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PDBsum entry 5eeh
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References listed in PDB file
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Key reference
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Title
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Functional adomet isosteres resistant to classical adomet degradation pathways.
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Authors
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T.D.Huber,
F.Wang,
S.Singh,
B.R.Johnson,
J.Zhang,
M.Sunkara,
S.G.Van lanen,
A.J.Morris,
G.N.Phillips,
J.S.Thorson.
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Ref.
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Acs Chem Biol, 2016,
11,
2484-2491.
[DOI no: ]
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PubMed id
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Abstract
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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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