Chapter 15 Glycogen Metabolism PDF

15 The Metabolism of Glycogen in Animals © 2021 Macmillan Learning  Principle 1 (1 of 2) Glycogen provides vertebrate animals with a ready source of glucose to supply the brain and skeletal muscles with energy. Although animals store about 100 times more energy as fa...

15 The Metabolism of Glycogen in Animals © 2021 Macmillan Learning  Principle 1 (1 of 2) Glycogen provides vertebrate animals with a ready source of glucose to supply the brain and skeletal muscles with energy. Although animals store about 100 times more energy as fat than as glycogen, they cannot metabolize fat into glucose. The highly branched polymeric structure of glycogen granules allows cells in the liver and muscle to make large numbers of glucose and glucose phosphate monomers available quickly without raising the osmolarity of the cytosol by storing them in monomeric form.  Principle 2 (1 of 3) Monomers are released from glycogen granules by a phosphorolysis reaction that creates phosphorylated glucose molecules that can enter glycolysis to supply energy to the cell. Skeletal muscle cells especially require stores of glycogen to supply energy for bursts of activity. In the liver, the phosphate can be removed, allowing free glucose to be transported out of the cell to the blood for use in the brain and other tissues when dietary glucose is not sufficient.  Principle 3 (1 of 4) Glycogen synthesis requires a protein primer and an activated glucose precursor. Individual glucose molecules activated as sugar nucleotides are added to the nonreducing end of the growing linear chains in the outer tiers of the glycogen β-granules, and a branching enzyme adds branches periodically.  Principle 4 (1 of 7) Regulation of the balance between the formation of glycogen from excess glucose and the release of glucose from glycogen polymers when it is needed in metabolism is a critical function of cellular and organismal homeostasis. This balance, ultimately controlled by the hormones epinephrine, glucagon, and insulin, is achieved through allosteric regulation and phosphorylation of the synthetic and degradative enzymes. These enzymes and the regulatory proteins that act on them are integral parts of the glycogen granule. 15.1 The Structure and Function of Glycogen  Principle 1 (2 of 2) Glycogen provides vertebrate animals with a ready source of glucose to supply the brain and skeletal muscles with energy. Although animals store about 100 times more energy as fat than as glycogen, they cannot metabolize fat into glucose. The highly branched polymeric structure of glycogen granules allows cells in the liver and muscle to make large numbers of glucose and glucose phosphate monomers available quickly without raising the osmolarity of the cytosol by storing them in monomeric form. Vertebrate Animals Require a Ready Fuel Source for Brain and Muscle glycogen = a polymeric storage form of glucose in animals that is found primarily in muscle and liver glycogen breakdown in muscle delivers glucose needed for muscle contraction within seconds glycogen stored in the liver provides a reservoir that maintains homeostasis of blood glucose Glycogen Granules Have Many Tiers of Branched Chains of D-Glucose glycogen β-granules = cytosolic granules that vary in size, structure, and subcellular location – appear as electron-dense particles  β-Granules Cluster to Form α- Granules in the Liver α-granules = protein-rich granules composed of 20-40 clustered β-granules – release glucose slower than β-granules – visible in well-fed animals, but absent after a 24-hour fast – often associate with tubules of the smooth ER Structure of a Glycogen β-Granule glycogenin dimer = serves as a primer tiers of glucose residues are in (α1⟶4) linkage, with (α1⟶6)-linked branches – provides many free nonreducing ends  Clicker Question 1 Consider the way that glycogen is stored within a cell. Which answer choice correctly ranks the glycogen storage particles from smallest to largest? A. glucose, α-granule, β-granule B. α-granule, β-granule, glucose