PubMed:20689974 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PubMed/sourceid/20689974","sourcedb":"PubMed","sourceid":"20689974","source_url":"http://www.ncbi.nlm.nih.gov/pubmed/20689974","text":"Inhibition of a bacterial O-GlcNAcase homologue by lactone and lactam derivatives: structural, kinetic and thermodynamic analyses.\nThe dynamic, intracellular, O-GlcNAc modification is of continuing interest and one whose study through targeted \"chemical genetics\" approaches is set to increase. Of particular importance is the inhibition of the O-GlcNAc hydrolase, O-GlcNAcase (OGA), since this provides a route to elevate cellular O-GlcNAc levels, and subsequent phenotypic evaluation. Such a small molecule approach complements other methods and potentially avoids changes in protein-protein interactions that manifest themselves in molecular biological approaches to O-GlcNAc transferase knockout or over-expression. Here we describe the kinetic, thermodynamic and three-dimensional structural analysis of a bacterial OGA analogue from Bacteroides thetaiotaomicron, BtGH84, in complex with a lactone oxime (LOGNAc) and a lactam form of N-acetylglucosamine and compare their binding signatures with that of the more potent inhibitor O-(2-acetamido-2-deoxy-D-glucopyranosylidene)amino N-phenyl carbamate (PUGNAc). We show that both LOGNAc and the N-acetyl gluconolactam are significantly poorer inhibitors than PUGNAc, which may reflect poorer mimicry of transition state geometry and steric clashes with the enzyme upon binding; drawbacks that the phenyl carbamate adornment of PUGNAc helps mitigate. Implications for the design of future generations of inhibitors are discussed.","tracks":[{"project":"Allie","denotations":[{"id":"SS1_20689974_2_0","span":{"begin":365,"end":376},"obj":"expanded"},{"id":"SS2_20689974_2_0","span":{"begin":378,"end":381},"obj":"abbr"},{"id":"SS1_20689974_4_0","span":{"begin":1018,"end":1104},"obj":"expanded"},{"id":"SS2_20689974_4_0","span":{"begin":1106,"end":1112},"obj":"abbr"}],"relations":[{"id":"AE1_20689974_2_0","pred":"abbreviatedTo","subj":"SS1_20689974_2_0","obj":"SS2_20689974_2_0"},{"id":"AE1_20689974_4_0","pred":"abbreviatedTo","subj":"SS1_20689974_4_0","obj":"SS2_20689974_4_0"}],"attributes":[{"subj":"SS1_20689974_2_0","pred":"source","obj":"Allie"},{"subj":"SS2_20689974_2_0","pred":"source","obj":"Allie"},{"subj":"SS1_20689974_4_0","pred":"source","obj":"Allie"},{"subj":"SS2_20689974_4_0","pred":"source","obj":"Allie"}]},{"project":"NGLY1-deficiency","denotations":[{"id":"PD-NGLY1-deficiency-B_T1","span":{"begin":161,"end":167},"obj":"chem:24139"},{"id":"PD-NGLY1-deficiency-B_T2","span":{"begin":347,"end":353},"obj":"chem:24139"},{"id":"PD-NGLY1-deficiency-B_T3","span":{"begin":434,"end":440},"obj":"chem:24139"},{"id":"PD-NGLY1-deficiency-B_T4","span":{"begin":672,"end":678},"obj":"chem:24139"},{"id":"PD-NGLY1-deficiency-B_T5","span":{"begin":939,"end":958},"obj":"chem:24139"}],"namespaces":[{"prefix":"hgnc","uri":"https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:"},{"prefix":"omim","uri":"https://www.omim.org/entry/"},{"prefix":"chem","uri":"https://pubchem.ncbi.nlm.nih.gov/compound/"}],"attributes":[{"subj":"PD-NGLY1-deficiency-B_T1","pred":"source","obj":"NGLY1-deficiency"},{"subj":"PD-NGLY1-deficiency-B_T2","pred":"source","obj":"NGLY1-deficiency"},{"subj":"PD-NGLY1-deficiency-B_T3","pred":"source","obj":"NGLY1-deficiency"},{"subj":"PD-NGLY1-deficiency-B_T4","pred":"source","obj":"NGLY1-deficiency"},{"subj":"PD-NGLY1-deficiency-B_T5","pred":"source","obj":"NGLY1-deficiency"}]}],"config":{"attribute types":[{"pred":"source","value type":"selection","values":[{"id":"Allie","color":"#ceec93","default":true},{"id":"NGLY1-deficiency","color":"#ec93e8"}]}]}}