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Thirteen glucose analogues bearing electrophilic groups were synthesized (five of themfor the first time) and screened as inhibitors of the glucose transporter (EII Glc )of the Escherichia coli phosphoenolpyruvate–sugar phospho-transferase system (PTS). 2¢,3¢-Epoxypropyl b-D-glucopyr-anoside (3a) is an inhibitor and also a pseudosubstrate. Five analogues are inhibitorsofnonvectorialGlcphosphorylation by EII Glc but not pseudosubstrates. | Eur. J. Biochem. 269 4969-4980 2002 FEBS 2002 doi 10.1046 j.1432-1033.2002.03197.x The glucose-specific carrier of the Escherichia coliphosphotransferase system Synthesis of selective inhibitors and inactivation studies Luis Fernando Garcia-Alles Vera Navdaeva Simon Haenni and Bernhard Erni Departement fur Chemie und Biochemie Universitat Bern Freiestrasse 3 CH-3012 Bern Switzerland Thirteen glucose analogues bearing electrophilic groups were synthesized five of them for the first time and screened as inhibitors of the glucose transporter EIIGlc of the Escherichia coli phosphoenolpyruvate-sugar phosphotransferase system PTS . 2 3 -Epoxypropyl b-D-glucopyr-anoside 3a is an inhibitor and also a pseudosubstrate. Five analogues are inhibitors of nonvectorial Glc phosphorylation by EIIGlc but not pseudosubstrates. They are selective for EIIGlc as demonstrated by comparison with EIIMan another Glc-specific but structurally different transporter. 3a is the only analogue that inhibits EIIGlc by binding to the high-affinity cytoplasmic binding site and also strongly inhibits sugar uptake mediated by this transporter. The most potent inhibitor in vitro methyl 6 7-anhydro-D L-glycero-a-D-gluco-heptopyranoside 1d preferentially interacts with the low-affinity cytoplasmic site but only weakly inhibits Glc uptake. Binding and or phosphorylation from the cytoplasmic side of EIIGlc is more permissive than sugar binding and or translocation of substrates via the periplasmic site. EIIGlc is rapidly inactivated by the 6-ơ-bromoacetyl esters of methyl a-D-glucopyranoside 1a and methyl a-D-manno-pyranoside 1c methyl 6-deoxy-6-isothiocyanato-a-D-glucopyranoside 1e b-D-glucopyranosyl isothiocyanate 3c and b-D-glucopyranosyl phenyl isothiocyanate 3d . Phosphorylation of EIIGlc protects indicating that inactivation occurs by alkylation of Cys421. Glc does not protect but sensitizes EIIGlc for inactivation by 1e and 3d which is interpreted as the effect of glucose-induced conformational .
