J Am Chem Soc
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States.
Published: August 2011
Flavin-dependent monooxygenases (FMOs) are involved in important biosynthetic pathways in diverse organisms, including production of the siderophores used for the import and storage of essential iron in serious pathogens. We have shown that the FMO from Aspergillus fumigatus, an ornithine monooxygenase (Af-OMO), is mechanistically similar to its well-studied distant homologues from mammalian liver. The latter are highly promiscuous in their choice of substrates, while Af-OMO is unusually specific. This presents a puzzle: how do Af-OMO and other FMOs of the biosynthetic classes achieve such specificity? We have discovered substantial enhancement in the rate of O(2) activation in Af-OMO in the presence of L-arginine, which acts as a small molecule regulator. Such protein-level regulation could help explain how this and related biosynthetic FMOs manage to couple O(2) activation and substrate hydroxylation to each other and to the appropriate cellular conditions. Given the essentiality of Fe to Af and the avirulence of the Af-OMO gene knock out, inhibitors of Af-OMO are likely to be drug targets against this medically intractable pathogen.
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http://dx.doi.org/10.1021/ja203397s | DOI Listing |
Proc Natl Acad Sci U S A
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School of Biomolecular Science and Engineering, Vidyasirimedhi Institute of Science and Technology (VISTEC), Rayong 10120, Thailand.
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School of Biomolecular Science and Engineering, Vidyasirimedhi Institute of Science and Technology (VISTEC) Wangchan Valley Rayong Thailand
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Max Planck Institute for Chemical Ecology, Department of Natural Product Biosynthesis, Jena, Germany. Electronic address:
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