Letter

Nature 447, 342-345 (17 May 2007) | doi:10.1038/nature05702; Received 17 January 2007; Accepted 23 February 2007

Structural basis for cofactor-independent dioxygenation in vancomycin biosynthesis

Paul F. Widboom1,2, Elisha N. Fielding1,2, Ye Liu1 & Steven D. Bruner1

  1. Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, USA
  2. These authors contributed equally to this work.

Correspondence to: Steven D. Bruner1 Correspondence and requests for materials should be addressed to S.D.B. (Email: bruner@bc.edu).

Enzyme-catalysed 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 antibiotics2. Furthermore, mechanistic parallels exist between DpgC and cofactor-dependent flavoenzymes3, providing information regarding the general mechanism of enzymatic oxygen activation.

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