C. glucose, β-granule, α-granule D. β-granule, α-granule, glucose  Clicker Question 1, Response Consider the way that glycogen is stored within a cell. Which answer choice correctly ranks the glycogen storage particles from smallest to largest? C. glucose, β-granule, α-granule In muscle, β-granules are 20–30 nm in diameter and have an Mr of 10–10. They consist of up to 55,000 glucose residues with about 2,000 nonreducing ends available for degradative enzymes to work on. In the liver, 20 to 40 β-granules cluster together to form protein-rich α-granules as large as 300 nm in diameter and of Mr greater than 108. 15.2 Breakdown and Synthesis of Glycogen Glycogenolysis and Glycogenesis glycogenolysis = the breakdown of cellular glycogen to glucose 1-phosphate glycogenesis = the synthesis of glycogen  Principle 2 (2 of 3) Monomers are released from glycogen granules by a phosphorolysis reaction that creates phosphorylated glucose molecules that can enter glycolysis to supply energy to the cell. Skeletal muscle cells especially require stores of glycogen to supply energy for bursts of activity. In the liver, the phosphate can be removed, allowing free glucose to be transported out of the cell to the blood for use in the brain and other tissues when dietary glucose is not sufficient. Glycogen Breakdown Is Catalyzed by Glycogen Phosphorylase glycogen phosphorylase = catalyzes phosphorolytic cleavage at the nonreducing ends of glycogen chains – requires pyridoxal phosphate – acts repetitively until it reaches a point four residues away from a (α1⟶6) branch point  Debranching Enzyme debranching enzyme = transfers branches onto main chains and releases the residue at the (α1⟶6) branch as free glucose Glucose 1-Phosphate Can Enter Glycolysis or, in Liver, Replenish Blood Glucose phosphoglucomutase = catalyzes the reversible conversion of glucose 1-phosphate to glucose 6-phosphate  Clicker Question 2 Glycogenolysis releases a form of glucose that cannot enter glycolysis. What enzyme can transform it into a glycolytic intermediate? A. glycogen phosphorylase B. phosphoglucomutase C. NDP-sugar pyrophosphorylase D. transglycolase E. glycogenin  Clicker Question 2, Response Glycogenolysis releases a form of glucose that cannot enter glycolysis. What enzyme can transform it into a glycolytic intermediate? B. phosphoglucomutase Phosphoglucomutase transforms glucose 1-phosphate into glucose 6-phosphate.  Principle 2 (3 of 3) Monomers are released from glycogen granules by a phosphorolysis reaction that creates phosphorylated glucose molecules that can enter glycolysis to supply energy to the cell. Skeletal muscle cells especially require stores of glycogen to supply energy for bursts of activity. In the liver, the phosphate can be removed, allowing free glucose to be transported out of the cell to the blood for use in the brain and other tissues when dietary glucose is not sufficient.  Fates of Glucose 6-Phosphate in skeletal muscle, glucose 6-phosphate enters glycolysis in liver, glucose 6-phosphatase converts glucose 6- phosphate to glucose in the ER for export to replenish blood glucose  Clicker Question 3 In glycogenolysis, why is the glucose 6-phosphatase activity in the ER lumen? A. Glycogenolysis occurs in the ER lumen. B. It prevents a futile cycle with enzymes of the glycolytic pathway. C. The first steps of glycolysis are in the ER lumen. D. It allows glucose to be easily exported from the liver by GLUT2. E. It allows lipogenesis to occur rapidly.  Clicker Question 3, Response In glycogenolysis, why is the glucose 6-phosphatase activity in the ER lumen? B. It prevents a futile cycle with enzymes of the glycolytic pathway. By having the active site of glucose 6-phosphatase in the ER lumen, the cell separates this reaction from the process of glycolysis, which takes place in the cytosol and would be aborted by the action of glucose 6- phosphatase.  