Carbohydrate Metabolism

What are the reactions of the Pentose Phosphate Pathway and how does it reduce damage from oxidative stress ?

● The most important functions of the pentose phosphate pathway are to reduce two molecules of NADP+ to NADPH for each molecule of glucose-6-P and to generate ribose-5-P for nucleotide and coenzyme biosynthesis.

● NADPH functions as a strong reductant in anabolic pathways and in detoxification reactions that neutralize reactive oxygen species. NAD+ is primarily used as an oxidant in catabolic pathways.

● The pentose phosphate pathway is divided into the oxidative phase, which generates NADPH, and the nonoxidative phase, which interconverts sugar phosphates to regenerate glucose-6-P using transketolase and transaldolase enzymes.

● Flux through the pentose phosphate pathway is regulated to meet three distinct metabolic states of the cell: (1) a need for NADPH; (2) a need to replenish nucleotide pools; and (3) a need to generate ATP from glucose-6-P.

● Glucose-6-phosphate dehydrogenase (G6PD) catalyzes the commitment step in the pentose phosphate pathway and is highly regulated by the NADP+-to-NADPH concentration ratio to control flux through the pathway (NADP+ stimulates enzyme activity to increase NADPH levels in the cell).

● Mutations in the human G6PD gene cause the most common enzyme deficiency in the world. This deficiency results in reduced intracellular levels of NADPH, which is required to reduce glutathione and protect cells from compounds that can induce oxidative stress, such as primaquine (antimalarial drug) and vicine (from fava beans).

What are the reactions of the Gluconeogenic Pathway and how does it function in the Cori Cycle?

● Gluconeogenesis synthesizes glucose from noncarbohydrate sources when dietary glucose is limiting and glucose stores have been depleted. Much of the glucose used by the brain and erythrocytes in humans comes from gluconeogenesis occurring in liver and kidney cells.

● Gluconeogenesis and glycolysis share seven enzymes, catalyzing reversible reactions in both pathways. The four solely gluconeogenic enzymes are pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose-1,6-bisphosphatase (FBPase-1), and glucose-6-phosphatase, which bypass three exergonic reactions in glycolysis (catalyzed by hexokinase, phosphofructokinase-1, and pyruvate kinase).

● Pyruvate carboxylase and phosphoenolpyruvate carboxykinase catalyze the pyruvate kinase bypass reactions by converting pyruvate to phosphoenolpyruvate, using phosphoryl transfer energy from ATP (pyruvate carboxylase reaction) and GTP (phosphoenolpyruvate carboxykinase reaction).

● FBPase-1 catalyzes the phosphofructokinase-1 (PFK-1) bypass reaction by converting fructose-1,6-BP to fructose-6-P. FBPase-1 and PFK-1 are reciprocally regulated by the allosteric effectors AMP, fructose-2,6-BP, and citrate in response to energy charge and hormonal signaling.

● The hexokinase reaction in glycolysis is bypassed by the gluconeogenic enzyme glucose-6-phosphatase, which is localized to the ER lumen and thus physically isolated from the hexokinase reaction in the cytosol.

● Hormonal control of PFK-1 and FBPase-1 is mediated in liver cells by fructose-2,6-BP. Fructose-2,6-BP is structurally related to fructose-6-P and fructose-1,6-BP but is not a metabolic intermediate in either the glycolytic or gluconeogenic pathways.

● The Cori cycle uses gluconeogenesis in liver cells to convert muscle-derived lactate into glucose, thereby replenishing glucose levels and supporting muscle contraction. The energy cost of running gluconeogenesis (liver) and glycolysis (muscle) at the same time is net 4 ATP equivalents (the difference between 2 ATP produced by anaerobic glycolysis and 4 ATP + 2 GTP consumed by gluconeogenesis).

What are the molecular determinants of glycogen degradation and synthesis?

● Glycogen is a storage form of glucose in animals and consists of branched homopolysaccharides linked by α(1–>4) and α(1–>6) glycosidic bonds. Glycogen degradation and synthesis occur in the cytosol, with the substrate for these reactions being the free ends (nonreducing ends) of the branched polymer.

● The four key enzymes required for reversible degradation and synthesis of glycogen are glycogen phosphorylase, glycogen synthase, and the glycogen branching and debranching enzymes.

● Glycogen phosphorylase catalyzes a reaction that releases glucose-1-P from glycogen in a phosphorolysis reaction involving inorganic phosphate and cleavage of the α(1–>4) glycosidic bond. Glucose-1-P is converted to glucose-6-P, which is either used for glycolysis in muscle cells or dephosphorylated in liver cells and exported to other tissues. Glycogen phosphorylase activity is stimulated by glucagon and epinephrine signaling.

● Glycogen synthase is activated by insulin signaling and adds glucose to the nonreducing ends in a reaction involving UDP-glucose. Glycogen synthase uses the bond energy available in UDP-glucose to form α(1–>4) glycosidic bonds at the nonreducing ends of the glycogen particle.

● Branching and debranching enzymes modify glycogen complexes to facilitate glycogen degradation (debranching) and glycogen synthesis (branching) through the cleavage and formation of α(1–>6) glycosidic bonds. Both enzymes also catalyze reactions involving the transfer of glucose oligosaccharides between branched and unbranched regions of the molecule.

● Glycogen degradation and synthesis require the enzyme phosphoglucomutase, which interconverts glucose-1-P and glucose-6-P through the formation of a bisphosphorylated enzyme intermediate.

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