Glycogen Metabolism and the Pentose Phosphate Pathway Lectures

Section 10: Glycogen Metabolism and The Pentose Phosphate Pathway Lectures: Chapter 24: Glycogen Degradation Chapter 25: Glycogen Synthesis Chapter 26: The Pentose Phosphate Pathway By the end of this section, you should be able to: List and describe the steps of glycogen breakdown, and identify the enzymes required. Explain the regulation of glycogen breakdown. Describe the steps of glycogen synthesis, and identify the enzymes required. Explain the regulation of glycogen synthesis. Describe how glycogen degradation and synthesis are coordinated. Identify the two stages of the pentose phosphate pathway, and explain how the pathway is coordinated with glycolysis and gluconeogenesis. Identify the enzyme that controls the pentose phosphate pathway CHAPTER 24: Glycogen Degradation Glycogen is a key source of energy for runners. Glycogen mobilization—the conversion of glycogen into glucose Glycogen depletion as a result of exercise Glycogen: • Glycogen is a highly branched homopolymer of glucose present in all tissues. • The largest stores of glycogen are in liver and muscle. • The liver breaks down glycogen and releases glucose to the blood to provide energy for the brain and red blood cells. • Muscle glycogen stores are mobilized to provide energy for muscle contraction. Glycogen Remodeling Cross‐sectional View of glycogen (debranching enzyme) • Phosphoglucomutase forms glucose 6‐phosphate from glucose 1‐phosphate with the use of a glucose 1, 6‐bisphosphate intermediate. • Glucose 6‐phosphatase generates free glucose from glucose 6‐phosphate in liver. Glucose 6‐phosphatase is absent in most other tissues. Answer Phosphorylase, transferase, glucosidase, phosphoglucomutase, and glucose 6- phosphatase. The regulatory cascade for glycogen breakdown Clinical Insights: Hers disease results from a deficiency in the liver isozyme of glycogen phosphorylase. Glycogen accumulates in the liver and hypoglycemia results, both manifestations of the inability to mobilize glycogen. (more active) (Less active) Answer In muscle, the b form of phosphorylase is activated by AMP. In the liver, the a form is inhibited by glucose. The difference corresponds to the difference in the metabolic role of glycogen in each tissue. Muscle uses glycogen as a fuel for contraction, whereas the liver uses glycogen to maintain proper blood- glucose concentration. The hormonal control of glycogen breakdown Glucagon (in liver) and epinephrine (in muscle) initiate G‐protein cascades that result in the production of cAMP. Glycogen Remodeling Cross‐sectional View of glycogen (debranching enzyme) CHAPTER 25: Glycogen Synthesis Pasta and pizza are good energy sources for a host of athletic contests. • Glycogen degradation yields glucose 1‐phosphate. • UDP‐glucose is the monomer that is used to extend the glycogen chain in synthesis. • UDP‐glucose is synthesized by UDP‐ glucose pyrophosphorylase. • Glycogen synthase, the key regulatory enzyme in glycogen synthesis, transfers a glucose moiety from UDP‐glucose to the C‐4 terminal residue of a glycogen chain to form an α‐1,4‐glycosidic bond. • Glycogen synthase requires an oligosaccharide of glucose residues as primer. • The primer is synthesized by glycogenin, a dimer of two identical subunits. • Each subunit of glycogenin generated an oligosaccharide of glucose residues 10‐20 molecules long. • Glycogen synthase then extends this primer. Glycogen synthase is usually Branching reaction inactive when in the phosphorylated b form, and is usually active when in the unphosphorylated a form. Binding glucose 6‐phosphate to glycogen synthase converts the b form in the T state to the active R state of the b form. Note that phosphorylation has opposite effects on glycogen synthase than on glycogen phosphorylase. The branching enzyme removes an oligosaccharide of approximately seven residues from the nonreducing end and creates an internal ‐1,6 linkage. Coordinate control of glycogen metabolism Protein kinase A, along with glycogen synthase kinase, inactivates glycogen synthase, shutting down glycogen synthesis The regulation of glycogen synthesis by protein phosphatase 1 PP1 stimulates glycogen synthesis while inhibiting glycogen breakdown. The regulation of PP1 in muscle takes place in two steps protein phosphatase 1 A key regulatory subunit is the G subunit (GL in liver and GM in muscle) Insulin inactivates glycogen synthase kinase. • Insulin triggers a cascade that leads to the phosphorylation and inactivation of glycogen synthase kinase and prevents the phosphorylation of glycogen synthase. Protein phosphatase 1 (PP1) removes the phosphoryl groups from glycogen synthase, thereby activating the enzyme and allowing glycogen synthesis. Abbreviation: