Glycogen Phosphorylase: Difference between revisions
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[[1xoi]] - hGP + indoloyl derivative inhibitor<br /> | [[1xoi]] - hGP + indoloyl derivative inhibitor<br /> | ||
[[1fc0]] - hGP + glucopyranosyl derivative<br /> | [[1fc0]] - hGP + glucopyranosyl derivative<br /> | ||
[[2c4m | [[2c4m]] – GP + vitamin B6 complex – ''Corynebacterium callunae'' | ||
===Glycogen phosphorylase ternary complex with inhibitor=== | ===Glycogen phosphorylase ternary complex with inhibitor=== | ||
Revision as of 12:48, 29 November 2011
IntroductionIntroduction
Glycogen phosphorylase catalyzes the hydrolysis of glycogen to generate glucose-1-phosphate and shortened glycogen molecule and is considered the rate limiting step in the degradation of glycogen[1]. It is a part of the glucosyltransferase family and acts on the α-1,4-glycosidic linkage; the phosphorylase comes to a standstill 4 residues from an α-1,6-branchpoint, where debranching enzyme takes over [2]. The glucose-1-phophate is then further degraded via the pathway of glycolysis. Studies have found that mammals have liver, muscle and brain isoforms of phosphorylase but it is found among all species; muscle glycogen phosphorylase is present to degrade glycogen to forms of energy by means of glycolysis during muscle contractions and liver glycogen is present to regulate the blood glucose levels within the blood [2][3].
Structure and FunctionStructure and Function
Glycogen phosphorylase is a dimer consisting of two identical subunits and has an essential cofactor, [3]. Glycogen phosphorylase can be found in two different states, glycogen phosphorylase a (GPa) and glycogen phosphorylase b (GPb)[1]The difference in the structures is due to phosphorylation of the residue which results in the active form (GPa). Protein phosphatases dephosphorylate the GPa to the inactive form, also known as GPb. Both forms of glycogen phosphorylase can also be found in T and R states where T is the inactive state because it appears to have a low affinity for substrate and R is the active state where it appears to have a greater affinity for substrate[4].
The secondary structures of T and R states of GPa and b are similar with an and a .Each domain also contains subdomains which undergo conformational changes on the interconversion of T and R states [4]. C terminal domain has the cofactor PLP and part of the active site, it is made up of five α helices and 6 β strands[5]. The N-terminal domain consisting of fifteen α helices and nine β strands, is considered to be more complex and is divided in the middle of its β sheet core into subdomains. The first domain binds the effector molecule of AMP and also has a recognition site of the introconverting phosphorylase kinase and phosphatase[4][5]. The second domain has the polysaccharide binding domain where phosphorylase is able to attach to the glycogen substrate [5]. The R states of GPa and GPb are almost identical; the difference lays in the modification of the Ser-14 residue where GPa has a covalently linked phosphate group whereas GPb has a non-covalently linked sulfide group . GPa is activated by phosphorylation of the serine residue whereas GPb can be activated by the binding of AMP to the that are present within the molecule[4]. GPa does not require the binding of AMP but attachment enhances the activity of the enzyme upwards to 25% [6].
Glycogen phosphorylase is different from other enzymes that require the cofactor PLP because instead of utilizing the pyrimidine ring, phosphorylase uses the phosphate group [6]. The 4'aldehyde of PLP binds to the ε-amino group of lysine 680 and the 5'-phosphate of PLP has been found to be the group participating in the catalysis of glycogen phosphorylase [3]. The binding sites in glycogen phosphorylase include: a catalytic, inhibiting, AMP, glycogen and new allosteric site [1]. The glycogen binding site is located more than 30Å from the catalytic and allosteric sites. The residues that make up the site are [6]. The binds purine analogs or fused-ring molecules such as adenosine, caffeine, FMN, NADH and AMP when there are increased concentrations available[4]. The heterocyclic rings of the compounds bind to the inhibiting site, stablilizing it and blocking access to the catalytic center [6]. The can be accessed once the Ser-14 residue has been phosphorylated and conformational changes in glycogen phosphorylation have been observed[5][6]. The structure and function of glycogen phosphorylase is complex, though the function of the enzyme is due to the structure.
