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Structural characterization of the mitomycin 7‐ O ‐methyltransferase
Author(s) -
Singh Shanteri,
Chang Aram,
Goff Randal D.,
Bingman Craig A.,
Grüschow Sabine,
Sherman David H.,
Phillips George N.,
Thorson Jon S.
Publication year - 2011
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.23040
Subject(s) - methyltransferase , mitomycin c , chemistry , methylation , dna methyltransferase , biochemistry , enzyme , stereochemistry , dna , biology , genetics
Mitomycins are quinone‐containing antibiotics, widely used as antitumor drugs in chemotherapy. Mitomycin‐7‐ O ‐methyltransferase (MmcR), a key tailoring enzyme involved in the biosynthesis of mitomycin in Streptomyces lavendulae , catalyzes the 7‐ O ‐methylation of both C9β‐ and C9α‐configured 7‐hydroxymitomycins. We have determined the crystal structures of the MmcR– S ‐adenosylhomocysteine (SAH) binary complex and MmcR–SAH–mitomycin A (MMA) ternary complex at resolutions of 1.9and 2.3 Å, respectively. The study revealed MmcR to adopt a common S ‐adenosyl‐ L ‐methionine‐dependent O ‐methyltransferase fold and the presence of a structurally conserved active site general acid–base pair is consistent with a proton‐assisted methyltransfer common to most methyltransferases. Given the importance of C7 alkylation to modulate mitomycin redox potential, this study may also present a template toward the future engineering of catalysts to generate uniquely bioactive mitomycins. Proteins 2011. © 2011 Wiley‐Liss, Inc.