Harper's Biochemistry Chapter 18 - Gluconeogenesis & the Control of Blood Glucose.PDF

C H A P T E R Metabolism of Glycogen Owen P. McGuinness, PhD 18 OBJ E C TI VE S Describe the structure of glycogen and its importance as a carbohydrate...

C H A P T E R Metabolism of Glycogen Owen P. McGuinness, PhD 18 OBJ E C TI VE S Describe the structure of glycogen and its importance as a carbohydrate reserve. After studying this chapter, Describe the synthesis and breakdown of glycogen and how the processes are you should be able to: regulated in response to hormone action. Describe the various types of glycogen storage diseases. BIOMEDICAL IMPORTANCE oes not irectly yiel free glucose because muscle lacks glucose-6-phosphatase. During muscle glycogenolysis, pyruvate Glycogen is the major storage carbohyrate in animals, cor- forme by glycolysis in muscle can unergo transamination to responing to starch in plants; it is a branche polymer of alanine or reuce to lactate. They can be exporte from mus- α-d-glucose (see Figure 15–12). It occurs mainly in liver an cle an use for gluconeogenesis in the liver (see Figure 19–4). muscle, with moest amounts in the brain. The concentration After a meal, the replenishment of liver glycogen stores is not (mg glycogen/g liver) of glycogen in the liver is greater than solely ue to the liver irectly taking up glucose an convert- that of muscle. The total muscle mass of the boy is consier- ing it to glycogen. About 50% of the glycogen accretion is from ably greater than that of the liver. Thus, about three-quarters iversion of gluconeogenic carbon (lactate, glucogenic amino of total boy glycogen is in muscle (Table 18–1). acis) into glycogen (calle inirect glycogen synthesis; see Glycogen in liver an muscle has iffering roles in glucose Chapter 19). homeostasis. Liver glycogen functions as a reserve to main- Glycogen storage diseases are a rare (18 h of fasting) liver athletes aapt muscle metabolism to maintain a slower, glycogen is almost totally eplete. Muscle glycogen pro- more sustaine release of glucose-1-phosphate in muscle, vies a reaily available source of glucose-1-phosphate for to preserve muscle glycogen stores an exercise enur- glycolysis within the muscle itself. Muscle glycogen breakown ance. Consuming a iet that supplies ample carbohyrates an energy (calories) to meet or excee aily expeniture (Note: you will not store if you on’t eat aitional calo- This was aapte from the 30th eition by Davi A. Bener, PhD, & ries to match any change in the training regimen) grau- Peter A. Mayes, PhD, DSc ally augments muscle glycogen stores over ays an weeks. 171 172 SECTION IV Metabolism of Carbohydrates TABLE 18–1 Storage of Carbohydrate in a 70-kg Person O CH2OH Percentage HN Uracil O of Tissue Tissue Body OH O O O N Weight Weight Content (g) OH O P O P O CH2 O O Liver glycogen 5.0 1.8 kg 90 OH O– O– Ribose Muscle glycogen 0.7 35 kg 245 Extracellular glucose 0.1 10 L 10 Glucose OH OH Uridine Some enurance athletes practice carbohydrate loading— exercise to exhaustion (when muscle glycogen is very FIGURE 18–2 Uridine diphosphate glucose (UDPGlc). low or largely eplete) followe by a high-carbohyrate meal, which results in rapi glycogen synthesis, with fewer or switching to a low carbohyrate iet (ecreases total gly- branch points than normal an an increase in total stores. cogen stores) in part is ue to water an unfortunately not Carbohyrate ingestion uring exercise prolongs enur- as much fat loss. ance. This is because it helps maintain liver glycogen stores We o have small glycogen stores in brain. This is primar- an may spare muscle glycogen especially in fast twitch ily in astrocytes, non-neuronal cells, that support neighboring muscle cells. For each gram of glycogen there is 3 g of neurons. This may help explain some of the neurologic symp- water. Thus the early rapi weight loss we see when ieting toms seen in some of the glycogen storage iseases. FIGURE 18–1 Pathways of glycogenesis and glycogenolysis in the liver. ( , stimulation; , inhibition.) Insulin decreases the level of cAMP only after it has been raised by glucagon or epinephrine; that is, it antagonizes their action. Glucagon acts on heart muscle but not on skeletal muscle. *Glucan transferase and debranching enzyme appear to be two separate activities of the same enzyme.  