MechanismMechanism
In muscle, glycogen phosphorylase is activated by hormones and neural signals such as epinephrine, that stimulate phosphorylase kinase which phosphorylates the Ser-14 residue of the protein. A second messenger of cyclic AMP (cAMP) increases in concentration due to epinephrine or glucagon, and this increase results in an enzyme cascade [5]. Activation of phosphorylase kinase is due to increased concentrations of Ca2+ or by the phosphorylation by protein kinase A which is cAMP dependent. The activated kinase in turn activates the glycogen phosphorylase enzyme by phosphorylating the Ser-14 residue. In the liver, glucagon is the primary signal which catalyzes this enzyme cascade[5][6].
Glycogen phosphorylase is regulated by phosphorylation, binding of allosteric effectors and by the catalytic mechanism; phosphorylation takes glycogen phosphorylase from a disordered state to an ordered one, allosteric effector provide changes in the structure of the enzyme and when coupled with phosphorylation allow access to the buried catalytic site[6]. The catalytic mechanism itself is dependent upon the proximity of PLP and the substrate phosphate which is directed by the surrounding groups which stabilize the interactions[5] and create the perfect environment to phosphohydrolyze the glycosidic bond[6]. The environment is established by the phosphate compound making a hydrogen bond with the 5'-phosphate of PLP and being stable enough to successfully cleave the bond yielding the product of glucose-1-phosphate.[3].
3D structures of glycogen phosphorylase3D structures of glycogen phosphorylase
Updated November 2011
3e3n, 1pyg, 7gpb, 8gpb – rGP + AMP - rabbit
3e3o – rGP + IMP
2pyd, 2gpb – rGP + glucose
3e3l, 1c50, 1bx3, 2gpn, 1gpb – rGP
1abb – rGP + modified cofactor
1z8d – hGP + AMP + glucose - human
1fa9 – hGP + AMP
1ygp – GP + phosphate – yeast
Glycogen phosphorylase binary complex with inhibitorGlycogen phosphorylase binary complex with inhibitor
3np7, 3np9, 3npa, 3msc, 3mqf, 3mrt, 3mrv, 3mrx, 3ms2, 3ms4, 3ms7, 3mt7, 3mt8, 3mt9, 3mta, 3mtb, 3mtd, 3nc4, 3l79, 3l7a, 3l7b, 3l7c, 3l7d, 3g2h, 3g2i, 3g2j, 3g2k, 3g2l, 3cut, 3cuu, 3cuv, 3cuw, 3bcs, 3bd7, 3bd8, 3bda, 2qn3, 2qn7, 2qn8, 2qn9, 2qnb, 2qlm, 2qln, 2fet, 2ff5, 2ffr, 2f3p, 2f3q, 2f3s, 2f3u, 1ww2, 1ww3, 1xkx, 1xl0, 1xl1, 1xc7, 1p4g, 1p4h, 1p4j, 1kti, 1k06, 1k08, 1hlf, 1fs4, 1ftq, 1ftw, 1fty, 1fu4, 1fu7, 1fu8, 1ggn, 2prj, 5gpb, 3s0j – rGP + glucopyranosyl derivative inhibitor
3g2n – rGP + acylglucosylamine
3ebo – rGP + chrysin
3ebp, 1gfz, 1c8k, 1e1y – rGP + flavopiridol
3dd1, 3dds, 3ddw – rGP + anthranilimide
2pyi – rGP + glucosyl triazoleacetamide
1gg8 – rGP + glucoside inhibitor
2pri– rGP + deoxyglucosephosphate inhibitor
3gpb, 4gpb, 6gpb – rGP + phosphorylated glucose derivative
1gpa – rGP phosphorylated
3bcr – rGP + AZT
