Flavin-dependent Monooxygenases in Siderophore Biosynthesis

Abstract

Microbial N-hydroxylating monooxygenases (NMOs) are a class of flavin-dependent enzymes involved in the biosynthesis of hydroxamate-containing siderophores. These flavoenzymes catalyze the NADPH- and oxygen-dependent N-hydroxylation of a narrow group of substrates that include L-ornithine, L-lysine, and primary aliphatic diamines. Siderophores are essential for microbial pathogenesis and the activities of NMOs are essential for their biosynthesis and function. To date, only a small number of NMOs have been characterized. While the biochemical properties of NMOs vary, two common characteristics have been observed. These include a high degree of substrate specifi city and the stabilization of a long-lived C4a-hydroperoxyflavin intermediate. These properties ensure effi cient hydroxylation of the appropriate substrate and minimal release of hydrogen peroxide, respectively. Recent mechanistic and structural studies have provided insight into the molecular mechanisms of these two traits. The high substrate specifi city has been attributed to a unique "molecular ruler mechanism," and stabilization of the C4a-hydroperoxyflavin is achieved by specifi c interactions with NADP+. In addition, a high-throughput screening assay that allows for identifi cation of NMO inhibitors from small molecule libraries has been developed. This, compounded with rational drug design, holds promise for the identifi cation of inhibitors to combat increasingly virulent microbes.

Department(s)

Chemistry

International Standard Book Number (ISBN)

978-311029834-5;978-311029828-4

Document Type

Article - Journal

Document Version

Citation

File Type

text

Language(s)

English

Rights

© 2024 Walter de Gruyter GmbH, All rights reserved.

Publication Date

01 Jan 2013

Link to Full Text

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