Multidisciplinary Team Develops New Platform Technologies for Drug Discovery and Epigenetics
Jun 11, 2014
A research article describing chemoenzymatic strategies for the synthesis and utilization of S-adenosyl-L-methionine analogues is the UK College of Pharmacy Research Publication Highlight for May 2014.
The article was published in Angewandte Chemie and is entitled, “Facile Chemoenzymatic Strategies for the Synthesis and Utilization of S-Adenosyl-L-Methionine Analogues.”
This research represents a broad collaboration between investigators within the College of Pharmacy and the College of Medicine at the University of Kentucky. The lead Pharmaceutical Sciences investigative team includes co-corresponding author Research Assistant Professor Shanteri Singh, postdoctoral scholar Dr. Jianjun Zhang, second-year graduate student Mr. Tyler Huber and co-corresponding author Professor Jon Thorson. The collaborative research team includes postdoctoral fellow Dr. Goujun Wang, Research Associates Wen Zhang and Manjula Sunkara, as well as Professors Jurgen Rohr, Steven Van Lanen, Chunming Liu and Andrew Morris. Previous contributors in the Thorson University of Wisconsin lab include Ms. Katherine Hurley and Dr. Randal Goff.
In this study, the investigators probed the surprising permissiveness of substrate specificity of a broad set of 5 diverse methionine adenosyltransferase (MAT) enzymes by using 44 newly synthesized, non-native S/Se-alkylated methionine analogues. The publication is the first to report that human MAT2/2A, an enzyme overexpressed in a number of cancers, is capable of producing wide array of novel S-adenosylmethionine (SAM) analogs from non-native L-methionine precursors. A structural comparison of the stringent and permissive MATs delineated as part of this study suggested regions within the architecture of the enzyme that may influence permissiveness, setting the stage for future MAT engineering toward next generation catalysts with enhanced synthetic capabilities. The research also describes an efficient hMAT2/2A chemoenzymatic platform for the synthesis of SAM analogs that can be directly coupled to downstream SAM-utilizing enzymes for a range of synthetic and diagnostic applications. As an example of the former, the chemoenzymatic synthesis of SAM analogs when coupled to a model methylation reaction led to the generation of a small set of previously undescribed differentially alkylated analogs of the anticancer agent rebeccamycin as a proof of concept of natural product ‘alkylrandomization’ (a term to describe the differential alkylation of a target drug or biomolecule).
“Coupling of SAM synthesis and utilization in a single vessel circumvents major issues such as rapid decomposition and stability of SAM analogues, and thereby, paves the way for the investigation of other SAM utilizing enzymes.” said Linda Dwoskin, Associate Dean for Research. “Further, the user-friendly approach described in this publication may provide a useful toolbox for the rational design of a range of biologics for other therapeutic indications which could lead to significant advances in the field.”