Structural characterization of the mitomycin 7-O-methyltransferase

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.