Glycogen Storage Diseases genetic Type (name) Enzyme affected Primary organ/ cells affected Symptoms Type 0 Glycogen synthase Liver Low blood glucose, high ketone, defects in bodies, early death Type Ia (von Gierke) Glucose 6-phosphatase Liver Enlarged liver, kidney failure either glucose Type Ib Microsomal glucose Liver As in type Ia; also high 6-phosphate translocase susceptibility to bacterial 6-phosphatase infections Type Ic Microsomal P, transporter Liver As in type Ia or the glucose Type II (Pompe) Lysosomal glucosidase Skeletal and cardiac Infantile form: death by age 2; 6-phosphate muscle juvenile form: muscle defects (myopathy); adult form: as in transporter T1 Type IIIa (Cori or Forbes) Debranching enzyme Liver, skeletal, and muscular dystrophy Enlarged liver in infants; cause type Ia Type IIIb Liver debranching enzyme cardiac muscle Liver myopathy Enlarged liver in infants glycogen (muscle enzyme normal) Type IV (Andersen) Branching enzyme Liver, skeletal Enlarged liver and spleen, storage muscle myoglobin in urine Type V (McArdle) Muscle phosphorylase Skeletal muscle Exercise-induced cramps and disease pain; myoglobin in urine Type VI (Hers) Liver phosphorylase Liver Enlarged liver Type VII (Tarui) Muscle PFK-1 Muscle, erythrocytes As in type V; also hemolytic anemia Table 1 Glycogen Type VIb, VIII, or IX Phosphorylase kinase Liver, leukocytes, Enlarged liver Storage Diseases of muscle Type XI (Fanconi-Bickel) Glucose transporter Liver Failure to thrive, enlarged liver, Humans (GLUT2) rickets, kidney dysfunction  Clicker Question 4 A patient was seen by a gastrointestinal specialist and diagnosed with a glycogen storage disease. A liver biopsy showed that the patient was producing very little glycogen, the molecules were relatively small, and they only had α (14) glycosidic linkages. Blood and liver glucose concentrations were within normal ranges. What enzyme is LIKELY affected in this disease? A. glycogen synthase B. hexokinase C. glycosyl (46) transferase D. glycogenin E. UDP-glucose pyrophosphorylase  Clicker Question 4, Response A patient was seen by a gastrointestinal specialist and diagnosed with a glycogen storage disease. A liver biopsy showed that the patient was producing very little glycogen, the molecules were relatively small, and they only had α (14) glycosidic linkages. Blood and liver glucose concentrations were within normal ranges. What enzyme is LIKELY affected in this disease? C. glycosyl (46) transferase The glycogen-branching enzyme, also called amylo (14) to (16) transglycosylase or glycosyl (46) transferase, makes the (16) bonds found at the branch points of glycogen.  The Sugar Nucleotide UDP-Glucose Donates Glucose for Glycogen Synthesis sugar nucleotides = compounds in which the anomeric carbon of a sugar is activated by attachment to a nucleotide through a phosphate ester linkage – involved in reactions where hexoses are transformed or polymerized  Principle 3 (2 of 4) Glycogen synthesis requires a protein primer and an activated glucose precursor. Individual glucose molecules activated as sugar nucleotides are added to the nonreducing end of the growing linear chains in the outer tiers of the glycogen β-granules, and a branching enzyme adds branches periodically.  Properties of Sugar Nucleotides sugar nucleotides are suitable for biosynthetic reactions because: – their formation is metabolically irreversible – the nucleotide moiety has many groups that can undergo noncovalent interactions with enzymes – the nucleotidyl group (UDP, ADP) is an excellent leaving group, facilitating nucleophilic attack – “tagging” with nucleotidyl groups distinguishes the hexoses from hexoses destined for other purposes  Formation of a Sugar Nucleotide rapid removal of the product, driven by the large, negative free-energy change of PPi (∆G′° = −19.2 kJ/mol) hydrolysis, pulls the synthetic reaction forward Glycogen Synthesis Begins With Glucose 6-Phosphate sources of glucose 6-phosphate: – hexokinase isozymes derive glucose 6-phosphate from glucose – lactate taken up by the liver is converted to glucose 6-phosphate by gluconeogenesis phosphoglucomutase = converts glucose 6-phosphate to glucose 1-phosphate  UDP-Glucose Pyrophosphorylase Catalyzes