Gluconeogenesis phosphoenolpyruvate

In pigeon, chicken, and rabbit liver, phospho-enolpymvate carboxykinase is a mitochondrial enzyme, and phosphoenolpyruvate is transported into the cytosol for gluconeogenesis. In the rat and the mouse, the enzyme is cytosolic. Oxaloacetate does not cross the mitochondrial inner membrane it is converted to malate, which is transported into the cytosol, and convetted back to oxaloacetate by cytosolic malate dehydrogenase. In humans, the guinea pig, and the cow, the enzyme is equally disttibuted between mitochondria and cytosol. 

Kidney Excretion and glu-coneogenesis Gluconeogenesis Free fatty acids, lactate, glycerol Glucose Glycerol kinase, phosphoenolpyruvate carboxy kinase... 

This enzyme, similar to all C02 assimilating enzymes, contains biotin for a cofactor. Oxaloacetate is released from the mitochondria into the cytoplasm to enter gluconeogenesis. In the cytoplasm, oxaloacetate converts to phosphoenolpyruvate via a reaction catalyzed by phosphoenolpyruvate carboxylase ... 

Phosphoenolpyruvate carboxykinase (PEPCK) catalyzes a critical reaction in gluconeogenesis, which under many conditions is the rate-limiting step in the pathway. A cAlVfP response element (CRE) and a glucocorticoid response element (GRE) are each located upstream from the transcription start site. 

A problem for gluconeogenesis is that pyruvate carboxylase, which produces oxaloacetate from pyravate, is present in the mitochondria but phosphoenolpyruvate carboxylase, at least in human liver, is present in the cytosol. For reasons given in Chapter 9, oxaloacetate cannot cross the mitochondrial membrane and so a transporter is not present in any cells. Hence, oxaloacetate is converted to phosphoenolpyruvate which is transported across the membrane (Figure 6.25). 

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.

The way in which a typical eukaryotic gene is organized is illustrated here using a gene that codes for a key enzyme in gluconeogenesis (see p. 154)—the phosphoenolpyruvate car-boxykinase (PEP-CK). 

Phosphoenolpyruvate carboxykinase (PEP-CK), a key enzyme in gluconeogenesis, is regulated by several hormones, all of which affect the transcription of the PEP-CK gene. Cortisol, glucagon, and thyroxin induce PEP-CK, while insulin inhibits its induction (see p. 158). 

OVERSATURATION OXALOACETATE DECARBOXYLASE Oxaloacetate, synthesis in gluconeogenesis, PYRUVATE CARBOXYLASE PHOSPHOENOLPYRUVATE CARBOXYKI-NASE (PYROPHOSPHATE)... 

Figure 6-7. Conversion of mitochondrial pyruvate to cytosolic phosphoenolpyruvate to initiate gluconeogenesis. Oxaloacetate cannot pass across the inner mitochondrial membrane, so it is reduced to malate, which can do so.

Figure 6-8. Conversion of phosphoenolpyruvate to glucose during gluconeogenesis. Except for the indicated enzymes that are needed to overcome irreversible steps of glycolysis, all other steps occur by the reverse reactions catalyzed by the same enzymes as those used in glycolysis.

The glucocorticoids have important dose-related effects on carbohydrate, protein, and fat metabolism. The same effects are responsible for some of the serious adverse effects associated with their use in therapeutic doses. Glucocorticoids stimulate and are required for gluconeogenesis and glycogen synthesis in the fasting state. They stimulate phosphoenolpyruvate carboxykinase, glucose-6-phosphatase, and glycogen synthase and the release of amino acids in the course of muscle catabolism. 

Because the carbon atoms of acetate molecules that enter the citric acid cycle appear eight steps later in oxaloacetate, it might seem that this pathway could generate oxaloacetate from acetate and thus generate phosphoenolpyruvate for gluconeogenesis. However, as an examination of the stoichiometry of the citric acid cycle shows, there is no net conversion of acetate to ox-... 

The first "roadblock" to overcome in the synthesis of glucose from pyruvate is the irreversible conversion in glycolysis of pyruvate to phosphoenolpyruvate (PEP) by pyruvate kinase. In gluconeogenesis, pyruvate is first carboxylated by pyruvate carboxylase to oxaloacetate (OAA), which is then converted to PEP by the action of PEP-carboxykinase (Figure 10.3). 

Uptake of Ca2+ into cells, or release of this ion from intracellular stores, is a major regulatory mechanism in many if not all cells (see Section E). Mn2+ activates phosphoenolpyruvate carboxykinase (Eq. 13-46) and maybe a regulator of gluconeogenesis.142 Iron controls the synthesis of ferritin and of transferrin receptors137 (Chapter 16). The specific metal ions present in many biological macromolecules are likely to participate in additional regulatory processes. 

Gluconeogenesis Consumes ATP Conversion of Pyruvate to Phosphoenolpyruvate Requires Two High Energy Phosphates Conversion of Phosphoenolpyruvate to Fructose-1,6-bisphosphate Uses the Same Enzymes as Glycolysis... 

The problem of how to oxidize oxaloacetate is solved by the action of phosphoenolpyruvate carboxykinase, which we discussed in connection with gluconeogenesis (see equa-... 

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