CHAPTER 18 Metabolism of Glycogen 173 FIGURE 18–3 The biosynthesis of glycogen. The mechanism of branching as revealed by feeding 14C-labeled glucose and examining liver glycogen at intervals. GLYCOGENESIS OCCURS MAINLY Branching Involves Detachment of IN MUSCLE & LIVER Existing Glycogen Chains When a growing chain is at least 11 glucose resiues long, Glycogen Biosynthesis Involves branching enzyme transfers a part of the 1 → 4 chain UDP-Glucose (at least six glucose resiues) to a neighboring chain to form As in glycolysis, glucose is phosphorylate to glucose-6-phos- a 1 → 6 linkage, establishing a branch point. The branches phate, catalyze by hexokinase in muscle an glucokinase grow by further aitions of 1 → 4-glucosyl units an further in liver (Figure 18–1). Glucose-6-phosphate is isomerize to branching. glucose-1-phosphate by phosphoglucomutase. The enzyme itself is phosphorylate, an the phosphate group takes part in GLYCOGENOLYSIS IS NOT THE a reversible reaction in which glucose 1,6-bisphosphate is an intermeiate. Next, glucose-1-phosphate reacts with uriine tri- REVERSE OF GLYCOGENESIS, phosphate (UTP) to form the active nucleotie uridine diphos- IT IS A SEPARATE PATHWAY phate glucose (UDPGlc) an pyrophosphate (Figure 18–2), Glycogen phosphorylase catalyzes the rate-limiting step in catalyze by UDPGlc pyrophosphorylase. The reaction pro- glycogenolysis—the phosphorolytic cleavage of the 1 → 4 link- cees in the irection of UDPGlc formation because pyrophos- ages of glycogen to yiel glucose-1-phosphate (Figure 18–4). phatase catalyzes hyrolysis of pyrophosphate to 2× phosphate, There are ifferent isoenzymes of glycogen phosphorylase in so removing one of the reaction proucts. UDPGlc pyrophos- phorylase has a low Km for glucose-1-phosphate an is present in relatively large amounts, so that it is not a regulatory step in glycogen synthesis. The initial steps in glycogen synthesis involve the protein glycogenin, a 37-kDa protein that is glucosylate on a specific tyrosine resiue by UDPGlc. Glycogenin catalyzes the trans- fer of a further seven glucose resiues from UDPGlc, in 1 → 4 linkage, to form a glycogen primer that is the substrate for gly- cogen synthase. The glycogenin remains at the core of the glycogen granule (see Figure 15–12). It is believe that the self- glycosylation of glycogen an the oligosaccharie primer that results is require for glycogen synthesis to occur. One genetic report of a efect in this gene (GSD-IV) primarily impairs heart function. Glycogen synthase catalyzes the formation of a gly- cosie bon between C-1 of the glucose of UDPGlc an C-4 of a terminal glucose resiue of glycogen, liberating UDP. The aition of a glucose resiue to a preexisting glycogen chain, or “primer,” occurs at the nonreucing, outer en of the molecule, so that the branches of the glycogen molecule become elongate as successive 1 → 4 linkages are forme (Figure 18–3). FIGURE 18–4 Steps in glycogenolysis. 174 SECTION IV Metabolism of Carbohydrates liver, muscle, an brain, encoe by ifferent genes. Glycogen 1 → 6-glycosie bon to liberate free glucose. Further phos- phosphorylase requires pyrioxal phosphate (see Chapter 44) phorylase action can then procee. The combine action of as its coenzyme. Unlike the reactions of amino aci metab- phosphorylase an these other enzymes leas to the complete olism (see Chapter 28), in which the alehye group of the breakown of glycogen. coenzyme is the reactive group, in phosphorylase the phos- The reaction catalyze by phosphoglucomutase is revers- phate group is catalytically active. ible, so that glucose-1-phosphate erive from hyrolysis of The terminal glucosyl resiues from the outermost chains glycogen can form glucose-6-phosphate. In liver, but not of the glycogen molecule are remove sequentially until muscle, glucose-6-phosphatase catalyzes hyrolysis of approximately four glucose resiues