A Key Step of Glycogen Biosynthesis UDP-glucose pyrophosphorylase = converts glucose 1-phosphate to UDP-glucose glucose 1-phosphate + UTP ⟶ UDP-glucose + PPi  Clicker Question 5 Which nucleotide is required for glycogen synthesis? A. ATP B. UTP C. CTP D. GTP E. cAMP  Clicker Question 5, Response Which nucleotide is required for glycogen synthesis? B. UTP To start glycogen synthesis, the glucose 6-phosphate is converted to glucose 1-phosphate in the phosphoglucomutase reaction: glucose 1-phosphate ⇌ glucose 6-phosphate The product is then converted to UDP-glucose by the action of UDP-glucose pyrophosphorylase in a key step of glycogen biosynthesis: glucose 1-phosphate + UTP ⟶ UDP-glucose + PPi  Principle 3 (3 of 4) Glycogen synthesis requires a protein primer and an activated glucose precursor. Individual glucose molecules activated as sugar nucleotides are added to the nonreducing end of the growing linear chains in the outer tiers of the glycogen β-granules, and a branching enzyme adds branches periodically. UDP-Glucose Donates Glucose to a Nonreducing End of Glycogen glycogen synthase = catalyzes the transfer of the glucose residue from UDP-glucose to a nonreducing end of a branched glycogen molecule, forming an (α1⟶ 4) linkage  Glycogen-Branching Enzyme glycogen-branching enzyme = catalyzes the formation of the (α1⟶6) bonds found at the branch points of glycogen  Principle 3 (4 of 4) Glycogen synthesis requires a protein primer and an activated glucose precursor. Individual glucose molecules activated as sugar nucleotides are added to the nonreducing end of the growing linear chains in the outer tiers of the glycogen β-granules, and a branching enzyme adds branches periodically. Glycogenin Primes the Initial Sugar Residues in Glycogen glycogen synthase requires a primer glycogenin = the primer on which new chains are assembled and the enzyme that catalyzes their assembly  The Glycogenin Mechanism 1st reaction = autocatalytic formation of a glycosidic bond between the glucose of UDP-glucose and Tyr194 of glycogenin 2nd reaction = addition of seven more glucose residues, each from UDP- glucose, to form a primer that can be acted on by glycogen synthase  Clicker Question 6 Glycogenesis: A. begins the production of a new glycogen molecule with the reactions of glycogenin. B. involves the action of glycogen debranching enzyme. C. involves transfer of glucose from CDP-glucose to a nonreducing end of a glycogen chain. D. only occurs in the liver and muscle.  Clicker Question 6, Response Glycogenesis: A. begins the production of a new glycogen molecule with the reactions of glycogenin, The intriguing protein glycogenin is both the primer on which new chains are assembled and the enzyme that catalyzes their assembly. 15.3 Coordinated Regulation of Glycogen Breakdown and Synthesis  Principle 4 (2 of 7) Regulation of the balance between the formation of glycogen from excess glucose and the release of glucose from glycogen polymers when it is needed in metabolism is a critical function of cellular and organismal homeostasis. This balance, ultimately controlled by the hormones epinephrine, glucagon, and insulin, is achieved through allosteric regulation and phosphorylation of the synthetic and degradative enzymes. These enzymes and the regulatory proteins that act on them are integral parts of the glycogen granule. Glycogen Phosphorylase Is Regulated by Hormone-Stimulated Phosphorylation and by Allosteric Effectors skeletal glycogen phosphorylase has two forms: – glycogen phosphorylase a = catalytically active – glycogen phosphorylase b = much less active  Regulation of Muscle Glycogen Phosphorylase by Covalent Modification epinephrine (from vigorous muscle activity) and glucagon (in the liver) trigger phosphorylation of phosphorylase b, converting it to phosphorylase a  Clicker Question 7 In muscle, what are two allosteric activators of glycogen phosphorylase? A. Mg2+ and ATP B. Ca2+ and AMP C. fructose-2,6-bisphosphate and citrate D. AMP and glucose E. cAMP and acetylCoA  Clicker Question 7, Response In muscle, what are two allosteric activators of glycogen phosphorylase? A. Ca2+ and AMP In muscle, Ca2+, the signal for muscle contraction, binds to the δ subunit of phosphorylase kinase, which activates glycogen phosphorylase. AMP, which accumulates in vigorously contracting muscle as a result of ATP breakdown, binds to and activates phosphorylase, speeding the release of glucose 1-phosphate from glycogen.  