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 language | English |
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Pages (from-to) | 2181-2188 |
Number of pages | 8 |
Journal | Proteins: Structure, Function and Bioinformatics |
Volume | 79 |
Issue number | 7 |
DOIs | |
State | Published - 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