remain on either sie of glucose-6-phosphate, yieling glucose that is exporte, lea- a 1 → 6 branch (see Figure 18–4). The debranching enzyme ing to an increase in the bloo glucose concentration. Glucose- has two catalytic sites in a single polypeptie chain. One is 6-phosphatase is in the lumen of the smooth enoplasmic a glucan transferase that transfers a trisaccharie unit from reticulum, an genetic efects of the glucose-6-phosphate one branch to the other, exposing the 1 → 6 branch point. transporter can cause a variant of type I glycogen storage The other is a 1,6-glycosiase that catalyzes hyrolysis of the isease (Table 18–2). TABLE 18–2 Glycogen Storage Diseases Type Name Enzyme Deficiency Affected Gene Clinical Features 0 0a Glycogen synthase GYS2 Hypoglycemia; hyperketonemia; early death 0b GYS1 I Ia von Gierke disease Glucose-6-phosphatase G6PC Glycogen accumulation in liver and renal tubule cells; hypoglycemia; lactic acidemia; ketosis; hyperlipemia Ib von Gierke Endoplasmic reticulum SLC37A4 glucose-6-phosphate Disease transporter II Pompe disease Lysosomal α1 → 4 and GAA Accumulation of glycogen in lysosomes: juvenile-onset α1 → 6 glucosidase (acid variant, muscle hypotonia, death from heart failure by age 2; maltase) adult-onset variant, muscle dystrophy III Cori/Forbes disease Liver and muscle AGL Fasting hypoglycemia; hepatomegaly in infancy; debranching enzyme accumulation of characteristic branched polysaccharide (Type IIa-b) (limit dextrin); variable muscle weakness IV Amylopectinosis, Glycogen Branching GBE1 Hepatosplenomegaly; accumulation of polysaccharide with Andersen’s disease enzyme few branch points; death from heart or liver failure before age 5 V McArdle disease Muscle phosphorylase PYGM Poor exercise tolerance; muscle glycogen abnormally high (2.5-4%); blood lactate very low after exercise VI Hers disease Liver phosphorylase PYGL Hepatomegaly; accumulation of glycogen in liver; mild hypoglycemia; generally good prognosis VII Tarui disease Muscle and erythrocyte PFKM Poor exercise tolerance; muscle glycogen abnormally high phosphofructokinase 1 (2.5-4%); blood lactate very low after exercise; also hemolytic anemia IX IXa Liver and muscle PHKA2 Hepatomegaly; accumulation of glycogen in liver and phosphorylase kinase muscle; mild hypoglycemia; generally good prognosis IXb PHKB IXc PHKG2 IXd PHKA1 X Muscle phosphoglycerate PGAM2 Hepatomegaly; accumulation of glycogen in liver mutase XI Fanconi-Bickel Glucose transporter 2 SLC2A2 Liver and kidney are affected, weak bones, small for age, renal dysfunction, generally good XII Aldolase A ALDOA Myopathy, exercise intolerance, hemolytic anemia XIII Beta-enolase ENO3 Exercise intolerance and myalgia XV Glycogenin-1 GYG1 Cardiomegaly  CHAPTER 18 Metabolism of Glycogen 175 Glycogen granules can also be engulfe by lysosomes, where aci maltase catalyzes the hyrolysis of glycogen to glucose. This may be especially important in glucose homeo- stasis in neonates. Genetic lack of lysosomal aci maltase causes type II glycogen storage isease (Pompe isease; see Table 18–2). The lysosomal catabolism of glycogen is uner hormonal control. CYCLIC AMP INTEGRATES THE REGULATION OF GLYCOGENOLYSIS & GLYCOGENESIS The principal enzymes controlling glycogen metabolism— glycogen phosphorylase an glycogen synthase—are regulate in opposite irections by allosteric mechanisms, subcellular localization, an covalent moification by reversible phos- phorylation an ephosphorylation of enzyme protein in response to hormone action (see Chapter 9). Phosphorylation of glycogen phosphorylase increases its activity; phosphoryla- tion of glycogen synthase reuces its activity. Phosphorylation is increase in response to cyclic AMP (cAMP) (Figure 18–5) forme from ATP by adenylyl cyclase at the inner surface of cell membranes in response to hor- mones such as epinephrine, norepinephrine, an glucagon. cAMP is hyrolyze by phosphodiesterase, so terminat- ing hormone action; in liver insulin increases the activity of phosphoiesterase. Glycogen Phosphorylase Regulation Is Different in Liver & Muscle In the liver, the role of glycogen is to provie free glucose for export to maintain the bloo concentration of glucose; in FIGURE 18–5 The formation and hydrolysis of cyclic AMP muscle, the role of glycogen is to provie a source of glucose- (3′,5′-adenylic acid, cAMP). 