3bcu – rGP + thymidine
2gj4 – rGP + ligand
1gpy – rGP + glucose-6-phosphate
2gm9 – rGP + thienopyrrole
1axr – rGP + azolopyridine inhibitor
2g9q, 2g9r, 2g9u, 2g9v – rGP + iminosugar
2amv – rGP + pyridine derivative inhibitor
2ieg, 2iei – rGP + quinolone derivative inhibitor
1z62, 1uzu - rGP + indirubin derivative inhibitor
3bd6 – rGP + ribofuranosyl cyanuric acid
2qrg, 2qrh, 2qrm, 2qrp, 2qrq – rGP + spiro-isoxazoline inhibitor
1a8i - rGP + spiro-hydantoine inhibitor
2qn1, 2qn2 – rGP + pentacyclic triterpene inhibitor
2off, 9gpb - rGP + allosteric inhibitor
1wv0, 1wv1, 1wuy - rGP + acyl urea derivative inhibitor
1z6p, 1z6q - rGP + AMP site inhibitor
1b4d – rGP + amidocarbamate inhibitor
1p29, 1p2b, 1p2d, 1p2g - rGP + cyclodextrin derivative inhibitor
1lwn, 1lwo – rGP + hypoglycaemic drug
2gpa, 2amv, 3amv - rGP + antidiabetic drug
2qll – hGP + GL C terminal peptide
2ati, 1wut – hGP + acyl urea derivative inhibitor
1xoi - hGP + indoloyl derivative inhibitor
1fc0 - hGP + glucopyranosyl derivative
2c4m – GP + vitamin B6 complex – Corynebacterium callunae
Glycogen phosphorylase ternary complex with inhibitorGlycogen phosphorylase ternary complex with inhibitor
1noi, 1noj, 1nok – rGP + transition state analog + phosphate
1h5u - rGP + antidiabetic drug + glucose
1c8l - rGP + antidiabetic drug + caffeine
2zb2 – hGP + carboxamide derivative + glucose
1em6, 1exv – hGP + nucleoside + inhibitor
1l5q, 1l7x – hGP + caffeine + glucopyranosyl derivative + inhibitor
1l5r - hGP + riboflavin + glucopyranosyl derivative + inhibitor
1l5s - hGP + uric acid + glucopyranosyl derivative + inhibitor
Additional ResourcesAdditional Resources
For additional information, see: Carbohydrate Metabolism
ReferencesReferences
- ↑ 1.0 1.1 1.2 Kristiansen M, Andersen B, Iversen LF, Westergaard N. Identification, synthesis, and characterization of new glycogen phosphorylase inhibitors binding to the allosteric AMP site. J Med Chem. 2004 Jul 1;47(14):3537-45. PMID:15214781 doi:10.1021/jm031121n
- ↑ 2.0 2.1 Roach PJ. Glycogen and its metabolism. Curr Mol Med. 2002 Mar;2(2):101-20. PMID:11949930
- ↑ 3.0 3.1 3.2 3.3 Palm D, Klein HW, Schinzel R, Buehner M, Helmreich EJM. The role of pyridoxal 5’-phosphate in glycogen phosphorylase catalysis. Biochemistry. 1990 Feb 6; 29(5):1099-1107.
- ↑ 4.0 4.1 4.2 4.3 4.4 Barford D, Hu SH, Johnson LN. Structural mechanism for glycogen phosphorylase control by phosphorylation and AMP. J Mol Biol. 1991 Mar 5;218(1):233-60. PMID:1900534
- ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 5.7 Fletterick RJ, Sprang SR. Glycogen phosphorylase Structures and function. Accounts of Chemical Research. 1982 Nov; 15(11):361-369.
- ↑ 6.0 6.1 6.2 6.3 6.4 6.5 6.6 6.7 Johnson LH. Glycogen Phosphorylase: Control by phosphorylation and allosteric effectors. The FASEB Journal. 1992 March;6:2274-2282.