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J. Biol. Chem., Vol. 278, Issue 14, 12214-12221, April 4, 2003
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From the Evolutionary links between cytochrome
P450 monooxygenases, a superfamily of extraordinarily divergent
heme-thiolate proteins catalyzing a wide array of NADPH/NADH- and
O2-dependent reactions, are becoming
better understood because of availability of an increasing number of
fully sequenced genomes. Among other reactions, P450s catalyze the
site-specific oxidation of the precursors to macrolide antibiotics in
the genus Streptomyces introducing regiochemical diversity
into the macrolide ring system, thereby significantly increasing
antibiotic activity. Developing effective uses for Streptomyces enzymes in biosynthetic processes and
bioremediation requires identification and engineering of additional
monooxygenases with activities toward a diverse array of small
molecules. To elucidate the molecular basis for substrate
specificity of oxidative enzymes toward macrolide
antibiotics, the x-ray structure of CYP154C1 from Streptomyces
coelicolor A3(2) was determined (Protein Data Bank code 1GWI).
Relocation of certain common P450 secondary structure elements, along
with a novel structural feature involving an additional
The atomic coordinates and the structure factors (code 1GWI) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).
The 1.92-Å Structure of Streptomyces
coelicolor A3(2) CYP154C1
A NEW MONOOXYGENASE THAT FUNCTIONALIZES MACROLIDE RING
SYSTEMS*
§,,,
,,,
Department of Biochemistry,
Vanderbilt University School of Medicine, Nashville, Tennessee
37232-0146, the ¶ Argonne National Laboratory, Structural
Biology Center, Argonne, Illinois 60439, the Department of
Microbiology and BioTechnology Institute, University of Minnesota,
Minneapolis, Minnesota 55455, and the ** Wolfson
Laboratory of P-450 Biodiversity, Institute of Biological Sciences,
University of Wales Aberystwyth, Aberystwyth,
Wales SY23 3DA, United Kingdom
-strand transforming the five-stranded -sheet into a six-stranded
variant, creates an open cleft-shaped substrate-binding site between
the two P450 domains. High sequence similarity to macrolide
monooxygenases from other microbial species translates into catalytic
activity of CYP154C1 toward both 12- and 14-membered ring macrolactones
in vitro.
*
This work was supported by National Institutes of
Health Grants GM37942 and ES00267 (to M. R. W.), P30 ES00267 (to
L. M. P.), GM48562 (to D. H. S.), by
Biotechnology and Biological Sciences Research Council and a
Welcome Trust Grant (to S. L. K. and D. C. L.), and
by NCI Cancer Biology Training Grant CA09138 (to B. J. B.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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