Inhibition of rabbit muscle glycogen phosphorylase by α-d-glucopyranose 1,2-cyclic phosphate

Hu, Hsiang-Yun; Allen, Martin

doi:10.1016/0005-2744(78)90199-7

Cited by 21 publications

(14 citation statements)

References 13 publications

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“…The reaction that occurs within the glycogen synthase active site is illustrated using the block arrows, whereas dephosphosphorylation of glycogen by Laforin is shown by the dashed arrow. The standard glucosyl transfer reaction follows route A, whereas the formation of GCP and its subsequent transfer follows route B. active site (27) where it acts as a transitition-state mimic and inhibitor rather than a substrate of phosphorylase (28).…”

Section: Discussionmentioning

confidence: 99%

Structural basis for 2′-phosphate incorporation into glycogen by glycogen synthase

Chikwana

Khanna

Baskaran

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Significance Glycogen is a branched glucose polymer found in most animals, fungi, bacteria, and archaea as an osmotically neutral means of energy storage. Glycogen also contains minor amounts of phosphate which can be removed by a dual specificity phosphatase, laforin. Accumulation of phosphate results in highly insoluble glycogen deposits and underlies Lafora disease, a devastating form of myoclonus epilepsy. In this paper, we present structural and kinetic data that support a plausible mechanism by which phosphate is directly incorporated into glycogen by glycogen synthase.

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Section: Discussionmentioning

confidence: 99%

Structural basis for 2′-phosphate incorporation into glycogen by glycogen synthase

Chikwana

Khanna

Baskaran

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…The importance of the internal hydrogen bond between the phosphate and the 0 2 hydroxyl in stabilization of the conformation of heptulose-2-P (which has an unusual torsion angle about the C1-01 bond) has already been noted . Glucose-1,2-cyclic phosphate is a reasonable inhibitor of glycogen phosphorylase (K, = 0.3 mM) (Hu & Gold, 1978;Kokesh et al, 1977;Jenkins et al, 1981;Withers et al, 1982). In this compound the phosphate is covalently attached to the 2-oxygen and the phosphate is constrained to adopt a similar conformation as in heptulose-2-P.…”

Section: Discussionmentioning

confidence: 99%

Laue and monochromatic diffraction studies on catalysis in phosphorylase b crystals

et al. 1994

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The conversion of substrate, heptenitol, to product, 0-1-C-methyl, a-D-glucose-1-phosphate (heptulose-2-P), in crystals of glycogen phosphorylase b has been studied by Laue and monochromatic diffraction methods. The phosphorolysis reaction in the crystal was started following liberation of phosphate from a caged phosphate compound, 3,Sdinitrophenyl phosphate (DNPP). The photolysis of DNPP, stimulated by flashes from a xenon flash lamp, was monitored in the crystal with a diode array spectrophotometer.In the Laue diffraction experiments, data to 2.8 A resolution were collected and the first time shot was obtained at 3 min from the start of reaction, and data collection comprised three 800-ms exposures. Careful data processing of Laue photographs for the large enzyme resulted in electron density maps of almost comparable quality to those produced by monochromatic methods. The difference maps obtained from the Laue measurements showed that very little catalysis had occurred 3 min and 1 h after release of phosphate, and a distinct peak consistent with the position expected for phosphate, in the attacking position was observed.Data collection times with monochromatic crystallographic methods on a home source took 16 h for data to 2.3 A resolution. Sufficient phosphate was released from the caged phosphate in the crystal from 5 flashes with a xenon flashlamp within 1 min for the reaction to go to completion within the time scale of the monochromatic data collection procedures. The heptulose-2-P product complex has been refined and the model agrees with that obtained previously with the major difference that the interchange of an aspartic acid (Asp 283) by an arginine (Arg 569) was not observed at the catalytic site. This change is part of the activation process of glycogen phosphorylase and may not have taken place in the current experiments because the caged compound binds weakly at the inhibitor site, restricting conformational change, and because activators of the enzymic reaction were not present in the crystal. In experiments with monochromatic radiation in which low phosphate concentrations were generated either by fewer photons or by diffusion of known phosphate concentrations, mixtures of substrate and product were observed. It was not possible through crystallographic refinement at 2.3 A resolution to establish the fractional occupancies of the enzyme-substrate and enzyme-product complexes, but the results did indicate that the reaction was proceeding slowly, consistent with approximate calculations for the likely rate of the reaction in the crystal. In these experiments in which only partial reaction had occurred, there was connecting density between the phosphate and the 0 2 hydroxyl of the sugar substrate. The recent evidence for the influence of the 0 2 hydroxyl on the catalytic mechanism is discussed.Keywords: enzyme mechanism; glycogen phosphorylase; Laue diffraction; time-resolved experiments Laue diffraction, utilizing the white X-ray beam of bright synchrotron radiation sources and very short...

