Skip to Main contentScienceDirectJournals BooksRegisterSign in Sign inRegisterJournals BooksHelpGlycogen PhosphorylaseGlycogen phosphorylase (GP) is an important therapeutic target for type 2 diabetes having a direct influence on blood glucose levels through the glycogenolysis pathway.From: Discovery and Development of Antidiabetic Agents from Natural Products, 2017Related terms:GlycogenGluconeogenesisGlycogenolysisPhosphorylasePhosphoproteinGlycogen SynthaseNested GeneView all TopicsDownload as PDFSet alertAbout this pageComputer-Aided Discovery of Glycogen Phosphorylase Inhibitors Exploiting Natural ProductsJoseph M. Hayes, in Discovery and Development of Antidiabetic Agents from Natural Products, 2017AbstractGlycogen phosphorylase (GP) is an important therapeutic target for type 2 diabetes having a direct influence on blood glucose levels through the glycogenolysis pathway. GP is an allosteric enzyme and with seven different binding sites discovered to date, there are multiple opportunities for modulation of its activity. Considerable efforts toward the design of drug-like GP inhibitors have taken place in recent years. Many of these inhibitors are natural products and their analogues. Focusing mainly on recent studies, this chapter will present the role that different in silico methods have played in their discovery.View chapterPurchase bookRead full chapterURL: https://www.sciencedirect.com/science/article/pii/B9780128094501000028Metabolic Pathways in the Human BodyTsugikazu Komoda, Toshiyuki Matsunaga, in Biochemistry for Medical Professionals, 2015Glycogen DegradationGlycogen phosphorylase acts on the reaction at the initiation of glycogen degradation (Figure 4.5). Thereby, glucose can be obtained from glycogen. Glycogen phosphorylase causes phosphoroclastic cleavage into glycogen, and produces glycogen-1-phosphate. However, a non-reducing terminal is removed when cleaving glucose from glycogen. Moreover, if glucose-1-phosphate produced from glycogen is changed into G6P by phosphoglucomutase, it can proceed directly to glycolysis. It should be mentioned that the direct progress to glycolysis leads to the exclusion of ATP consumption required for converting glucose to G6P. Therefore, three ATPs are made if the glucose generated from glycogen is used by glycolysis. The glycogen metabolism is controlled by the activity of glycogen synthase and glycogen phosphorylase. The major regulatory feature involved in the metabolism is phosphorylation, which inactivates glycogen synthase and activates glycogen phosphorylase.Figure 4.5. Glycogen hydrolysis by glycogen phosphorylase and glycogen debranching enzyme.View chapterPurchase bookRead full chapterURL: https://www.sciencedirect.com/science/article/pii/B9780128019184000049Introduction to Glycoscience; Synthesis of CarbohydratesM. Bols, ... F. Ortega-Caballero, in Comprehensive Glycoscience, 20071.21.1.2.2 GP inhibitorsGP is the main regulatory enzyme in the liver, being responsible for the control of blood glucose level, and for that reason it is considered as a new target for the treatment of diabetes type 2.15 One of the approaches to modulate the action of GP is the use of glucose derivatives as inhibitors.16 Molecular design, organic synthesis, protein crystallography, and biological assays led to glucopyranosylidene-spiro-hydantoin (15, Ki = 3.4 μM) as an efficient GP inhibitor.17,17a Modification of 15 allowed the preparation of N-acyl-N′-β-d-glucopyranosyl urea derivative 16 (Ki = 0.4 μM) as one of the best glucose analog inhibitors to date.18 Iminosugars such as isofagomine (17, IC50 = 0.7 μM), azafagomine (18, IC50 = 0.7 μM), and the recently prepared noeuromycin (19, IC50 = 4 μM) were found to inhibit GP (N. G. Oikonomakos, M. Kosmopoulou, D. D. Leonidas, E. D. Chrysina, and M. Bols, unpublished results);19 however, N-substitution could not improve the binding.19,20 Natural five-membered ring iminosugar 1,4-dideoxy-1,4-imino-arabinitol (DAB, 20) shows strong inhibition of GP