased... 

Fructose-1,6-bisphosphatase is an important rate-limiting step in gluconeogenesis. This gluconeogenic step antagonizes the opposite reaction that forms fructose-1, 6-bisphosphate from fmctose-6-phosphate and ATP... 

Answer 6. The negative AG value indicates the reaction is thermodynamically favorable (irreversible), requiring a different bypass reaction for conversion of FI, 6BP to F6P in the gluconeogenic pathway. 

Gluconeogenic amino acids (protein from muscle)... 

In humans, it is not possible to convert acetyl CoA to glucose. Inasmuch as most fatty acids are metabolized solely to acetyl CoA, they are not a major source of glucose either. One minor exception are odd-number carbon fatty acids (e.g., C17), which yield a small amount of propi-onyl CoA that is gluconeogenic. 

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. 

The effect is to divert important gluconeogenic substrates from entering the pathway. 

There are data from animal studies in mice, rats, and pigs that indicate that both carbohydrate metabolism and lipid metabolism may be affected by exposure to heptachlor or heptachlor epoxide (Enan et al. 1982 Halacka et al. 1974 Kacew and Singhal 1973 Pelikan 1971). Alterations in gluconeogenic enzymes and an increase in cellular steatosis in the liver have been reported. Granulomas and fibrotic liver have also been observed. In addition, hepatocellular carcinoma was identified as causally related to heptachlor in the diet in a mouse study conducted by the National Cancer Institute (NCI 1977). The existing evidence suggests that heptachlor and heptachlor epoxide are hepatic toxicants. 

In fact, these two processes are metabolically linked. The oxidation generates ATP whereas gluconeogenesis utilises this ATP. Consequently, in the well-fed human, gluconeogenesis is essential for oxidation of amino acids, otherwise oxidation is limited by the need to utilise the ATP (Chapter 8). The reactions in which amino acids are converted to compounds that can enter the gluconeogenic pathway are described in Chapter 8. The position in the gluconeogenic pathway where amino acids, via their metabolism (Chapter 8), enter the pathway is indicated in Figure 6.23. 

The pathway for gluconeogenesis is shown in Figures 6.23 and 6.24. Some of the reactions are catalysed by the glycolytic enzymes i.e. they are the near-equilibrium. The non-equilibrium reactions of glycolysis are those catalysed by hexokinase (or glucokinase, in the liver), phosphofructokinase and pyruvate kinase and, in order to reverse these steps, separate and distinct non-equilibrium reactions are required in the gluconeogenic pathway. These reactions are ... 

Figure 6.23 Positions in the gluconeogenic pathway where amino acids, fructose and glycerol enter the pathway. For details of the metabolism that provides the intermediates that actually enter the pathway from the amino acids, see Chapter 8. Not all of the carbon in some of the amino acids is incorporated into glucose (e.g. tryptophan). Two amino acids, leucine and lysine, do not give rise to glucose.

Figure 6.24 The gluconeogenic pathway indicating the glycolytic and gluconeogenic non-equilibrium reactions. The non-equilibrium reactions provide for the substrate cycles. (See Chapter 3 for a discussion of substrate cycles and their role in regulation.)...

Figure 6.25 The intracellular location of the gluconeogenic enzymes. The gluconeogenic enzymes are located in the cytosol, except for pyruvate carboxylase which is always present within the mitochondria phosphoenolpyruvate carboxykinase is cytoplasmic in some species including humans. Consequently phosphoenolpyruvate must be transported across the inner mitochondrial enzyme by a transporter molecule in order for gluconeogenesis to take place.

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