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Title: Structural Basis for Cofactor-Independent Dioxygenation in Vancomycin Biosynthesis

Abstract

Enzyme-catalyzed oxidations are some of the most common transformations in primary and secondary metabolism. The vancomycin biosynthetic enzyme DpgC belongs to a small class of oxygenation enzymes that are not dependent on an accessory cofactor or metal ion1. The detailed mechanism of cofactor-independent oxygenases has not been established. Here we report the first structure of an enzyme of this oxygenase class in complex with a bound substrate mimic. The use of a designed, synthetic substrate analogue allows unique insights into the chemistry of oxygen activation. The structure confirms the absence of cofactors, and electron density consistent with molecular oxygen is present adjacent to the site of oxidation on the substrate. Molecular oxygen is bound in a small hydrophobic pocket and the substrate provides the reducing power to activate oxygen for downstream chemical steps. Our results resolve the unique and complex chemistry of DpgC, a key enzyme in the biosynthetic pathway of an important class of antibiotics. Furthermore, mechanistic parallels exist between DpgC and cofactor-dependent flavoenzymes, providing information regarding the general mechanism of enzymatic oxygen activation.

Authors:
; ; ;
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL) National Synchrotron Light Source
Sponsoring Org.:
Doe - Office Of Science
OSTI Identifier:
930677
Report Number(s):
BNL-81192-2008-JA
TRN: US200901%%177
DOE Contract Number:  
DE-AC02-98CH10886
Resource Type:
Journal Article
Resource Relation:
Journal Name: Nature; Journal Volume: 447
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; ANTIBIOTICS; BIOSYNTHESIS; CHEMISTRY; ELECTRON DENSITY; ENZYMES; METABOLISM; OXIDATION; OXYGEN; OXYGENASES; SUBSTRATES; TRANSFORMATIONS; national synchrotron light source

Citation Formats

Widboom,P., Fielding, E., Liu, Y., and Bruner, S. Structural Basis for Cofactor-Independent Dioxygenation in Vancomycin Biosynthesis. United States: N. p., 2007. Web. doi:10.1038/nature05702.
Widboom,P., Fielding, E., Liu, Y., & Bruner, S. Structural Basis for Cofactor-Independent Dioxygenation in Vancomycin Biosynthesis. United States. doi:10.1038/nature05702.
Widboom,P., Fielding, E., Liu, Y., and Bruner, S. Mon . "Structural Basis for Cofactor-Independent Dioxygenation in Vancomycin Biosynthesis". United States. doi:10.1038/nature05702.
@article{osti_930677,
title = {Structural Basis for Cofactor-Independent Dioxygenation in Vancomycin Biosynthesis},
author = {Widboom,P. and Fielding, E. and Liu, Y. and Bruner, S.},
abstractNote = {Enzyme-catalyzed oxidations are some of the most common transformations in primary and secondary metabolism. The vancomycin biosynthetic enzyme DpgC belongs to a small class of oxygenation enzymes that are not dependent on an accessory cofactor or metal ion1. The detailed mechanism of cofactor-independent oxygenases has not been established. Here we report the first structure of an enzyme of this oxygenase class in complex with a bound substrate mimic. The use of a designed, synthetic substrate analogue allows unique insights into the chemistry of oxygen activation. The structure confirms the absence of cofactors, and electron density consistent with molecular oxygen is present adjacent to the site of oxidation on the substrate. Molecular oxygen is bound in a small hydrophobic pocket and the substrate provides the reducing power to activate oxygen for downstream chemical steps. Our results resolve the unique and complex chemistry of DpgC, a key enzyme in the biosynthetic pathway of an important class of antibiotics. Furthermore, mechanistic parallels exist between DpgC and cofactor-dependent flavoenzymes, providing information regarding the general mechanism of enzymatic oxygen activation.},
doi = {10.1038/nature05702},
journal = {Nature},
number = ,
volume = 447,
place = {United States},
year = {Mon Jan 01 00:00:00 EST 2007},
month = {Mon Jan 01 00:00:00 EST 2007}
}