with Ki values in the nanomolar range (Figure 3).21Figure 3. Azasugars and other glycosidase inhibitors.View chapterPurchase bookRead full chapterURL: https://www.sciencedirect.com/science/article/pii/B9780444519672001008Vitamin B6: PhysiologyD.A. Bender, in Encyclopedia of Human Nutrition (Third Edition), 2013The Role of Pyridoxal Phosphate in Glycogen PhosphorylaseGlycogen phosphorylase catalyzes the sequential phosphorolysis of glycogen to release glucose-1-phosphate; it is thus the key enzyme in the utilization of muscle and liver reserves of glycogen.Unlike other pyridoxal phosphate-dependent enzymes, in which the carbonyl group is essential for catalysis, the internal Schiff base between pyridoxal phosphate and lysine in glycogen phosphorylase is not broken during the reaction. The catalytic region of the coenzyme is the 5 -phosphate group. The initial stage in the phosphorolysis of glycogen is protonation of the glycosidic oxygen of the polysaccharide by inorganic phosphate. The resultant oxycarbonium ion is stabilized by the inorganic phosphate. The role played by pyridoxal phosphate is that of a proton shuttle or buffer to stabilize the oxycarbonium–phosphate ion pair, allowing covalent binding of the phosphate to the oxycarbonium ion, to form glucose-1-phosphate.View chapterPurchase bookRead full chapterURL: https://www.sciencedirect.com/science/article/pii/B9780123750839002750Carbohydrate BioengineeringP. Drueckes, ... R. Schinzel, in Progress in Biotechnology, 19951 INTRODUCTIONGlycogen phosphorylases (EC 2.4.1.1) are key enzymes of the carbohydrate metabolism. They catalyse the phosphorolytic cleavage of α-1,4-linked glucose units to produce α-D-glucose 1- phosphate:glucosen+Pi↔glucosen−1+glucose1‐phosphateIn muscle glucose 1-phosphate is further metabolised via glycolysis to provide energy, and in liver phosphorylase helps to maintain a constant blood glucose level via the action of glucose 6-phosphatase [4]. Therefore, suppression of glucose output from the liver may be achieved by inhibition of glycogen phosphorylase. Such inhibitors may be of use for therapy of the non-insulin dependent form of diabetes (NIDDM or Type II diabetes). One class of phosphorylase inhibitors consists of glucose analogs which stabilise the inactive T-form of the enzyme. Since there are only weak physiological inhibitors known, a variety of glucose compounds with better inhibitory properties were designed, synthesised and tested by L. Johnson, G. Fleet, N. Oikonomakos and coworkers [13, 23].An alternate way to look for potent inhibitors other than glucose compounds would be to design analogs derived from the oligosaccharide substrate.However, present knowledge about substrate binding sites of glucosyl residues in phosphorylases is still incomplete. From x-ray crystallography, molecular recognition and site directed mutagenesis studies the binding of glucose 1-phosphate and its derivatives in ground state and transition state is well characterised [20, 21, 3, 12]. Substantially less is known about productive binding of the polysaccharide awaiting degradation. So far no binding of oligosaccharides at the active site of rabbit muscle glycogen phosphorylase has been observed in crystals [18, 12], although there is at least gross structural information on a second carbohydrate binding site responsible for the attachment of carbohydrates to glycogen particles, the glycogen storage site [9, 12].From kinetic studies with branched and linear oligosaccharides French and coworkers [7, 8] suggested a five glucose unit binding site, four subsites for the primer and one for the glucose moiety (Fig. 1). This subsite concept is comparable to that described for other oligosaccharide degrading enzymes [11, 16]. However, glycogen phosphorylases differ from those enzymes:Figure 1. Schematic drawing of the substrate binding site of maltodextrin phosphorylase. Subsites 5-2 are the primer subsites.First, in the reaction of phosphorylase a glucosyl residue is transferred