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It was observed that pyruvic acid and lactic acid formed in the muscle during glycolysis can be reconverted into glucose (or glycogen) when energy is available (in aerobiosis) and one could wonder whether this neoglucogenesis (or gluconeogenesis, or neoglycogenesis) follows — in the reverse direction — the glycolytic path.
In fact, among the reactions leading from glucose to pyruvic acid (or lactic acid) there are 3 which, owing to the great variation of free energy taking place, are not easily reversible in physiological conditions; these 3 reactions are catalyzed by kinases:
1. Transformation of phospho-enol-pyruvic acid into pyruvic acid (pyruvate kinase);
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2. Phosphorylation of fructose-6-℗ to fructose 1, 6-bis-℗ (phosphofructokinase);
3. Phosphorylation of glucose to glucose-6-℗ (glucokinase or hexokinase).
Neoglucogenesis can therefore take place by reverse glycolytic reactions except at these 3 steps where different reactions (catalyzed by different enzymes or enzymatic systems) will have to be used.
1. Conversion of Pyruvic Acid into Phospho-Enol-Pyruvic Acid:
The phosphorylation of pyruvic acid by ATP in presence of pyruvate-kinase has been reported, but its contribution is meagre. Phospho-enol-pyruvic acid is generally formed in two steps: first, the carboxylation of pyruvic acid to oxaloacetic acid and then the phosphorylating decarboxylation of the latter to phospho-enol-pyruvic acid.
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A. Carboxylation of pyruvic acid into oxaloacetic acid:
Two pathways are possible (fig. 4-34):
a) A direct path, catalyzed by pyruvate-carboxylase (whose coenzyme is biotin) by a reaction mechanism similar to that of acetyl-coenzyme A-car- boxylase (described in figure 5-16);
b) An indirect path, implying the intermediate formation of malic acid followed by oxidation to oxaloacetic acid.
B. Phosphorylating Decarboxylation of Oxaloacetic Acid into Phosphoenol-Pyruvic Acid:
It is brought about by phospho-enol-pyruvate-carboxykinase, in presence of inosine-triphosphate (ITP) or guanosine triphosphate (GTP). The IDP (or GDP) formed will be rephosphorylated to ITP (or GTP) by ATP (fig. 4-34).
The sum of these reactions can be written as follows (neglecting the trans-hydrogenation which takes place while passing through malic acid):
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pyruvic acid + 2ATP → phospho-enol-pyruvic acid + 2ADP + Pi
It must be stated right now that compounds like the fatty acids (and also about ten amino acids precisely called glucoformers) which can be transformed into pyruvic acid or oxaloacetic acid (through the Krebs cycle, for example) can contribute to the phenomenon of neoglucogenesis.
2. Conversion of Fructose-1, 6-bis-℗ into Fructose-6-℗:
This hydrolysis is catalyzed by fructose-1, 6-bis-phosphatase. Regulation phenomena are observed at this stage; they will be referred to in the following paragraph.
3. Conversion of Glucose-6-℗ into Glucose:
This hydrolysis is catalyzed by glucose- 6-phosphatase. The fact that the pathway of glycolysis and that of neoglucogenesis differ at three stages offers the advantage of a different regulation of the two processes; we will now consider an aspect of this regulation; in this study we may refer to figure 4-35 and consult the recapitulative diagram representing the reactions of anaerobic glycolysis and some reactions directly connected with it.
