Structural characterization of the mitomycin 7-O-methyltransferase

Shanteri Singh, Aram Chang, Randal D. Goff, Craig A. Bingman, Sabine Grüschow, David H. Sherman, George N. Phillips, Jon S. Thorson

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)2181-2188
Number of pages8
JournalProteins: Structure, Function and Bioinformatics
Volume79
Issue number7
DOIs
StatePublished - Jul 2011

Keywords

  • Biosynthesis
  • Cancer
  • Methyltransferase
  • Mitomycin
  • Natural product
  • S-adenosyl-L-methionine
  • X-ray crystallography

ASJC Scopus subject areas

  • Structural Biology
  • Biochemistry
  • Molecular Biology

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