to a phosphate group rather than to a water molecule. Consequently the exclusion of water from the active site is of essence for the phosphorylase reaction. Indeed, mutations of active site residues cause an increase of the remarkably low error rate, eg release of glucose rather than glucose 1-phosphate [15].Further, the phosphorolytic cleavage of oligosaccharides is freely reversible. At equilibrium (Keq = Pi/Glc-1-P = 3.6 at pH 6.8) synthesis is favoured. In the cell the physiological role of phosphorylase is the energy conserving mobilisation of storage polysaccharides through phosphorolysis due to the relatively high phosphate concentration in the cell.The work presented here is aimed at mapping the oligosaccharide binding site by a combination of a kinetic studies with linear oligosaccharides of increasing length and site-directed mutagenesis. The E. coli maltodextrin phosphorylase is used as a model system, since this enzyme binds short linear oligosaccharides better than glycogen phosphorylase. In addition, the bacterial enzyme lacks the glycogen storage site, which makes determination of kinetic parameters less complicatedView chapterPurchase bookRead full chapterURL: https://www.sciencedirect.com/science/article/pii/S0921042306800936TransferasesJOHN ESBEN KIRK, in Enzymes of the Arterial Wall, 1969HUMAN VASCULAR TISSUEAnalytical ProcedureGlycogen phosphorylase activities exhibited by various types of human vascular tissue have been measured by the present author (Kirk, 1962, 1963, 1964, supplementary). In these studies the assays were made on freshly prepared 10% aqueous tissue homogenates by a macromodification of the procedure described by Buell et al. (1958). Glucose-1-phosphate was used as substrate for the enzyme, and the amount of orthophosphate liberated was measured colorimetrically. Since AMP was consistently added to the substrate medium, this assured the determination of the total glycogen phosphorylase activity, including both the active (phosphorylase a) and inactive (phosphorylase b) form of the enzyme. All employed glassware had been cleaned with warm hydrochloric acid and rinsed with glass-distilled water.The final millimolar concentrations used (total volume, 6.0 ml) were: glucose-1-phosphate, 30.0; sodium fluoride, 50.0; adenosine-5-monophosphate, 1.0; and cysteine hydrochloride, 15.0; the glycogen concentration was 0.5%. The pH s of the glucose-1-phosphate and cysteine hydrochloride solutions were adjusted to 6.7, the glucose-1-phosphate substrate serving as buffer in the enzyme reaction. The glucose-1-phosphate solution was stored in a deep freeze between use; the cysteine hydrochloride solution was prepared fresh daily. An amount of homogenate corresponding to 100 mg of fresh tissue was used for each activity determination. A tissue test without addition of glucose-1-phosphate was run with each sample and a reagent blank with each set of analyses. The control tissue tests showed only minimal release of inorganic phosphate from other sources.The substrate solution was preheated for 5 minutes at 38°C before the addition of the tissue homogenate. The samples were subsequently incubated for 30 minutes at 38°C in a water bath provided with a shaking mechanism, and 1.0 ml aliquots of the incubation mixture were removed at 0, 15, and 30 minutes. Each aliquot was added to 1.0 ml of 10% trichloroacetic acid contained in a test tube placed in ice water; after centrifugation of the tube for 5 minutes, 1.0 ml of the resulting supernatant was pipetted off for colorimetric determination of the inorganic phosphate content of the sample.The reagent solution for the assay of inorganic phosphate was prepared fresh daily as described by Buell et al. (1958). The phosphate determination was made by adding 1.0 ml of the supernatant sample to 5.0 ml of reagent solution; the color intensity developed after 10 minutes was measured at 570 mµ using a Beckman DU spectrophotometer. The observed millimolar extinction coefficient at