6-phosphate for glycolysis in response to the nee for ATP for muscle contraction. In both tissues, the enzyme is activate by phosphorylation catalyze by phosphorylase kinase (to yiel Liver glycogen is release to control plasma glucose. It has to phosphorylase a) an inactivate by ephosphorylation cata- be fast as glucose emans can change rapily. For example in lyze by phosphoprotein phosphatase (to yiel phosphorylase exercise liver glucose prouction increases twofol within a b), in response to hormonal an other signals. few minutes of exercise. Glucose levels woul fall if there was a There is instantaneous overriing of this hormonal con- elay. If exogenous glucose is given the liver must rapily stop trol. Active phosphorylase a in both tissues is allosterically making glucose an become a glucose consumer to prevent inhibite by ATP an glucose-6-phosphate; in liver, but not hyperglycemia an maximize glycogen repletion. In muscle, muscle, free glucose is also an inhibitor. Muscle phosphorylase glycogen is use by the contracting muscle an thus it woul iffers from the liver isoenzyme in having a bining site for 5′ be very sensitive to the energy state of the muscle (5′ AMP as AMP (see Figure 18–5), which acts as an allosteric activator well as calcium). of the (inactive) ephosphorylate b-form of the enzyme. 5′ AMP acts as a potent signal of the energy state of the mus- cle cell; it is forme as the concentration of ADP begins to cAMP ACTIVATES GLYCOGEN increase (inicating the nee for increase substrate metabo- lism to permit ATP formation), as a result of the reaction of PHOSPHORYLASE aenylate kinase: 2 × ADP ↔ ATP + 5′ AMP. The iffering Phosphorylase kinase is activate in response to cAMP regulation of muscle an liver glycogen phosphorylase likely (Figure 18–6). Increasing the concentration of cAMP acti- reflects the iffering roles of glycogen in liver an muscle. vates cAMP-dependent protein kinase, which catalyzes 176 FIGURE 18–6 Control of glycogen phosphorylase in muscle. The sequence of reactions arranged as a cascade allows amplification of the hormonal signal at each step. (G6P, glucose- 6-phosphate; n, number of glucose residues.)  CHAPTER 18 Metabolism of Glycogen 177 the phosphorylation by ATP of inactive phosphorylase The Activities of Glycogen Synthase kinase b to active phosphorylase kinase a, which in turn, phosphorylates phosphorylase b to phosphorylase a. In the & Phosphorylase Are Reciprocally liver, cAMP is forme in response to glucagon, which is Regulated secrete in response to falling bloo glucose (or exercise). There are ifferent isoenzymes of glycogen synthase in liver, Muscle is insensitive to glucagon; in muscle, the signal for muscle, an brain. Like phosphorylase, glycogen synthase exists increase cAMP formation is the action of epinephrine, in both phosphorylate an nonphosphorylate states, an the which is secrete in response to fear or fright, when there is effect of phosphorylation is the reverse of that seen in phos- a nee for increase glycogenolysis to permit rapi muscle phorylase (Figure 18–7). Active glycogen synthase a is ephos- activity. phorylate an inactive glycogen synthase b is phosphorylate. Six ifferent protein kinases act on glycogen synthase, an there are at least nine ifferent serine resiues in the enzyme Ca2+ Synchronizes the Activation of that can be phosphorylate. Two of the protein kinases are Ca2+/ Glycogen Phosphorylase With Muscle calmoulin epenent (one of these is phosphorylase kinase). Contraction Another kinase is cAMP-epenent protein kinase, which Glycogenolysis in muscle increases several 100-fol at the allows cAMP-meiate hormone action to inhibit glycogen onset of contraction; the same signal (increase cytosolic Ca2+ synthesis synchronously with the activation of glycogenolysis. ion concentration) is responsible for initiation of both con- Insulin