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| {{STRUCTURE_1jak| PDB=1jak | SCENE= }} | | {{STRUCTURE_1jak| PDB=1jak | SCENE= }} |
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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)'''
| | ===Streptomyces plicatus beta-N-acetylhexosaminidase in Complex with (2R,3R,4S,5R)-2-acetamido-3,4-dihydroxy-5-hydroxymethyl-piperidinium chloride (IFG)=== |
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| ==Overview==
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| 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.
| | The line below this paragraph, {{ABSTRACT_PUBMED_11522797}}, adds the Publication Abstract to the page |
| | (as it appears on PubMed at http://www.pubmed.gov), where 11522797 is the PubMed ID number. |
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| | {{ABSTRACT_PUBMED_11522797}} |
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| ==About this Structure== | | ==About this Structure== |
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| [[Category: Isofagomine inhibitor complex]] | | [[Category: Isofagomine inhibitor complex]] |
| [[Category: Substrate-assisted catalysis]] | | [[Category: Substrate-assisted catalysis]] |
| ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 20:59:02 2008'' | | |
| | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 1 16:59:59 2008'' |