this wavelength was 2592. The corresponding value at 700 mµ was 4200; this is in good agreement with the molar extinction coefficient of 4000 reported by Buell and associates who used readings at 700 mµ for determination of phosphate in their microprocedure.The reaction curves for the tissue tests were found to be linear over a period of at least 45 minutes under the experimental conditions, indicating enzyme kinetics of zero order type; a close relationship was observed between the quantities of tissue used and the recorded enzyme activities over a 40–200 mg tissue range. The amount of glucose-1-phosphate metabolized in the tests rarely exceeded 3% of the quantity present in the incubation mixture.ResultsThe average glycogen phosphorylase activities observed for various types of blood vessels are listed in Table II-9. Higher activities were found for pulmonary artery than aortic samples from the same subjects (Table II-10), and greater levels were also displayed by the brachial artery and inferior vena cava. For comparative purposes glycogen phosphorylase measurements were made on 10 samples of human pectoral muscle, using only 10 mg of tissue in these assays. The average enzyme value for the human striated muscular specimens was 3.154 mmoles of phosphate liberated/gm wet tissue/hour; this activity was 51.2 times higher than that exhibited by aortic samples from the same individuals.TABLE II-9. MEAN GLYCOGEN PHOSPHORYLASE ACTIVITIES OF HUMAN VASCULAR TISSUEaAge group (years)Wet tissueTissue nitrogenVascular sampleNo.Means.d. distr.Means.d. distr.ReferenceAorta, normalb0–970.11240.03342.5930.856Kirk, 1962, and10–1930.1330–3.503–supplementary20–2950.09220.04232.2981.00030–3980.10560.03142.7010.85040–49170.10170.04942.9121.52650–59300.08410.03582.4401.05860–69210.05980.03661.7941.12670–8970.07140.03082.0400.874Mean values0–89980.08670.04372.4251.10920–89880.08310.04322.3631.104Aorta, lipid-arterioscleroticb30–3920.0830–2.631–Kirk, 1962, and40–4940.11003.245–supplementary50–59110.06990.02182.1150.79660–6940.0393–1.383–70–8930.0495–1.673–Mean values30–89240.06980.03342.1731.097Aorta, fibrous-30–3920.0570–1.605–Kirk, 1962, and supplementaryarterioscleroticb40–4930.0203–0.580–50–5960.03530.01091.2700.53960–69140.02710.01730.9310.61670–8940.0292–0.963–Mean values30–89290.03030.01881.0160.662Pulmonary artery0–930.2093–4.630–Kirk, 1962, and supplementary10–1920.1685–4.410–20–2920.1370–4.081–30–3970.13300.04684.1921.63740–49160.12740.07823.7832.23450–59210.12590.05343.8601.66560–69170.12040.05923.9882.38170–8970.12860.05164.1811.853Mean values0–89750.13070.05883.9841.85220–89700.12660.05893.9441.897Coronary artery,0–910.1330–3.923–Kirk, 1962, 1963, and supplementarynormal10–1910.1348–4.271–20–2930.1327–4.217–30–3970.10140.04213.5441.41640–4960.06930.03462.7771.46250–5940.0670–2.368–60–7980.04200.01561.5940.530Mean values0–79300.07980.04412.8521.49320–79280.07590.04382.7611.513Coronary artery, lipid-arteriosclerotic40–69100.03060.01701.1270.458Kirk, 1962, 1963, and supplementaryBrachial artery, normal20–79120.09860.04242.8151.119Kirk, 1963Vena cava inferior20–2940.1312–4.218–Kirk, 1964, and supplementary30–3960.10980.04632.8451.02740–4970.11490.08483.2732.44050–79100.11800.08323.1522.098Mean values20–79270.11730.07243.2732.144Brachial vein6010.0566–1.595–Kirk, supplementaryaValues expressed as millimoles of inorganic phosphate liberated per gram wet tissue and per gram tissue nitrogen per hour.bThoracic descending aorta.TABLE II-10. MEAN GLYCOGEN PHOSPHORYLASE ACTIVITIES OF PULMONARY ARTERY, NORMAL CORONARY ARTERY, BRACHIAL ARTERY, AND VENA CAVA INFERIOR SAMPLES EXPRESSED IN PERCENT OF ACTIVITIES OF NORMAL AORTIC TISSUE FROM THE SAME SUBJECTSAge group (years)Wet tissueTissue nitrogenVascular sampleNo.%t of diff.