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5npc

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Crystal Structure of D412N nucleophile mutant cjAgd31B (alpha-transglucosylase from Glycoside Hydrolase Family 31) in complex with unreacted alpha Cyclophellitol Cyclosulfate probe ME647

Structural highlights

5npc is a 1 chain structure with sequence from Cellvibrio japonicus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.96Å
Ligands:	, , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

OL4AG_CELJU Alpha-transglucosylase that specifically transfers single glucosyl units from alpha(1->4)-glucans to the non-reducing terminal 4-OH of glucose and alpha(1->4)- and alpha(1->6)-linked glucosyl residues. Acts on amylose, amylopectin, glycogen and maltooligosaccharides, with the highest activity with maltotriose as a donor, and also accepts maltose. Does not act as a hydrolase: weak hydrolysis activity is only observed on the disaccharide maltose.^[1]

Publication Abstract from PubMed

The essential biological roles played by glycosidases, coupled to the diverse therapeutic benefits of pharmacologically targeting these enzymes, provide considerable motivation for the development of new inhibitor classes. Cyclophellitol epoxides and aziridines are recently established covalent glycosidase inactivators. Inspired by the application of cyclic sulfates as electrophilic equivalents of epoxides in organic synthesis, we sought to test whether cyclophellitol cyclosulfates would similarly act as irreversible glycosidase inhibitors. Here we present the synthesis, conformational analysis, and application of novel 1,6-cyclophellitol cyclosulfates. We show that 1,6-epi-cyclophellitol cyclosulfate (alpha-cyclosulfate) is a rapidly reacting alpha-glucosidase inhibitor whose 4C1 chair conformation matches that adopted by alpha-glucosidase Michaelis complexes. The 1,6-cyclophellitol cyclosulfate (beta-cyclosulfate) reacts more slowly, likely reflecting its conformational restrictions. Selective glycosidase inhibitors are invaluable as mechanistic probes and therapeutic agents, and we propose cyclophellitol cyclosulfates as a valuable new class of carbohydrate mimetics for application in these directions.

1,6-Cyclophellitol Cyclosulfates: A New Class of Irreversible Glycosidase Inhibitor.,Artola M, Wu L, Ferraz MJ, Kuo CL, Raich L, Breen IZ, Offen WA, Codee JDC, van der Marel GA, Rovira C, Aerts JMFG, Davies GJ, Overkleeft HS ACS Cent Sci. 2017 Jul 26;3(7):784-793. doi: 10.1021/acscentsci.7b00214. Epub, 2017 Jul 13. PMID:28776021^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Larsbrink J, Izumi A, Hemsworth GR, Davies GJ, Brumer H. Structural enzymology of Cellvibrio japonicus Agd31B reveals alpha-transglucosylase activity in glycoside hydrolase family 31. J Biol Chem. 2012 Nov 6. PMID:23132856 doi:http://dx.doi.org/10.1074/jbc.M112.416511
↑ Artola M, Wu L, Ferraz MJ, Kuo CL, Raich L, Breen IZ, Offen WA, Codee JDC, van der Marel GA, Rovira C, Aerts JMFG, Davies GJ, Overkleeft HS. 1,6-Cyclophellitol Cyclosulfates: A New Class of Irreversible Glycosidase Inhibitor. ACS Cent Sci. 2017 Jul 26;3(7):784-793. doi: 10.1021/acscentsci.7b00214. Epub, 2017 Jul 13. PMID:28776021 doi:http://dx.doi.org/10.1021/acscentsci.7b00214