Cells not only are able to catabolize glucose and other carbohydrates to meet their energy needs but also can synthesize sugars and polysaccharides needed for other purposes. The process of glucose synthesis is called gluconeogenesis, which literally means the genesis, or formation, of new glucose. More specifically, gluconeogenesis is defined as the process by which animal (and other) cells synthesize glucose (and other carbohydrates) from three-carbon and four-carbon precursors that are usually non-carbohydrate in nature.
The most common starting material is pyruvate, or the lactate into which pyruvate is converted under anaerobic conditions. Figure compares gluconeogenesis and glycolysis. The two pathways share much in common; in fact, seven of the reactions in the gluconeogenic pathway occur by simple reversal of the corresponding reactions in glycolysis (reactions Gly-2 and Gly-4 through Gly-9).
In each case, the same enzyme is used in both directions. As Figure illustrates, three of the reactions of the glycolytic pathway, the first, third, and tenth, are accomplished by other means in the direction of gluconeogenesis. In fact, these differences illustrate well an important principle of cellular metabolism: Biosynthetic pathways are seldom just the reversal of the corresponding catabolic pathways. For a metabolic pathway to b e thermodynamically favorable in a specific direction, it must be sufficiently exergonic in that direction.
That certainly is true of glycolysis; recall that the overall sequence from glucose to pyruvate as summarized by reaction: Glucose + 2NAD+ + 2ADP + 2P� � 2 Pyruvate + 2NADH + 2H++ 2ATP (Reactions Gly-1 through Gly-10) has a �G°´ value of about –20 kcal/mol under typical intracellular conditions in the human body. Clearly, then, �G°´ for the reverse process would be about +20 kcal/mol, making glucose synthesis by the direct reversal of glycolysis highly endergonic and therefore thermodynamically impossible. Gluconeogenesis is possible because the three most exergonic reactions in the glycolytic pathway (Gly-1, Gly-3, and Gly-10) do not simply “run in reverse” in the gluconeogenic direction.
Instead, the gluconeogenic pathway has bypass reactions at each of those three sites, which are alternative reactions that effectively circumvent the three glycolytic reactions that would be the most difficult to drive in the reverse direction. In each of these three instances, the bypass reactions of gluconeogenesis circumvent the irreversibility of the glycolytic step. In the case of both Gly-1 and Gly-3, the requirement for ATP synthesis in the reverse direction is bypassed by a simple hydrolytic reaction.
In the case of the interconversion of glucose and glucose-6-phosphate, for example, the reaction is exergonic in the glycolytic direction because of the input of an ATP molecule. And in the gluconeogenic direction, exergonicity is ensured by the simple hydrolysis of the phosphoester bond, which has a �G°´ of -3.3 kcal/mol. The third site of irreversibility in the glycolytic pathway, reaction Gly-10, is bypassed in gluconeogenesis by a two-reaction sequence. Both of these reactions are driven by the hydrolysis of a phosphoanhydride bond, from ATP in one case and from the related compound GTP in the other. (GTP is the abbreviation for guanosine triphosphate; for the structure of guanine.)
The first of these two steps is the addition of CO2 to pyruvate, which is a carboxylation reaction. This forms a four-carbon compound called oxaloacetate, which we will meet again in the next chapter. In the second step, the carboxyl group is removed via a decarboxylation reaction to form phosphoenolpyruvate (PEP). In this case, both the phosphate group and the energy are provided by GTP, which is energetically the equivalent of ATP. What these bypass reactions accomplish becomes clear when the glycolytic and gluconeogenic pathways are compared directly.
Glycolysis uses two ATPs but generates four ATPs, for a net yield of two ATP molecules formed per molecule of glucose catabolized. Gluconeogenesis, on the other hand, requires four ATPs and two GTPs per glucose, or the equivalent of six ATP molecules consumed per molecule of glucose synthesized. The difference of four ATP molecules per glucose represents enough energy to ensure that gluconeogenesis proceeds at least as exergonically in the direction of glucose synthesis as glycolysis does in the direction of glucose breakdown.
THE WRITER IS AN ASSOCIATE PROFESSOR (RETD.) & FORMER HEAD, DEPARTMENT OF BOTANY, ANANDA MOHAN COLLEGE.