Functional AdoMet Isosteres Resistant to Classical AdoMet Degradation Pathways

• DOI: 10.1021/acschembio.6b00348
• Publication Date: 2016-06-28T18:39:33Z
• Authors: Tyler D. Huber; Fengbin Wang; Shanteri Singh; Brooke R. Johnson; Jianjun Zhang; Manjula Sunkara; Steven G. Van Lanen; Andrew J. Morris; George N. Phillips; Jon S. Thorson
• Keywords: Epimer

S-adenosyl-l-methionine (AdoMet) is an essential enzyme cosubstrate in fundamental biology with expanding range of biocatalytic and therapeutic applications. We report the design, synthesis, evaluation stable, functional AdoMet isosteres that are resistant to primary contributors degradation (depurination, intramolecular cyclization, sulfonium epimerization). Corresponding biochemical structural studies demonstrate surrogates serve as competent cosubstrates bind a prototypical class I model methyltransferase (DnrK) manner nearly identical AdoMet. Given this conservation function molecular recognition, presented anticipated useful other AdoMet-dependent processes may also be to, and/or potentially even inhibit, therapeutically relevant metabolic transformations (such validated drug target decarboxylase). This work highlights ability DnrK accept non-native surrogate acceptors enabling feature new high-throughput assay.