Bicyclic Picomolar OGA Inhibitors Enable Chemoproteomic Mapping of Its Endogenous Post-translational Modifications was written by Gonzalez-Cuesta, Manuel;Sidhu, Peter;Ashmus, Roger A.;Males, Alexandra;Proceviat, Cameron;Madden, Zarina;Rogalski, Jason C.;Busmann, Jil A.;Foster, Leonard J.;Garcia Fernandez, Jose M.;Davies, Gideon J.;Ortiz Mellet, Carmen;Vocadlo, David J.. And the article was included in Journal of the American Chemical Society in 2022.Electric Literature of C8H6FNS This article mentions the following:
Owing to its roles in human health and disease, the modification of nuclear, cytoplasmic, and mitochondrial proteins with O-linked N-acetylglucosamine residues (O-GlcNAc) has emerged as a topic of great interest. Despite the presence of O-GlcNAc on hundreds of proteins within cells, only two enzymes regulate this modification. One of these enzymes is O-GlcNAcase (OGA), a dimeric glycoside hydrolase that has a deep active site cleft in which diverse substrates are accommodated. Chem. tools to control OGA are emerging as essential resources for helping to decode the biochem. and cellular functions of the O-GlcNAc pathway. Here we describe rationally designed bicyclic thiazolidine inhibitors that exhibit superb selectivity and picomolar inhibition of human OGA. Structures of these inhibitors in complex with human OGA reveal the basis for their exceptional potency and show that they extend out of the enzyme active site cleft. Leveraging this structure, we create a high affinity chemoproteomic probe that enables simple one-step purification of endogenous OGA from brain and targeted proteomic mapping of its post-translational modifications. These data uncover a range of new modifications, including some that are less-known, such as O-ubiquitination and N-formylation. We expect that these inhibitors and chemoproteomics probes will prove useful as fundamental tools to decipher the mechanisms by which OGA is regulated and directed to its diverse cellular substrates. Moreover, the inhibitors and structures described here lay out a blueprint that will enable the creation of chem. probes and tools to interrogate OGA and other carbohydrate active enzymes. In the experiment, the researchers used many compounds, for example, 4-Fluorobenzylisothiocyanate (cas: 2740-88-7Electric Literature of C8H6FNS).
4-Fluorobenzylisothiocyanate (cas: 2740-88-7) belongs to esters. Esters are also usually derived from carboxylic acids. It may also be obtained by reaction of acid anhydride or acid halides with alcohols or by the reaction of salts of carboxylic acids with alkyl halides. Esters contain a carbonyl center, which gives rise to 120° C–C–O and O–C–O angles. Unlike amides, esters are structurally flexible functional groups because rotation about the C–O–C bonds has a low barrier. Their flexibility and low polarity is manifested in their physical properties; they tend to be less rigid (lower melting point) and more volatile (lower boiling point) than the corresponding amides. Electric Literature of C8H6FNS
Referemce:
Ester – Wikipedia,
Ester – an overview | ScienceDirect Topics