Regulated O₂ Activation in Flavin-Dependent Monooxygenases

Abstract

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 O2 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 O2 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.

Characterization of the Link between Ornithine, Arginine, Polyamine and Siderophore Metabolism in Aspergillus fumigatus

“…Consistent with cellular balancing of SB and arginine metabolism, arginine was recently identified to allosterically activate the ornithine monooxygenase SidA and consequently SB-mediated ornithine consumption [42]. The rational for this regulation might be that A. fumigatus possesses reductive iron assimilation as an alternative ornithine-independent high-affinity iron acquisition system [4].…”

Quantifying Integrated Proteomic Responses to Iron Stress in the Globally Important Marine Diazotroph Trichodesmium

“…erythraeum IMS101 genome but Tery_3825 contains a putative lipase/esterase conserved domain (pfam01764) ( S2 Fig ). Tery_3824 (observed but not Fe regulated) contains a TrkA conserved domain predicted to be involved in inorganic ion transport (COG2072), whilst Tery_3826 has a conserved flavin-binding monooxygenase (pfam13738) known to be involved in siderophore production [ 67 ] ( S2 Fig ). Although not thought to produce siderophores, Trichodesmium colonies have been shown to be capable of Fe acquisition from externally derived siderophores [ 49 , 51 ].…”

Fungal siderophore metabolism with a focus onAspergillus fumigatus

“…l -arginine is vital for protein biosynthesis and ornithine is a precursor for polyamine biosynthesis. Recently, l -arginine was found to allosterically activate SidA enzyme activity, 84 i.e. is stimulated only if the cytosolic l -arginine pool is sufficient for all cellular needs.…”