Elevated [cAMP] Initiates an Enzyme Cascade enzyme cascade = sequence of enzymatic reactions in which a catalyst activates a catalyst, which activates a catalyst rise in [cAMP] activates PKA, which phosphorylates phosphorylase b kinase phosphorylase b kinase = catalyzes the phosphorylation of glycogen phosphorylase b  Clicker Question 8 A G-protein coupled receptor binds its ligand, activating a heterotrimeric G-protein that stimulates a two-fold increase in cAMP. What important result on carbohydrate metabolism do the phosphorylases covalently activated by protein kinase A have? A. They increase glycogen synthesis. B. They increase gluconeogenesis and decrease glycolysis. C. They inhibit hexokinase, especially in liver and muscle. D. They activate anaerobic metabolic pathways. E. They increase blood glucose concentration.  Clicker Question 8, Response A G-protein coupled receptor binds its ligand, activating a heterotrimeric G-protein that stimulates a two-fold increase in cAMP. What important result on carbohydrate metabolism do the phosphorylases covalently activated by protein kinase A have? E. They increase blood glucose concentration. The rise in [cAMP] activates cAMP-dependent protein kinase, also called protein kinase A (PKA). PKA then phosphorylates and activates phosphorylase b kinase, which catalyzes the phosphorylation of glycogen phosphorylase b, activating it and thus stimulating glycogen breakdown.  Principle 4 (3 of 7) Regulation of the balance between the formation of glycogen from excess glucose and the release of glucose from glycogen polymers when it is needed in metabolism is a critical function of cellular and organismal homeostasis. This balance, ultimately controlled by the hormones epinephrine, glucagon, and insulin, is achieved through allosteric regulation and phosphorylation of the synthetic and degradative enzymes. These enzymes and the regulatory proteins that act on them are integral parts of the glycogen granule.  Allosteric Control Mechanisms Ca2+ is a signal for muscle contraction – binds to and activates phosphorylase b kinase AMP accumulates in vigorously contracting muscle – binds to and activates phosphorylase to speed up glucose 1-phosphate release from glycogen ATP blocks the allosteric site, inactivating phosphorylase  Phosphoprotein Phosphatase 1 (PP1) phosphoprotein phosphatase 1 (PP1) = removes phosphoryl groups from phosphorylase a, converting it to the less active form, phosphorylase b Liver Glycogen Phosphorylase a is a Glucose Sensor glucose binds to an allosteric site on phosphorylase a, making it more susceptible to dephosphorylation by PP1  Clicker Question 9 Regulation of phosphorylase a is by phosphorylation. However, this covalent modification increases or decreases activity without completely inhibiting it. The velocity plot is sigmoidal. What statement can be made about this enzyme? A. It likely follows a Michaelis-Menten kinetic. B. Its reaction mechanism is likely exergonic. C. Its reaction mechanism includes covalent catalysis. D. The active site probably contains an SH2 domain. E. It is probably an allosteric enzyme.  Clicker Question 9, Response Regulation of phosphorylase a is by phosphorylation. However, this covalent modification increases or decreases activity without completely inhibiting it. The velocity plot is sigmoidal. What statement can be made about this enzyme? E. It is probably an allosteric enzyme. Phosphoprotein phosphatase 1 (PP1) removes phosphoryl groups from phosphorylase a, converting it to the less active form, phosphorylase b. Glucose binds to an allosteric site on phosphorylase a, making it more susceptible to dephosphorylation by PP1.  