Gluconeogenesis from pyruvate

FIGURE 21-21 Glyceroneogenesis. The pathway is essentially an abbreviated version of gluconeogenesis, from pyruvate to dihydroxyacetone phosphate (DHAP), followed by conversion of DHAP to glycerol 3-phosphate, which is used for the synthesis of triacylglycerol. 

Pyruvate Carboxylase Pyruvate carboxylase catalyzes the car-boxylation of pyruvate to oxaloacetate - both the first committed step of gluconeogenesis from pyruvate and also an important anaplerotic reaction, permitting repletion of tricarboxylic acid cycle intermediates and hence fatty acid synthesis. The mammalian enzyme is activated aUosterically by acetyl CoA, which accumulates when there is a need for increased activity of pyruvate carboxylase to synthesize oxaloacetate to permit increased citric acid cycle activity or for gluconeogenesis (Attwood, 1995 Jitrapakdee and Wallace, 1999). 

Gluconeogenesis from pyruvate is essentially the reverse of glycolysis, with the exception of three nonequilibrium reactions (Figure 15-1). These reactions are... 

Gluconeogenesis from pyruvate is not equal to the reverse process of glycolytic degradation of glucose to this 3-carbon intermediate. The glycolytic pathway and the gluconeogenetic pathway deviate at three steps. The conversion of pyruvate to PEP is not mediated by pyruvate kinase due to the irreversible nature of this metabolic step. Pyruvate, derived from either lactate or alanine, is converted to oxaloacetate in the mitochondrial matrix. This step is catalyzed by pyruvate carboxylase. Oxaloacetate per se cannot pass the mitochondrial inner membrane. However, with the use of the malate-aspartate shuttle, the 4-carbon skeleton of oxaloacetate can be transferred into the cytoplasmic compartment. Then oxaloacetate is converted to PEP by the action of PEP carboxykinase (Figure 1). 

The following is the sequence of reactions of gluconeogenesis from pyruvate to phos-phoenolpyruvate ... 

For example, gluconeogenesis from lactate, pyruvate, fructose, and alanine in perfused livers from starved adrenalectomized rats was compared with gluconeogenesis in nonadrenalectomized rats. In two laboratories in which gluconeogenesis from pyruvate and lactate was investigated, opposite results were obtained. One laboratory claimed that adrenalectomy decreased gluconeogenesis, while the other could not demonstrate such an effect. 

Glucagon stimulates gluconeogenesis and insulin slows it down. In perfused liver glucagon stimulates gluconeogenesis from pyruvate, lactate, and oxaloace-tate (but not from alanine). Crossover studies have established that glucagon acts on gluconeogenesis by activating pyruvic carboxylase. 

This conversion of malate to phospho-enolpyruvate (PEP) turned out to be of much interest later, especially thanks to work from Harland Wood s group. It is probably one of the main pathways in gluconeogenesis from pyruvate and COg and Utter and Kurahashi described precisely the coupling between carboxylation-decafboxylation reactions of the pyruvate system and phosphorylation of guanosine diphosphate to triphosphate. ... 

Biomolecules are synthesized as well as degraded, but the pathways for anabolism and catabolism are not the exact reverse of one another. Fatty acids are biosynthesized from acetate by an 8-step pathway, and carbohydrates are made from pyruvate by the 11-step gluconeogenesis pathway. 

The free glucose produced by this reaction is supplied to the blood from the tissues. As exemplified by gluconeogenesis, one may easily envision the economical organization of these metabolic routes, since, apart from four special gluconeogenesis enzymes-pyruvate carboxylase, phosphopyruvate carboxylase, fructose bisphosphatase, and glucose 6-phosphatase-individual glycolytic enzymes are also used in the gluconeogenesis. 

Gluconeogenesis makes glucose from pyruvate to help maintain blood glucose levels. 

There are two unusual aspects to the regulation of gluconeogenesis. The first step in the reaction, the formation of oxaloacetate from pyruvate, requires the presence of acetyl-CoA. This is a check to make sure that the TCA cycle is adequately fueled. If there s not enough acetyl-CoA around, the pyruvate is needed for energy and gluconeogenesis won t happen. However, if there s sufficient acetyl-CoA, the pyruvate is shifted toward the synthesis of glucose. 

The degradation of most amino acids is anaplerotic, because it produces either intermediates of the cycle or pyruvate glucogenic amino acids see p. 180). Gluconeogenesis is in fact largely sustained by the degradation of amino acids. A particularly important anaplerotic step in animal metabolism leads from pyruvate to oxaloacetic acid. This ATP-dependent reaction is catalyzed by pyruvate... 

A. The ability to synthesize new oxaloacetate from pyruvate is essential to maintain activity of the TCA cycle for cell growth and for gluconeogenesis. 

FIGURE 14-19 Alternative paths from pyruvate to phospho-enolpyruvate. The path that predominates depends on the glucogenic precursor (lactate or pyruvate). The path on the right predominates when lactate is the precursor, because cytosolic NADH is generated in the lactate dehydrogenase reaction and does not have to be shuttled out of the mitochondrion (see text). The relative importance of the two pathways depends on the availability of lactate and the cytosolic requirements for NADH by gluconeogenesis. 

TABLE 14-3 Sequential Reactions in Gluconeogenesis Starting from Pyruvate... 

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). 

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