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Proteins. 2011 Jul;79(7):2181-8. doi: 10.1002/prot.23040. Epub 2011 May 2.

Structural characterization of the mitomycin 7-O-methyltransferase.

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1
Division of Pharmaceutical Sciences, Wisconsin Center for Natural Product Research, School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin 53705, USA.

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.

PMID:
21538548
PMCID:
PMC3115387
DOI:
10.1002/prot.23040
[Indexed for MEDLINE]
Free PMC Article

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