Principle 4 (4 of 7) Regulation of the balance between the formation of glycogen from excess glucose and the release of glucose from glycogen polymers when it is needed in metabolism is a critical function of cellular and organismal homeostasis. This balance, ultimately controlled by the hormones epinephrine, glucagon, and insulin, is achieved through allosteric regulation and phosphorylation of the synthetic and degradative enzymes. These enzymes and the regulatory proteins that act on them are integral parts of the glycogen granule. Glycogen Synthase Also Is Subject to Multiple Levels of Regulation glycogen synthase has two forms: – glycogen synthase a = unphosphorylated and catalytically active – glycogen synthase b = phosphorylated and inactive unless glucose 6-phosphate is present glycogen synthase kinase 3 (GSK3) = catalyzes the phosphorylation of glycogen synthase a  Effects of GSK3 on Glycogen Synthase Activity insulin inactivates GSK3 and activates PP1 glucose 6- phosphate acts allosterically to make glycogen synthase b a better substrate for PP1 The Action of GSK3 is Hierarchical GSK3 cannot phosphorylate glycogen synthase until casein kinase II (CKII) has phosphorylated the glycogen synthase on a nearby residue (a priming event)  Clicker Question 10 Glycogen synthase kinase 3 (GSK3): A. functions only in regulation of glycogen synthase. B. phosphorylates glycogen synthase only after glycogen synthase has been phosphorylated by another kinase. C. is directly stimulated by insulin. D. phosphorylates casein kinase II.  Clicker Question 10, Response Glycogen synthase kinase 3 (GSK3): B. phosphorylates glycogen synthase only after glycogen synthase has been phosphorylated by another kinase. The action of GSK3 is hierarchical, meaning it cannot phosphorylate glycogen synthase until another protein kinase, casein kinase II (CKII), has first phosphorylated the glycogen synthase on a nearby residue, an event called priming.  Principle 4 (5 of 7) Regulation of the balance between the formation of glycogen from excess glucose and the release of glucose from glycogen polymers when it is needed in metabolism is a critical function of cellular and organismal homeostasis. This balance, ultimately controlled by the hormones epinephrine, glucagon, and insulin, is achieved through allosteric regulation and phosphorylation of the synthetic and degradative enzymes. These enzymes and the regulatory proteins that act on them are integral parts of the glycogen granule.  Glycogen-Targeting Proteins glycogen-targeting protein = regulatory subunit of PP1 that serves as a scaffold, binding glycogen, phosphorylase kinase, glycogen phosphorylase, and glycogen synthase  Allosteric and Hormonal Signals Coordinate Carbohydrate Metabolism Globally in the liver: – insulin activates glycogen synthase by inactivating GSK3 and activating PP1 – glucagon stimulates glycogen breakdown and gluconeogenesis while blocking glycolysis in muscle, epinephrine provides ATP by stimulating glycogen breakdown and glycolysis Regulation of Carbohydrate Metabolism in the Liver  Clicker Question 11 Which enzyme involved in glycogenesis and glycogenolysis is allosterically regulated? A. glycogen phosphorylase B. glycogen synthase C. phosphoprotein phosphatase 1 (PP1) D. All of the answers are correct.  Clicker Question 11, Response Which enzyme involved in glycogenesis and glycogenolysis is allosterically regulated? D. All of the answers are correct. In the liver, glucose acts allosterically to make phosphorylase a more susceptible to dephosphorylation/ inactivation by phosphoprotein PP1. Glucose 6-phosphate allosterically activates PP1. Glycogen synthase is inactive unless its allosteric activator, glucose 6-phosphate, is present.  Principle 4 (6 of 7) Regulation of the balance between the formation of glycogen from excess glucose and the release of glucose from glycogen polymers when it is needed in metabolism is a critical function of cellular and organismal homeostasis. This balance, ultimately controlled by the hormones epinephrine, glucagon, and insulin, is achieved through allosteric regulation and phosphorylation of the synthetic and degradative enzymes. These enzymes and the regulatory proteins that act on them are integral parts of the glycogen granule.  