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

Abstract

Malaria is transmitted from vertebrate host to mosquito vector by mature sexual blood-living stages called gametocytes. 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 degrees C below that of the vertebrate host, and a rise in pH from 7.4 to 8.0-8.2. In vivo the mosquito bloodmeal has a pH of between 7.5 and 7.6. It is thought that in vivo the second inducer is an unknown mosquito-derived gametocyte-activating factor. 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.

The development of malaria parasites in the mosquito midgut

“…Signals inducing gamete formation include a drop of temperature by approximately 5 °C, which is mandatory for gametocyte activation, and the presence of the mosquito‐derived molecule xanthurenic acid (XA), a metabolic intermediate of the tryptophan catabolism. An additional trigger of gametogenesis is the increase of extracellular pH from 7.2 to about 8 (Kawamoto et al ., 1991; Billker et al ., 1997, 1998; Garcia et al ., 1998; Sologub et al ., 2011). …”

Tryptophan metabolism in alcoholism

“…As TP controls the flux of Trp through the hepatic kynurenine-nicotinic acid pathway, it must be assumed to exert an important role in determining the rate of synthesis of the biologically active and other intermediates of the pathway. Biologically important intermediates are the convulsant kynurenine, the neurotoxic and powerful endogenous (if indirect-acting, via glutamate) agonist of the N-methyl-D-aspartate (NMDA)-type of glutamate receptors quinolinic acid, the NMDA receptor antagonist and cytoprotective kynurenic acid (Stone, 1993), the vitamin-like substance nicotinic acid, the important redox cofactors NAD + (P + ) and their reduced forms, and xanthurenic acid, which can inactivate insulin (Kotake & Murakami, 1971) and has been identified as the malaria gametocyte-activating agent (Billker et al 1998). Quinolinic acid can also inhibit gluconeogenesis (for references and discussion, see Bender, 1982).…”

Erythropoiesis and Molecular Mechanisms for Sexual Determination in Malaria Parasites

“…At the cellular level, responses to environmental changes are mediated by signaling pathways in which protein phosphorylation, in most cases, plays a crucial role. In Plasmodium, the instant environmental changes accompanying transmission from humans to mosquitos (change in temperature and pH and exposure to xanthurenic acid, a mosquito-derived molecule [10]) stimulate the process of gametogenesis, also called gametocyte activation, whereby the gametocytes develop into male or female gametes (4). Similar phenomena occur in other protozoan blood parasites, the trypanosomatids (Trypanosoma and Leishmania spp.…”