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Title: 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 C9{beta}- and C9{alpha}-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 1.9 and 2.3 {angstrom}, 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.
Authors:
; ; ; ; ; ; ;  [1] ;  [2]
  1. (Michigan)
  2. (
Publication Date:
OSTI Identifier:
1024046
Resource Type:
Journal Article
Resource Relation:
Journal Name: Proteins; Journal Volume: 79; Journal Issue: (7) ; 07, 2011
Research Org:
Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
Sponsoring Org:
DOE - BASIC ENERGY SCIENCESNIHOTHER U.S. STATESNCINIGMS
Country of Publication:
United States
Language:
ENGLISH
Subject:
60 APPLIED LIFE SCIENCES; ALKYLATION; ANTIBIOTICS; BIOSYNTHESIS; CATALYSTS; CHEMOTHERAPY; CRYSTAL STRUCTURE; CRYSTALLOGRAPHY; ENZYMES; MITOMYCIN; NEOPLASMS; REDOX POTENTIAL; STREPTOMYCES