TY - JOUR
T1 - Functional AdoMet Isosteres Resistant to Classical AdoMet Degradation Pathways
AU - Huber, Tyler D.
AU - Wang, Fengbin
AU - Singh, Shanteri
AU - Johnson, Brooke R.
AU - Zhang, Jianjun
AU - Sunkara, Manjula
AU - Van Lanen, Steven G.
AU - Morris, Andrew J.
AU - Phillips, George N.
AU - Thorson, Jon S.
N1 - Publisher Copyright:
© 2016 American Chemical Society.
PY - 2016/9/16
Y1 - 2016/9/16
N2 - S-adenosyl-l-methionine (AdoMet) is an essential enzyme cosubstrate in fundamental biology with an expanding range of biocatalytic and therapeutic applications. We report the design, synthesis, and evaluation of stable, functional AdoMet isosteres that are resistant to the primary contributors to AdoMet degradation (depurination, intramolecular cyclization, and sulfonium epimerization). Corresponding biochemical and structural studies demonstrate the AdoMet surrogates to serve as competent enzyme cosubstrates and to bind a prototypical class I model methyltransferase (DnrK) in a manner nearly identical to AdoMet. Given this conservation in function and molecular recognition, the isosteres presented are anticipated to serve as useful surrogates in other AdoMet-dependent processes and may also be resistant to, and/or potentially even inhibit, other therapeutically relevant AdoMet-dependent metabolic transformations (such as the validated drug target AdoMet decarboxylase). This work also highlights the ability of the prototypical class I model methyltransferase DnrK to accept non-native surrogate acceptors as an enabling feature of a new high-throughput methyltransferase assay.
AB - S-adenosyl-l-methionine (AdoMet) is an essential enzyme cosubstrate in fundamental biology with an expanding range of biocatalytic and therapeutic applications. We report the design, synthesis, and evaluation of stable, functional AdoMet isosteres that are resistant to the primary contributors to AdoMet degradation (depurination, intramolecular cyclization, and sulfonium epimerization). Corresponding biochemical and structural studies demonstrate the AdoMet surrogates to serve as competent enzyme cosubstrates and to bind a prototypical class I model methyltransferase (DnrK) in a manner nearly identical to AdoMet. Given this conservation in function and molecular recognition, the isosteres presented are anticipated to serve as useful surrogates in other AdoMet-dependent processes and may also be resistant to, and/or potentially even inhibit, other therapeutically relevant AdoMet-dependent metabolic transformations (such as the validated drug target AdoMet decarboxylase). This work also highlights the ability of the prototypical class I model methyltransferase DnrK to accept non-native surrogate acceptors as an enabling feature of a new high-throughput methyltransferase assay.
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U2 - 10.1021/acschembio.6b00348
DO - 10.1021/acschembio.6b00348
M3 - Article
C2 - 27351335
AN - SCOPUS:84987817680
SN - 1554-8929
VL - 11
SP - 2484
EP - 2491
JO - ACS Chemical Biology
JF - ACS Chemical Biology
IS - 9
ER -