Gluconeogenesis Pyruvic kinase

In gluconeogenesis, pyruvate kinase is circumvented by a multistep route which under standard conditions requires only 0.84 kJ mol . On con-... 

Acetyl-CoA is a potent allosteric effector of glycolysis and gluconeogenesis. It allosterically inhibits pyruvate kinase (as noted in Chapter 19) and activates pyruvate carboxylase. Because it also allosterically inhibits pyruvate dehydrogenase (the enzymatic link between glycolysis and the TCA cycle), the cellular fate of pyruvate is strongly dependent on acetyl-CoA levels. A rise in... 

Mechanism for Gluconeogenesis. Since the glycolysis involves three energetically irreversible steps at the pyruvate kinase, phosphofructokinase, and hexokinase levels, the production of glucose from simple noncarbohydrate materials, for example, pyruvate or lactate, by a reversal of glycolysis ( from bottom upwards ) is impossible. Therefore, indirect reaction routes are to be sought for. 

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 ... 

Adrenaline increases the rate of gluconeogenesis it binds to the a-receptor on the surface of the liver cell, which results in an increase in cytosolic concentration of Ca " ions (Chapter 12). This increases the activity of the Ca " -catmodulin-dependent protein kinase which phosphory-lates and causes similar changes in the activities of the enzymes PFK-2 and pyruvate kinase to those resulting from activation of cyclic-AMP-dependent protein kinase. Hence Ca " ions increase the rate of gluconeogenesis. 

The first steps of actual gluconeogenesis take place in the mitochondria. The reason for this detour is the equilibrium state of the pyruvate kinase reaction (see p. 150). Even coupling to ATP hydrolysis would not be sufficient to convert pyruvate directly into phos-phoenol pyruvate (PEP). Pyruvate derived... 

The answer is B. While all of the listed conditions are consistent with lethargy and developmental defects, the lactic acidosis rules out pyruvate kinase deficiency. Thiamine and niacin deficiencies are unlikely due to the lack of effect of vitamin supplementation. Excess pyruvate is the source of the elevated alanine in the serum. The clinical findings are thus consistent with pyruvate carboxylase deficiency, which is associated with severe hypoglycemia due to fasting due to impaired gluconeogenesis. 

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). 

Seven of the reactions of glycolysis are reversible and are used for gluconeogenesis in the liver and kidneys. Three reactions are physiologically irreversible and must be circum vented. These reactions are catalyzed by the glycolytic enzymes pyruvate kinase, phos phofructokinase, and hexokinase. 

After reading about glycolysis and gluconeogenesis do you find anything unusual about the name pyruvate kinase ... 

In gluconeogenesis, the thermodynamic barrier imposed by pyruvate kinase is overcome by coupling two separate reactions for the synthesis of PEP from pyruvate. 

Fig. 1. Comparison of gluconeogenesis and glycolysis. The three steps of glycolysis that are irreversible are numbered. (1) Flexokinase in glycolysis is reversed by glucose 6-phosphatase in gluconeogenesis (2) PFK in glycolysis is reversed by fructose 1,6-bisphosphatase in gluconeogenesis (3) pyruvate kinase in glycolysis is reversed by two sequential reactions in gluconeogenesis catalyzed by pyruvate carboxylase and PEP carboxykinase.

Thus, reversal of the glycolytic step from PEP to pyruvate requires two reactions in gluconeogenesis, pyruvate to oxaloacetate by pyruvate carboxylase and oxaloacetate to PEP by PEP carboxykinase. Given that the conversion of PEP to pyruvate in glycolysis synthesizes ATP, it is not surprising that the overall reversal of this step needs the input of a substantial amount of energy, one ATP for the pyruvate carboxylase step and one GTP for the PEP carboxy kinase step. 

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