Creative Biolabs provides potential targets exploiting and validation services for antifungal drug discovery. Based on extensive experience and advanced technology, we are able to offer flavin-dependent monooxygenase siderophore A target exploiting service for global customers.
Introduction of Flavin-dependent Monooxygenase Siderophore A
Flavin-dependent monooxygenase siderophore A (SidA) is a flavin-dependent monooxygenase that belongs to the Class B flavin-dependent monooxygenase family of enzymes. It has the ability to catalyze the hydroxylation of ornithine to N5-hydroxyornithine, which is subsequently incorporated into siderophores to make the iron binding hydroxamate moiety. Also, it can utilize NAD(P)H to reduce the flavin cofactor in order to react with molecular oxygen to form a C4a-hydroperoxyflavin intermediate, which is critical for hydroxylation. In the absence of ornithine, this intermediate is very stable, eventually decaying to hydrogen peroxide and oxidized flavin. However, rapid turnover will occur when ornithine is present. Furthermore, stabilization of the C4a-hydroperoxyflavin intermediate ensures that the enzyme couples NADPH oxidation and oxygen activation with ornithine hydroxylation.
Fig.1 Docking of celastrol in the active site of SidA. (Martín, 2016)
Flavin-dependent Monooxygenase Siderophore A as Potential Antifungal Target
Although abundant on the earth’s crust, the bioavailability of iron is low due to its reaction with oxygen. In particular, the availability of free iron in humans is even more limited because it is found in complex with iron-binding molecules (e.g. hemoglobin and myoglobin). During infection, the level of free iron is further decreased by the increased levels of ferritin and the release of lactoferrin from neutrophils. To overcome the iron starvation conditions present in humans, fungus, such as A. fumigates, turn on its siderophore-assisted iron uptake machinery by producing four hydroxamate containing siderophores. It has been reported that the first step in the biosynthesis of all four hydroxamate-containing siderophores is catalyzed by the enzyme siderophore A (SidA). Moreover, deletion of the gene coding for SidA (ΔsidA) results in a strain unable to produce siderophores. In this condition, SidA can be used as an attractive drug target for the treatment of fungus infections.
With the help of professional scientists, we have successfully offered a series of target identification and validation services for global customers. We will try our best to meet every client’s specific requirements. In addition to SidA target exploiting, we also provide other potential cellular function-related targets exploiting service for antifungal drug discovery, which including but not limited to:
Creative Biolabs is committed to promoting the development of global customers’ programs through various methods, such as WGS, computer-aided target identification and validation, gene expression profiling, etc. To learn more information about our antifungal drug discovery services, please feel free to contact us.
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