%t of diff.Pulmonary arterya0–195151.73.94198.22.9020–4925137.64.27150.55.1250–8945167.36.69184.28.30Mean values0–8975154.78.88172.410.18Coronary artery, normala0–793085.80.98126.52.16Brachial artery, normalb30–7910128.82.04133.22.20Vena cava inferiorc20–7926116.01.40146.22.38aFrom Kirk, 1962, and supplementary.bFrom Kirk, 1963.cFrom Kirk, 1964, and supplementary.A tendency was noted for the glycogen phosphorylase activity to decrease with age in aortic and coronary artery tissue, whereas no significant changes with aging were found for the pulmonary artery or inferior vena cava (Table II-11).TABLE II-11. COEFFICIENTS OF CORRELATION BETWEEN AGE AND GLYCOGEN PHOSPHORYLASE ACTIVITYAge group (years)Wet tissueTissue nitrogenVascular sampleNo.rtrtAorta, normala,b0–8998-0.313.30-0.262.7520–8988-0.353.47-0.252.40Aorta, lipid-arteriosclerotica,b30–8924-0.402.06-0.502.72Aorta, fibrous-arteriosclerotica,b30–8929-0.271.46-0.180.98Pulmonary arteryb0–8975-0.141.21-0.020.1720–8970-0.110.910.000.00Coronary artery, normalc0–7930-0.786.56-0.624.1520–7928-0.624.22-0.644.25Vena cava inferiord20–79270.000.00-0.080.40aThoracic descending aorta.bFrom Kirk, 1962, and supplementary.cFrom Kirk, 1962, 1963, and supplementary.dFrom Kirk, 1964, and supplementary.The results of comparing the enzyme activities of arteriosclerotic and normal tissue portions of the same aortic samples are presented in Table II-12. The statistical analysis of the data revealed significantly lower activities of the arteriosclerotic than of the normal tissue portions, both when calculated on the basis of wet tissue weight and tissue nitrogen content. In 98% of the cases the arteriosclerotic aortic tissue showed lower glycogen phosphorylase activity than that exhibited by the normal tissue. A rather conspicuous finding was a mean activity of the fibrous-arteriosclerotic samples which was only 50.5% (wet tissue) of that of the normal arterial sections.TABLE II-12. MEAN GLYCOGEN PHOSPHORYLASE ACTIVITIES OF ARTERIOSCLEROTIC TISSUE EXPRESSED IN PERCENT OF ACTIVITIES OF NORMAL TISSUE PORTIONS FROM THE SAME ARTERIAL SAMPLESAAge group (years)Wet tissueTissue nitrogenVascular sampleNo.%t of diff.%t of diff.Aorta, lipid-arterioscleroticb30–49666.24.7469.15.4050–591162.05.3268.03.7860–89757.02.5566.91.59Mean values30–892462.57.3568.25.30Aorta, fibrous-arteriosclerotica30–49541.74.0245.72.8550–59666.22.6581.81.1060–891849.16.6453.54.67Mean values30–892950.56.8557.85.26aFrom Kirk, 1962, and supplementary.bThoracic descending aorta.The decrease with age in the glycogen phosphorylase activity of the aorta and coronary artery and the markedly lower enzyme values recorded for arteriosclerotic than for normal aortic tissue portions probably reflect changes in the smooth muscle of the vessel wall in connection with aging and arteriosclerosis.View chapterPurchase bookRead full chapterURL: https://www.sciencedirect.com/science/article/pii/B9781483231778500070Glycogen Storage DiseaseDavid A. Weinstein, Joseph I. Wolfsdorf, in Encyclopedia of Gastroenterology, 2004DiagnosisGlycogen phosphorylase deficiency can be diagnosed by assaying activity of the enzyme in leukocytes and erythrocytes. A definitive diagnosis requires demonstration of the enzyme defect in a liver biopsy. Phosphorylase b kinase can also be assayed in leukocytes and erythrocytes. Because the enzyme has several isoenzymes, the diagnosis can be missed without studies of liver and muscle. Definitive diagnosis of phosphorylase b kinase deficiency, therefore, requires demonstration of the enzyme defect in affected tissues. Subtyping of the disease requires molecular genetic analyses. Mutation analysis is likely to become the standard method for diagnosing both GSDVI and the X-linked variant of GSDIX. It is unlikely, however, to be able to rule-out all forms of GSDIX, because multiple genes are involved in synthesizing the phosphorylase kinase protein.View chapterPurchase bookRead full chapterURL: https://www.sciencedirect.com/science/article/pii/B0123868602003403THE ROLE OF PROTEIN PHOSPHORYLATION IN THE COORDINATED CONTROL OF INTERMEDIARY METABOLISMP. Cohen, ... S. Shenolikar, in From Gene to Protein: Information Transfer in Normal and Abnormal Cells, 1979I PROTEIN PHOSPHORYLATION