also promotes glycogenesis in muscle at the same time traction an glycogenolysis. Muscle phosphorylase kinase, as inhibiting glycogenolysis by raising glucose-6-phosphate which activates glycogen phosphorylase, is a tetramer of four concentrations, which stimulates the ephosphorylation an ifferent subunits, α, β, γ, an δ. The α an β subunits contain activation of glycogen synthase. Dephosphorylation of glyco- serine resiues that are phosphorylate by cAMP-epenent gen synthase b is carrie out by protein phosphatase-1, which protein kinase. The δ subunit is ientical to the Ca2+-bining is uner the control of cAMP-epenent protein kinase. protein calmodulin (see Chapter 42) an bins four Ca2+. The bining of Ca2+ activates the catalytic site of the γ subunit GLYCOGEN METABOLISM IS even while the enzyme is in the ephosphorylate b state; the phosphorylate a form is only fully activate in the presence REGULATED BY A BALANCE IN of high concentrations of Ca2+. ACTIVITIES BETWEEN GLYCOGEN SYNTHASE & PHOSPHORYLASE Glycogenolysis in Liver Can Be At the same time, as phosphorylase is activate by a rise in concentration of cAMP (via phosphorylase kinase), glycogen cAMP-Independent synthase is converte to the inactive form; both effects are In the liver, there is cAMP-inepenent activation of glyco- meiate via cAMP-dependent protein kinase (Figure 18–8). genolysis in response to stimulation of α1 adrenergic recep- Thus, inhibition of glycogenolysis enhances net glycogenesis, tors by norepinephrine (in humans the number of α1 receptors an inhibition of glycogenesis enhances net glycogenolysis. is low). This involves mobilization of Ca2+ into the cytosol, Also, the ephosphorylation of phosphorylase a, phosphory- followe by the stimulation of a Ca2+/calmodulin-sensitive lase kinase, an glycogen synthase b is catalyze by a single phosphorylase kinase. cAMP-inepenent glycogenolysis is enzyme with broa specificity—protein phosphatase-1. In also activate by vasopressin, oxytocin, an angiotensin II acting turn, protein phosphatase-1 is inhibite by cAMP-epenent either through calcium or the phosphatiylinositol bisphosphate protein kinase via inhibitor-1. Insulin ability to inhibit glyco- pathway (see Figure 42–10). genolysis is via its ability to increase protein phosphatase-1 an lower cAMP. Thus, glycogenolysis can be terminate an glycogenesis can be stimulate, or vice versa, synchronously, Protein Phosphatase-1 Inactivates because both processes are epenent on the activity of cAMP- Glycogen Phosphorylase epenent protein kinase an the availability of cAMP. Both Both phosphorylase a an phosphorylase kinase a are ephos- phosphorylase kinase an glycogen synthase may be revers- phorylate an inactivate by protein phosphatase-1. Pro- ibly phosphorylate at more than one site by separate kinases tein phosphatase-1 is inhibite by a protein, inhibitor-1, an phosphatases. These seconary phosphorylations moify which is active only after it has been phosphorylate by the sensitivity of the primary sites to phosphorylation an cAMP-epenent protein kinase. Thus, cAMP controls ephosphorylation (multisite phosphorylation). They allow both the activation an inactivation of phosphorylase (see increases in glucose an insulin by way of increase glucose- Figure 18–6). Insulin reinforces this effect by inhibiting 6-phosphate (seconarily to an increase in plasma glucose that the activation of phosphorylase b. It oes this inirectly by activates glucokinase by translocating it from the nucleus to the increasing uptake of glucose, leaing to increase formation glycogen granule in the liver), to have effects that act to amplify of glucose-6-phosphate, which is an inhibitor of phosphory- the effects of insulin to attenuate glycogen mobilization or aug- lase kinase. ment glycogen synthesis (see Figures 18–6 an 18–7). 