Enzyme inhibition by iminosugars: analysis and insight into the glycosidase-iminosugar dependency of pH

TY - JOUR

T1 - Enzyme inhibition by iminosugars

T2 - analysis and insight into the glycosidase-iminosugar dependency of pH

AU - López, Óscar

AU - Qing, Feng-Ling

AU - Pedersen, Christian Marcus

AU - Bols, Mikael

N1 - Copyright © 2013 Elsevier Ltd. All rights reserved.

PY - 2013/8/15

Y1 - 2013/8/15

N2 - Imino- and azasugar glycosidase inhibitors display pH dependant inhibition reflecting that both the inhibitor and the enzyme active site have groups that change protonation state with pH. With the enzyme having two acidic groups and the inhibitor one basic group, enzyme-inhibitor complexes with three (EH3I), two (EH2I), one (EHI), or no protons (EI), are possible. In the present work an analysis method is presented that from pH-inhibition data allows one to distinguish between the different complexes and determine which protonation state is preferred. It is also possible to determine the pH-independent binding constants of the inhibitor. Analysis of pH data for imino- and azasugar inhibition of β-glucosidases revealed that basic glycosidase inhibitors bind as the monoprotonated (EHI) complex. Three neutral inhibitors were also studied and two of these were also bound exclusively as the EHI complex while a third bound both as a EHI and a EH2I complex.

AB - Imino- and azasugar glycosidase inhibitors display pH dependant inhibition reflecting that both the inhibitor and the enzyme active site have groups that change protonation state with pH. With the enzyme having two acidic groups and the inhibitor one basic group, enzyme-inhibitor complexes with three (EH3I), two (EH2I), one (EHI), or no protons (EI), are possible. In the present work an analysis method is presented that from pH-inhibition data allows one to distinguish between the different complexes and determine which protonation state is preferred. It is also possible to determine the pH-independent binding constants of the inhibitor. Analysis of pH data for imino- and azasugar inhibition of β-glucosidases revealed that basic glycosidase inhibitors bind as the monoprotonated (EHI) complex. Three neutral inhibitors were also studied and two of these were also bound exclusively as the EHI complex while a third bound both as a EHI and a EH2I complex.

U2 - 10.1016/j.bmc.2013.03.003

DO - 10.1016/j.bmc.2013.03.003

M3 - Journal article

C2 - 23583693

SN - 0968-0896

VL - 21

SP - 4755

EP - 4761

JO - Bioorganic & Medicinal Chemistry

JF - Bioorganic & Medicinal Chemistry

IS - 16

ER -