Difference in the Regulation of Carbohydrate Metabolism in Muscle skeletal muscle: – uses its stored glycogen only for its own needs – undergoes very large changes in its demand for ATP – lacks the enzymatic machinery for gluconeogenesis  Clicker Question 12 Which point is NOT a major difference between muscle and liver in terms of glucose regulation? A. Muscle uses stored glycogen only for its own needs. B. During exercise, muscle undergoes very large changes in need of ATP. C. Muscle lacks the enzyme machinery for gluconeogenesis. D. Muscle cells lack a receptor for glucagon. E. None of the answers is correct.  Clicker Question 12, Response Which point is NOT a major difference between muscle and liver in terms of glucose regulation? E. None of the answers is correct. The physiology of skeletal muscle differs from that of the liver in three important ways: muscle uses its stored glycogen only for its own needs; as it goes from rest to vigorous contraction, muscle undergoes very large changes in its demand for ATP, which is provided by glycolysis; and muscle lacks the enzymatic machinery for gluconeogenesis. Myocytes also lack receptors for glucagon, which are present on hepatocytes.  Clicker Question 13 Why are muscle and liver glycogen phosphorylase regulated differently? A. Muscle only consumes glucose, and liver both consumes and secretes glucose. B. They are isozymes and are encoded by different genes. C. Muscle and liver have different glucose transporters. D. Muscle has no glycogen phosphorylase a isoform. E. Liver has no glycogen phosphorylase kinase.  Clicker Question 13, Response Why are muscle and liver glycogen phosphorylase regulated differently? A. Muscle only consumes glucose, and liver both consumes and secretes glucose. Regulation serves different ends in muscle and liver. In extrahepatic tissues, typified by skeletal muscle (myocytes), phosphorylase supplies glucose for the tissue’s own needs. Conversely, liver phosphorylase supplies glucose to the blood for use by other tissues.  Principle 4 (7 of 7) Regulation of the balance between the formation of glycogen from excess glucose and the release of glucose from glycogen polymers when it is needed in metabolism is a critical function of cellular and organismal homeostasis. This balance, ultimately controlled by the hormones epinephrine, glucagon, and insulin, is achieved through allosteric regulation and phosphorylation of the synthetic and degradative enzymes. These enzymes and the regulatory proteins that act on them are integral parts of the glycogen granule. Carbohydrate and Lipid Metabolism Are Integrated by Hormonal and Allosteric Mechanisms the metabolism of fats and fatty acids is very closely tied to that of carbohydrates regulatory controls adjust metabolite flow through various metabolic pathways without causing major changes in the concentrations of intermediates shared with other pathways  Clicker Question 14 Strenuous physical activity in vertebrates can cause an increase in AMP levels. What is the biochemical response in carbohydrate metabolism? A. an increase in glycogen synthesis B. inhibition of glycolysis and stimulation of gluconeogenesis C. an increase in protein kinase A activity, mobilizing glucose D. an increase in fatty acid and carbohydrate catabolic pathways E. inhibition of transphosphorylation enzymes  Clicker Question 14, Response Strenuous physical activity in vertebrates can cause an increase in AMP levels. What is the biochemical response in carbohydrate metabolism? D. an increase in fatty acid and carbohydrate catabolic pathways AMP, which accumulates as a result of ATP breakdown, signals metabolic stress. Thus high [AMP] stimulates the catabolism of fatty acids and carbohydrates while inhibiting anabolic pathways such as gluconeogenesis and glycogen synthesis.