IRS, insulin‐ receptor substrate. • Insulin also facilitates glycogen synthesis by increasing the number of glucose transporters (GLUT4) in the plasma membrane. Blood glucose regulates liver‐glycogen metabolism The infusion of glucose into the bloodstream leads to the inactivation of phosphorylase followed by the activation of glycogen synthase in the liver. Glucose regulates liver‐glycogen metabolism Answer It prevents synthesis and breakdown from taking place simultaneously, which would lead to a useless expenditure of energy. See problem 9 in the Problems section. Answer Liver phosphorylase a is inhibited by glucose, which facilitates the R → T transion. This transion releases protein phosphatase 1, which inactivates glycogen breakdown and stimulates glycogen synthesis. Muscle phosphorylase is insensitive to glucose. Diabetes is characterized by the presence of excess glucose and underutilization of the fuel. Excess glucose is excreted in the urine. In type 1 diabetes, insulin in not produced. In type 2 diabetes, insulin is produced but the insulin‐ signaling pathway is not responsive, a condition referred to as insulin resistance. Glycogen storage diseases result from a variety of biochemical defects in glycogen metabolism. CHAPTER 26: The Pentose Phosphate Pathway Growth is an awesome biochemical feat. Two key biochemical components required for growth ‐ribose sugars and biochemical reducing power‐ are provided by the pentose phosphate pathway. NADPH, a key product of the pentose phosphate pathway, is the source of biosynthetic reducing power. 1) The first phase of the pentose phosphate pathway is the oxidative generation of NADPH. 2) The second phase is the nonoxidative interconversion of a variety of sugars. • Glucose 6‐phosphate dehydrogenase initiates the oxidative phase of the pentose phosphate pathway with the conversion of glucose 6‐phosphate into 6‐ phosphoglucono‐δ‐lactone. • In the process, glucose 6‐phosphate dehydrogenase reduces NADP+ to NADPH. • A second NADPH is generated in the oxidative phase when 6‐phosphogluconate is converted into ribulose 5‐phosphate and CO2. Excess ribose 5-phosphate formed by the pentose phosphate pathway can be completely converted into glycolytic intermediates • Ribulose 5‐phosphate, generated by the oxidative phase, is isomerized into ribose 5‐phosphate. • The nonoxidative phase consists of three reactions: • The net result of these reactions in the conversion of three pentoses into two hexoses and one triose. Answer The enzymes catalyze the transformation of the five‐carbon sugar formed by the oxidative phase of the pentose phosphate pathway into fructose 6‐phosphate and glyceraldehyde 3‐phosphate, intermediates in glycolysis (and gluconeogenesis). The first reaction of the pentose phosphate pathway, the dehydrogenation of glucose 6‐phosphate by glucose 6‐phosphate dehydrogenase, is the rate‐ limiting step of the pathway. The most important regulatory factor is the concentration of NADP+. Excess ribose 5-phosphate formed by the pentose phosphate pathway can be completely converted into glycolytic intermediates The pentose phosphate pathway can operate in four distinct modes that result from various combinations of the oxidative phase, the nonoxidative phase, glycolysis, and gluconeogenesis. 1. Ribose 5‐phosphate needs exceed the needs for NADPH. 2. The NADH and ribose 5‐phosphate needs are balanced. 3. More NADPH is needed than ribose 5‐phosphate. 4. NADPH and ATP are both required. Four modes of the pentose phosphate pathway Major products are shown in color. Ribose 5‐phosphate and NADPH are important resources for rapidly dividing cells, such as cancer cells. Cancer cells undergoing aerobic glycolysis divert some of the glucose 6‐ phosphate and other glycolytic intermediates into the pentose phosphate pathway for the generation of ribose 5‐phosphate and NADPH. Glutathione (GSH) helps to prevent damage by reactive oxygen species generated in the course of metabolism. NADPH generated by the pentose phosphate pathway is required to maintain adequate levels of reduced glutathione. Oxidized glutathione (GSSG) is converted into reduced glutathione by NADPH. If glucose 6‐phosphate dehydrogenase activity is compromised, adequate amounts of NADPH cannot be generated to maintain GSH levels. Glucose 6‐phosphate dehydrogenase deficiency protects against malaria by depriving the parasites of NADPH that they require for growth . Glutathione is used to eliminate peroxides, which are reactive oxygen species. Glutathione is also required to maintain the normal structure of hemoglobin. In the absence of glutathione, sulfhydryl bonds occur among hemoglobin molecules, forming aggregates called Heinz bodies. Heinz bodies can cause the red blood cells to lyse..

Load more