AS A REGULATORY DEVICEGlycogen phosphorylase was the first enzyme whose activity was shown to be regulated by a phosphorylation-dephosphorylation mechanism (1), and two other enzymes involved in glycogen metabolism, phosphorylase kinase (2) and glycogen synthase (3), were the second and third recorded examples of this phenomenon. Over the past few years, however, the number of proteins whose activities have been shown to be regulated in this manner has increased dramatically (4), and it seems likely that protein phosphorylation is the major general mechanism by which metabolic events in eukaryotic cells are controlled by external physiological stimuli.In the first part of this article, recent progress in understanding the regulation of glycogen metabolism in skeletal muscle by phosphorylation-dephosphorylation will be summarized. In the second part, evidence will be presented that several of the proteins in glycogen metabolism are also involved in the regulation of other metabolic processes. These findings have raised the exciting possibility that there are a relatively simple network of regulatory pathways which allow the activities of diverse but functionally related cellular processes to be controlled in a synchronous manner.View chapterPurchase bookRead full chapterURL: https://www.sciencedirect.com/science/article/pii/B9780126044508500298GLYCOGENM.H.M. Rocha Leão, in Encyclopedia of Food Sciences and Nutrition (Second Edition), 2003Biosynthesis and DegradationGlycogen phosphorylase is a dimmer catalyzing the first and controlled step in glycogen degradation generating glucose 1-phosphate. The cyclic adenosine monophosphate (cAMP) cascade action yields the active form of glycogen phosphorylase a, which has a phosphoryl group linked to Ser14 in each subunit. The less active form, which is phosphorylase b, is dephosphorylated. Both forms are finely regulated. They contain the vitamin B6 derivative pyridoxal-5-phosphate, covalently linked, which is required for their activities. The glucose 1-phosphate is converted by phosphoglucomutase to a glucose 1,6-bisphosphate intermediary which is an important enzyme regulator occurring in vivo at low concentration to maintain phosphoglucomutase fully active. To debranch the glycogen, two catalytic sites in debranching enzyme for both transferase and alpha (1→6)-glucosidase are required, increasing enzyme efficiency. Although the reaction catalyzed by glycogen phosphorylase is reversible, under physiological conditions glycogen breakdown is a thermodynamically favorable process. Consequently, glycogen biosynthesis and degradation must occur by two separate pathways. This strategy has two advantages: biosynthesis and degradation may occur at the same time and each pathway may be independently regulated. Since under physiological conditions the glycogen biosynthesis from glucose 1-phosphate to glycogen is an unfavorable process, the glycogen biosynthesis needs an exergonic step. So, glucose 1-phosphate reacts with uridine triphosphate (UTP) to form uridine diphosphate glucose (UDPG) via UDPG pyrophosphorylase catalysis. This reaction produces pyrophosphate (PPi) which is hydrolyzed in a thermodynamically highly favorable reaction catalyzed by pyrophosphatase. Both free energy of PPi and free energy of UTP are utilized to drive the glycogen biosynthesis pathway entropically. Glycogen synthase can only act on preexisting alpha (1→4)-linked glucose residues chain. So, the first step in glycogen biosynthesis is the attachment of glucose residue from UDPG to the Tyr group of an autocatalytic enzyme named glycogenin. Sequentially, the autocatalytical glycogenin extends the glucan chain by six or seven alpha-1,4-linked glucose residues, again derived from UDPG. Note that glycogenin is a glucosyl transferase enzyme and serves as an initiator for glycogen biosynthesis. The latter shows that glycogenin has a structural role in glycogen molecule and its biogenesis. Glycogen synthase associates with branching