178 SECTION IV Metabolism of Carbohydrates FIGURE 18–7 Control of glycogen synthase in muscle. (G6P, glucose-6-phosphate; GSK, glycogen synthase kinase; n, number of glucose residues.) The ability to rapily fine tune hepatic glycogen metabo- occur. Many iniviuals with long-staning iabetes evelop lism is critical as a failure to rapily increase hepatic glucose an unawareness of hypoglycemia. Nonsevere hypoglycemia prouction in response to an increase in glucose eman events usually generate autonomic an/or neuroglycopenic (ie, exercise) will cause hypoglycemia. It can cause eath if severe symptoms, which enable the iniviual to ientify the onset, enough, an even moerate hypoglycemia will prematurely an to treat the falling bloo glucose without requiring assis- terminate exercise. Gluconeogenesis is a slower process an tance as it is occurring. If they are unaware the hypoglycemia requires a rise in gluconeogenic substrate supply that helps to will get severe enough it will impair their ability to function sustain glucose prouction uring sustaine exercise. In fact, an will nee external assistance. One of the rescue meicines, in moerate intensity exercise glucose barely changes because if the person is unconscious or unable to swallow an ingest a of the tight coupling between liver glycogenolysis, gluconeo- fast-acting (high glycemic inex; see Chapter 15) carbohyrate, genesis, an muscle glucose eman. This occurs because of is glucagon. Glucagon is rapi in onset an is a potent stimulator a rise in glucagon an fall in insulin that rives liver glucose of glycogenolysis. prouction (remember uring exercise glucose uptake in muscle goes up inepenent of insulin, so even though insulin Glycogen Storage Diseases is falling glucose uptake in exercising muscle increases). Are Inherited Glycogen storage isease is a generic term to escribe a group CLINICAL ASPECTS of inherite isorers characterize by eposition of an abnormal type or quantity of glycogen in tissues, or failure to Hypoglycemia & Diabetes mobilize glycogen. The principal iseases are summarize in In iniviuals’ with iabetes the treatments are esigne to Table 18–2. Glycogen storage iseases are heterogenous an bring fasting glucose an meal glucose concentration into the rare. They preominantly affect liver, muscles, heart, an in normal range to minimize the long-term complications of ia- rare instance brain from infancy to aulthoo. Clinical suspicions betes. However, espite the best intentions hypoglycemia can can lea to iagnosis in primary care an in-patient setting.  CHAPTER 18 Metabolism of Glycogen 179 FIGURE 18–8 Coordinated control of glycogenolysis and glycogenesis by cAMP-dependent protein kinase. The reactions that lead to glycogenolysis as a result of an increase in cAMP concentrations are shown with bold arrows, and those that are inhibited by activation of protein phosphatase-1 are shown with dashed arrows. The reverse occurs when cAMP concentrations decrease as a result of phosphodiesterase activity, leading to glycogenesis. Newborn genetic screening is key to etecting glycogen stor- Cyclic AMP integrates the regulation of glycogenolysis an age isease. Many of the meical crises are preventable with glycogenesis by promoting the simultaneous activation of simple nutritional measures. They can limit growth retara- phosphorylase an inhibition of glycogen synthase. Insulin tion an intellectual isability. acts reciprocally by inhibiting glycogenolysis an stimulating glycogenesis. Inherite eficiencies of enzymes of glycogen metabolism in SUMMARY both liver, muscle, an brain cause glycogen storage iseases. Glycogen represents the principal storage carbohyrate in the boy, mainly in the liver an muscle. In the liver, its major function is to provie glucose for REFERENCES extrahepatic tissues. In muscle, it serves mainly as a source Ellingwoo SS, Cheng A. Biochemical an clinical aspects of of metabolic fuel for use in muscle. Muscle lacks glucose-6- glycogen storage iseases. J Enocrinol 2018;238(3):R131-R141. phosphatase an cannot release free glucose from glycogen. Doi:10.1530/JOE-18-0120. Glycogen is synthesize from glucose by the pathway of Murray B, Rosenbloom C. Funamentals of glycogen metabolism glycogenesis. It is broken own by a separate pathway, for coaches an athletes. Nutr Rev 2018;76(4):243-259. https:// glycogenolysis. www.ncbi.nlm.nih.gov/pmc/articles/PMC6019055/