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Identification of xanthurenic acid as the putative inducer of malaria development in the mosquito

Nature volume 392, pages 289–292 (1998)Cite this article

Abstract

Malaria is transmitted from vertebrate host to mosquito vector by mature sexual blood-living stages called gametocytes1,2. Within seconds of ingestion into the mosquito bloodmeal, gametocytes undergo gametogenesis. Induction requires the simultaneous exposure to at least two stimuli in vitro: a drop in bloodmeal temperature to 5 °C below that of the vertebrate host1,2,3, and a rise in pH from 7.4 to 8.0–8.2 (refs 1, 4). In vivo the mosquito bloodmeal has a pH of between 7.5 and 7.6 (refs 5, 6). It is thought that in vivo the second inducer is an unknown mosquito-derived gametocyte-activating factor5,7,8. Here we show that this factor is xanthurenic acid. We also show that low concentrations of xanthurenic acid can act together with pH to induce gametogenesis in vitro. Structurally related compounds are at least ninefold less effective at inducing gametogenesis in vitro. In Drosophila mutants with lesions in the kynurenine pathway of tryptophan metabolism (of which xanthurenic acid is a side product), no alternative active compound was detected in crude insect homogenates. These data could form the basis of the rational development of new methods of interrupting the transmission of malaria using drugs or new refractory mosquito genotypes to block parasite gametogenesis.

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Figure 1: Distribution of GAF activity following fractionation of crude extracts of Anopheles stephensi pupae by reverse-phase HPLC.
Figure 2: MS–MS collisionally activated decomposition spectrum of the GAF quasimolecular ion m/z 206 at 25–30 eV in argon on the Q-TOF instrument.
Figure 3
Figure 4: Ommochrome pathway of tryptophan metabolism and the effect of metabolites on exflagellation.
Figure 5: Xanthurenic acid extends the permissive pH range for exflagellation.

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Acknowledgements

We thank A. Reason and J. Redfern (M-Scan) for MALDI Voyager Elite studies. This work was supported by the UNDP/World Bank/WHO special programme for research and training in tropical diseases (R.E.S.), the German Academic Exchange Service (HSPIII grant to O.B.) and the Wellcome Trust (H.R.M., A.D.).

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Authors and Affiliations

  1. Department of Biology, Imperial College, London, SW7 2BB, UK

    O. Billker & R. E. Sinden

  2. Department of Biochemistry, Imperial College, London, SW7 2AZ, UK

    V. Lindo, M. Panico, A. E. Etienne, T. Paxton, A. Dell & H. R. Morris

  3. M-Scan Inc., 606 Brandywine Parkway, West Chester, 19380, Pennsylvania, USA

    M. Rogers

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Billker, O., Lindo, V., Panico, M. et al. Identification of xanthurenic acid as the putative inducer of malaria development in the mosquito. Nature 392, 289–292 (1998). https://doi.org/10.1038/32667

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