enzyme, elongating the glucan chain and building the glycogen molecule on to the protein backbone. The branching enzyme amylo-(1,4→1,6) transglycosilase breaks segments of at least 11 glucose residues of the linear chain (alpha-amylose), transferring to the C6-OH groups to the same or another chain.View chapterPurchase bookRead full chapterURL: https://www.sciencedirect.com/science/article/pii/B012227055X005630Animal Models of Human DiseaseH. Orhan Akman, ... William J. Craigen, in Progress in Molecular Biology and Translational Science, 2011A Glycogen Phosphorylase Deficiency (GSDV and VI)Glycogen phosphorylase (PYGM or PYGL) (EC 2.4.1.1) catalyzes the breakdown of glycogen to glucose-1-phosphate, providing the main source of glucose to the cell during fasting. There are three isoforms: muscle (PYGM), liver (PYGL), and brain (PYGB). During embryonic development, the brain isoform is expressed in all tissues. After tissue differentiation, the muscle and liver isoforms are expressed. Deficiency of PYGM causes McArdle disease, an autosomal recessive disorder that typically becomes clinically apparently in teens and young adults with symptoms of exercise intolerance and myoglobinuria, in particular during brief high-intensity exercise when glycogen breakdown provides the majority of energy in skeletal muscle. Recurrent episodes of myalgia and myoglobinuria associated with elevated CK are the norm and can progress to fixed muscle weakness in adulthood. Affected individuals often exhibit a \"second wind” phenomenon, where muscle fatigue can improve with continued exercise as muscle energy switches from glycogenolysis to fatty acid oxidation.A naturally occurring ovine model of McArdle disease was identified in a flock of sheep in Western Australia. The mutation occurs in the 3′ splice acceptor site of intron 19 of the PYGM gene, resulting in the activation of a cryptic splice-site site in exon 20 and the premature termination of the transcript.23 Affected animals display exercise intolerance, and histological examination of muscle revealed excess subsarcolemmal storage of glycogen and absent phosphorylase activity, as observed in McArdle patients.The second model has been described in Charolais cattle. Affected cattle are asymptomatic at rest, but when forced to exercise they collapse repeatedly. Much like McArdle patients, after a brief rest, the cattle are able to continue exercise (the \"second wind”). The genetic defect is C-to-T substitution, changing arginine to trptophan at amino acid position 489. The mutant residue is adjacent to the pyridoxal phosphate binding site and an active site residue, and the sequence around this position is highly conserved across different species.Due to their similarities in muscle mass to humans and the relative ease and low cost of maintenance, the ovine model of McArdle disease is preferable to the bovine model and important for testing therapeutic strategies.PYGL deficiency causes Hers disease (GSDVI), which has the features of mild hypoglycemia, ketosis, growth retardation, and prominent hepatomegaly.24 Given the liver-restricted expression of PYGL, heart and skeletal muscle are not affected. While targeted mouse embryonic stem cells are available for this locus from ES cell repositories, no reports of a mutant mouse strain exist.View chapterPurchase bookRead full chapterURL: https://www.sciencedirect.com/science/article/pii/B9780123848789000091Recommended publicationsInfo iconStructureJournalJournal of Molecular BiologyJournalMolecular CellJournalBiochimieJournalBrowse books and journalsAbout ScienceDirectRemote accessShopping cartAdvertiseContact and supportTerms and conditionsPrivacy policyWe use cookies to help provide and enhance our service and tailor content and ads. By continuing you agree to the use of cookies.Copyright © 2021 Elsevier B.V. or its licensors or contributors. ScienceDirect ® is a registered trademark of Elsevier B.V.ScienceDirect ® is a registered trademark of Elsevier B.V.