1jak
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Streptomyces plicatus beta-N-acetylhexosaminidase in Complex with (2R,3R,4S,5R)-2-acetamido-3,4-dihydroxy-5-hydroxymethyl-piperidinium chloride (IFG)
OverviewOverview
Azasugar inhibitors of the isofagomine class are potent competitive, inhibitors of configuration-retaining beta-glycosidases. This potency, results from the formation of a strong electrostatic interaction between a, protonated endocyclic nitrogen at the "anomeric" center of the inhibitor, and the catalytic nucleophile of the enzyme. Although the majority of, retaining beta-glycosidases use a mechanism involving a carboxylate, residue as a nucleophile, Streptomyces plicatus, beta-N-acetylhexos-aminidase (SpHEX) and related family 20 glycosidases, lack such a catalytic residue and use instead the carbonyl oxygen of the, 2-acetamido group of the substrate as a nucleophile to "attack" the, anomeric center. Thus, a strong electrostatic interaction between the, inhibitor and enzyme is not expected to occur; nonetheless, the, 1-N-azasugar, (2R,3R,4S,5R)-2-acetamido-3,4-dihydroxy-5-hydroxymethyl-piperidinium, hydrochloride (GalNAc-isofagomine.HCl), which was synthesized and assayed, for its ability to inhibit SpHEX, was found to be a potent competitive, inhibitor of the enzyme (K(i) = 2.7 microm). A crystallographic complex of, GalNAc-isofagomine bound to SpHEX was solved and refined to 1.75 A and, revealed that the lack of a strong electrostatic interaction between the, "anomeric" center of GalNAc-isofagomine and SpHEX is compensated for by a, novel 2.8-A hydrogen bond formed between the equatorial proton of the, endocyclic nitrogen of the azasugar ring and the carboxylate of the, general acid-base residue Glu-314 of SpHEX. This interaction appears to, contribute to the unexpected potency of GalNAc-isofagomine toward SpHEX.
About this StructureAbout this Structure
1JAK is a Single protein structure of sequence from Streptomyces plicatus with SO4, CL, IFG and GOL as ligands. Active as Beta-N-acetylhexosaminidase, with EC number 3.2.1.52 Full crystallographic information is available from OCA.
ReferenceReference
Biochemical and structural assessment of the 1-N-azasugar GalNAc-isofagomine as a potent family 20 beta-N-acetylhexosaminidase inhibitor., Mark BL, Vocadlo DJ, Zhao D, Knapp S, Withers SG, James MN, J Biol Chem. 2001 Nov 9;276(45):42131-7. Epub 2001 Aug 24. PMID:11522797
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