Fundamentals of Biochemistry - A. A. Anisimov 1986

Carbohydrates
Gluconeogenesis

The anaerobic phase of glucose breakdown—Glycolysis—ends with The formation of Pyruvate (PA) or lactic acid. Under certain conditions, these can be resynthesized back into glucose. Two molecules of lactic acid yield one molecule of glucose, effectively reversing glycolysis. This process is known as Gluconeogenesis. While glycolysis is the central pathway of Carbohydrate Catabolism, gluconeogenesis is an anabolic process and the most important general pathway for The Biosynthesis of mono- and Polysaccharides in humans, animals, and many Bacteria. In photosynthetic organisms, it typically plays a secondary role.

Most stages of gluconeogenesis represent the reversal of glycolytic reactions. However, glycolysis contains three irreversible steps accompanied by a significant release of energy; therefore, gluconeogenesis bypasses these specific stages.

The first irreversible step is The conversion of pyruvate into phosphoenolpyruvate. The phosphorylation of pyruvate is achieved through a sequence of Reactions Catalyzed by both cytoplasmic and mitochondrial Enzymes. The mitochondrial enzyme pyruvate carboxylase is active in animals only in the presence of acetyl-CoA. It catalyzes the following reaction:

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The resulting OAA is reduced to malate right there in the Cell/35.html">Mitochondria, with the participation of NADH. This reaction proceeds readily because the NADH/NAD⁺ ratio inside the mitochondria is high:

Malic acid diffuses from the mitochondria into the Cytoplasm. It easily crosses the mitochondrial membrane and serves as a carrier of reducing equivalents between two cellular compartments—the mitochondria and the cytoplasm. In the cytoplasm, malic acid is oxidized by cytoplasmic NAD-dependent malate dehydrogenase. Since the cytoplasmic NADH/NAD⁺ ratio is very low, the oxidation reaction proceeds easily:

Subsequent reactions also take place in the cytoplasm. Catalyzed by phosphoenolpyruvate carboxykinase, OAA is converted into phosphoenolpyruvate (PEP). GTP or ITP (inosine triphosphate) serves as the phosphate donor in this reaction:

This is the bypass pathway for PEP formation. Its overall equation is as follows:

ПВК + АТФ + ГТФ ФЕП + АДФ + ГДФ + Ф_н

The resulting PEP is then readily converted into fructose-1,6-diphosphate via a series of reversible glycolytic reactions (Fig. 6.18). Subsequently, the enzyme fructose diphosphatase catalyzes the hydrolytic removal of the phosphate group located at the first position:

Fig. 6.18. Reactions of gluconeogenesis

This overcomes the second irreversible step of glycolysis. In the next reversible reaction, fructose-6-phosphate is converted into glucose-6-phosphate:

In most Cells, glucose-6-phosphate is utilized as a precursor for mono-, di-, and polysaccharides. Only in certain Organs and Tissues—such as the Liver, Kidneys, intestinal epithelium of vertebrates, and the tissues of some plants—can it be converted into free glucose by the action of the enzyme glucose-6-phosphatase:

This is the third and final bypass pathway used for the Synthesis of glucose from pyruvate. The overall equation for the reactions of gluconeogenesis is as follows:

2СН₃СОСООН + 4АТФ + 2ГТФ + 2НАДН + 2Н⁺ + 6Н₂О →

→ Глюкоза + 2НАД⁺ + 4АДФ + 2ГДФ + 6Ф_Н

Thus, the synthesis of a single glucose molecule consumes six high-energy phosphate bonds and two molecules of NADH as a reducing agent. This chain of reactions provides a pathway for the formation of glucose from lactic acid or pyruvate, as well as from various precursors of pyruvate or phosphoenolpyruvate. Ultimately, TCA cycle intermediates can be incorporated into the glucose molecule because they are capable of being converted into OAA. Amino Acids that can be converted into OAA are able to form glucose (glucogenic amino acids). In plants and microorganisms, acetyl-CoA and all Amino acids are converted into CARBOHYDRATES via The Glyoxylate cycle and the Krebs cycle, followed by entry into The gluconeogenesis pathway.