Abstract
In the midgut of the mosquito Aedes aegypti, a vector of dengue and yellow fever, an intense release of heme and iron takes place during the digestion of a blood meal. Here, we demonstrated via chromatography, light absorption and mass spectrometry that xanthurenic acid (XA), a product of the oxidative metabolism of tryptophan, is produced in the digestive apparatus after the ingestion of a blood meal and reaches milimolar levels after 24 h, the period of maximal digestive activity. XA formation does not occur in the White Eye (WE) strain, which lacks kynurenine hydroxylase and accumulates kynurenic acid. The formation of XA can be diminished by feeding the insect with 3,4-dimethoxy-N-[4-(3-nitrophenyl)thiazol-2-yl] benzenesulfonamide (Ro-61-8048), an inhibitor of XA biosynthesis. Moreover, XA inhibits the phospholipid oxidation induced by heme or iron. A major fraction of this antioxidant activity is due to the capacity of XA to bind both heme and iron, which occurs at a slightly alkaline pH (7.5-8.0), a condition found in the insect midgut. The midgut epithelial cells of the WE mosquito has a marked increase in occurrence of cell death, which is reversed to levels similar to the wild type mosquitoes by feeding the insects with blood supplemented with XA, confirming the protective role of this molecule. Collectively, these results suggest a new role for XA as a heme and iron chelator that provides protection as an antioxidant and may help these animals adapt to a blood feeding habit.
Highlights
Feeding on vertebrate blood results in a potentially deleterious heme/iron overload in the midgut epithelium of mosquitoes [1]
Midgut homogenates from adult females were dissected 24 h after a blood meal (ABM) and analyzed by reverse phase HPLC
The species giving rise to this peak was collected and shown to be authentic kynurenic acid (KA) from its mass spectrum, which exhibited an ion peak at m/z 190.050 and daughter ions at m/z 172.039, 162.055 and 144.044 (Figure 1F and G). Peaks from both xanthurenic acid (XA) and KA from midgut showed ion peaks that were identical to those obtained upon fragmentation of standards (Spectra of standards and assignment of major ion peaks are shown in Figures S1 and S2)
Summary
Feeding on vertebrate blood results in a potentially deleterious heme/iron overload in the midgut epithelium of mosquitoes [1]. Heme degradation by heme oxygenase can lead to iron release, which can promote the formation of reactive oxygen species via the Fenton reaction [5]. Both heme accumulation and heme degradation by heme oxygenase – resulting in iron release – have been shown to occur in the midgut of Aedes aegypti [6,7]. Tryptophan is degraded by the kynurenine pathway, the first step of which is the oxidation of tryptophan, a reaction catalyzed by tryptophan 2,3-dioxygenase or indoleamine 2,3-dioxygenase, depending on the tissue and species studied [8,9] In insects, this pathway is responsible for the formation of eye pigments, the ommochromes [10]. We have demonstrated the occurrence of large amounts of XA in the midgut of Aedes aegypti and have provided evidence for an antioxidant role of XA against an oxidative challenge based on heme or iron
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