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“…This indicates kinetic behaviour identical with that observed with glucono-1,5-lactone (Gold et al, 1971;Tu et al, 1971;Kasvinsky, 1982) and glucal (Kasvinsky, 1982), which possess a half-chair conformation, but different to that observed with glucose (Helmreich et al, 1967; Fig. 4a), glucose 1-fluoride (Ariki & Fukui, 1977;Kasvinsky, 1982), methyl a-glucoside (Kasvinsky, 1982), UDP-glucose (Engers et al, 1970) and glucose 1,2-(cyclic)phosphate (Hu & Gold, 1978), which possess chair conformations and produce either non-linear or linear competitive kinetics with respect to phosphate. It may be suggested that the chair conformation of compound (II) is not favoured in the direction of glycogen phosphorolysis, and likewise for compound (I).…”

Section: Discussionmentioning

confidence: 91%

The binding of d-gluconohydroximo-1,5-lactone to glycogen phosphorylase. Kinetic, ultracentrifugation and crystallographic studies

Papageorgiou

Oikonomakos

Leonidas

et al. 1991

Biochemical Journal

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Combined kinetic, ultracentrifugation and X-ray-crystallographic studies have characterized the effect of the beta-glucosidase inhibitor gluconohydroximo-1,5-lactone on the catalytic and structural properties of glycogen phosphorylase. In the direction of glycogen synthesis, gluconohydroximo-1,5-lactone was found to competitively inhibit both the b (Ki 0.92 mM) and the alpha form of the enzyme (Ki 0.76 mM) with respect to glucose 1-phosphate in synergism with caffeine. In the direction of glycogen breakdown, gluconohydroximo-1,5-lactone was found to inhibit phosphorylase b in a non-competitive mode with respect to phosphate, and no synergism with caffeine could be demonstrated. Ultracentrifugation and crystallization experiments demonstrated that gluconohydroximo-1,5-lactone was able to induce dissociation of tetrameric phosphorylase alpha and stabilization of the dimeric T-state conformation. A crystallographic binding study with 100 mM-gluconohydroximo-1,5-lactone at 0.24 nm (2.4 A) resolution showed a major peak at the catalytic site, and no significant conformational changes were observed. Analysis of the electron-density map indicated that the ligand adopts a chair conformation. The results are discussed with reference to the ability of the catalytic site of the enzyme to distinguish between two or more conformations of the glucopyranose ring.

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Inhibition of rabbit muscle glycogen phosphorylase by α-d-glucopyranose 1,2-cyclic phosphate

Cited by 21 publications

References 13 publications

Structural basis for 2′-phosphate incorporation into glycogen by glycogen synthase

Structural basis for 2′-phosphate incorporation into glycogen by glycogen synthase

Laue and monochromatic diffraction studies on catalysis in phosphorylase b crystals

The binding of d-gluconohydroximo-1,5-lactone to glycogen phosphorylase. Kinetic, ultracentrifugation and crystallographic studies

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