title: Inhibitory properties of 1,4-dideoxy-1,4-imino-d-arabinitol (DAB) derivatives acting on glycogen metabolising enzymes.
abstract: Glycogen synthase (GS) and glycogen phosphorylase (GP) are the key enzymes that control, respectively, the synthesis and degradation of glycogen, a multi-branched glucose polymer that serves as a form of energy storage in bacteria, fungi and animals. An abnormal glycogen metabolism is associated with several human diseases. Thus, GS and GP constitute adequate pharmacological targets to modulate cellular glycogen levels by means of their selective inhibition. The compound 1,4-dideoxy-1,4-imino-d-arabinitol (DAB) is a known potent inhibitor of GP. We studied the inhibitory effect of DAB, its enantiomer LAB, and 29 DAB derivatives on the activity of rat muscle glycogen phosphorylase (RMGP) and E. coli glycogen synthase (EcGS). The isoform 4 of sucrose synthase (SuSy4) from Solanum tuberosum L. was also included in the study for comparative purposes. Although these three enzymes possess highly conserved catalytic site architectures, the DAB derivatives analysed showed extremely diverse inhibitory potential. Subtle changes in the positions of crucial residues in their active sites are sufficient to discriminate among the structural differences of the tested inhibitors. For the two Leloir-type enzymes, EcGS and SuSy4, which use sugar nucleotides as donors, the inhibitory potency of the compounds analysed was synergistically enhanced by more than three orders of magnitude in the presence of ADP and UDP, respectively. Our results are consistent with a model in which these compounds bind to the subsite in the active centre of the enzymes that is normally occupied by the glucosyl residue which is transferred between donor and acceptor substrates. The ability to selectively inhibit the catalytic activity of the key enzymes of the glycogen metabolism may represent a new approach for the treatment of disorders of the glycogen metabolism.
authors.affiliation: Departament de Bioquímica i Biomedicina Molecular, Universitat de Barcelona, Av. Diagonal 645, E-08028, Barcelona, Spain. jcferrer@ub.edu and Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac 10, E-08028, Barcelona, Spain and CIBER de Diabetes y Enfermedades Metabólicas (CIBERDEM), Madrid, Spain.
authors.forename: Mireia
authors.initials: M
authors.lastname: Díaz-Lobo
authors.affiliation: Department of Biological Chemistry and Molecular Modeling, Instituto de Química Avanzada de Cataluña, IQAC-CSIC, Barcelona, Spain.
authors.forename: Alda Lisa
authors.initials: AL
authors.lastname: Concia
authors.affiliation: Department of Biological Chemistry and Molecular Modeling, Instituto de Química Avanzada de Cataluña, IQAC-CSIC, Barcelona, Spain.
authors.forename: Livia
authors.initials: L
authors.lastname: Gómez
authors.affiliation: Department of Biological Chemistry and Molecular Modeling, Instituto de Química Avanzada de Cataluña, IQAC-CSIC, Barcelona, Spain.
authors.forename: Pere
authors.initials: P
authors.lastname: Clapés
authors.affiliation: Institut de Biologia Molecular de Barcelona (IBMB-CSIC), Baldiri Reixac 10, E-08028, Barcelona, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Fita
authors.affiliation: Departament de Bioquímica i Biomedicina Molecular, Universitat de Barcelona, Av. Diagonal 645, E-08028, Barcelona, Spain. jcferrer@ub.edu and Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac 10, E-08028, Barcelona, Spain and CIBER de Diabetes y Enfermedades Metabólicas (CIBERDEM), Madrid, Spain.
authors.forename: Joan J
authors.initials: JJ
authors.lastname: Guinovart
authors.affiliation: Departament de Bioquímica i Biomedicina Molecular, Universitat de Barcelona, Av. Diagonal 645, E-08028, Barcelona, Spain. jcferrer@ub.edu.
authors.forename: Joan C
authors.initials: JC
authors.lastname: Ferrer
mesh_terms: D000818:Animals; D001089:Arabinose / Q000737:chemistry* / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism*; D024981:Glycogen Phosphorylase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006006:Glycogen Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D050113:Imino Furanoses / Q000737:chemistry* / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D051381:Rats; D011198:Solanum tuberosum / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D013402:Sugar Alcohols / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D050113:Imino Furanoses; D013402:Sugar Alcohols; C058137:1,4-dideoxy-1,4-iminoarabinitol; D006003:Glycogen; D001089:Arabinose; D005964:Glucosyltransferases; D024981:Glycogen Phosphorylase; D006006:Glycogen Synthase; C022699:sucrose synthase