LONDON - More than 20 years after its existence was first predicted, scientists have unveiled the identity of a molecule that controls development of the malaria parasite in the mosquito.
The finding could enable the development of a new generation of antimalarial drugs, and could eventually lead to biological methods of control for malaria, using mutant mosquitoes which lack the chemical concerned and which therefore cannot pass on the parasite.
Since 1976, it has been known that a factor is present in the midgut of the mosquito which stimulates the next phase in the malarial parasite's life cycle following the ingestion of a blood meal.
Howard Morris, professor of biological chemistry at Imperial College of Science, Technology and Medicine, in London, now has shown the mystery molecule is xanthurenic acid, a byproduct of the tryptophan metabolic pathway which is involved in the production of eye color pigments in insects.
Morris, together with colleagues in the departments of biochemistry and biology at Imperial College, and at M-Scan Inc., of West Chester, Pa., reported the findings in a letter to Nature , March 19, 1998, titled “Identification of xanthurenic acid as the putative inducer of malaria development in the mosquito.“
Following ingestion by the mosquito of a blood meal containing malarial gametocytes, the gametocytes must escape from the red blood cells that contain them and transform into male or female gametes, a process called gametogenesis or exflagellation.
The gametes then must fertilize each other within 15 minutes if transmission of malaria to the mosquito is to be successful.
Molecule Suggested 20 Years Ago
Several decades ago, scientists showed gametogenesis could be triggered by a small fall in temperature together with a rise in pH. In 1976, however, scientist Mary Nijhout showed that even in the absence of a rise in pH, gametogenesis could be initiated in the midgut of the mosquito. She called the substance responsible “mosquito exflagellation factor,“ or MEF.
The identity of MEF remained unknown. Recently, Morris and his colleagues decided to take another look at this problem, following technological advances in purification methods and major improvements in the sensitivity of mass spectrometric structural elucidation techniques. They discovered MEF - also known as gametocyte activating factor, or GAF - was in fact xanthurenic acid.
It was already known that xanthurenic acid is manufactured as a byproduct of eye-pigment synthesis in insects. To confirm its biological role in malaria, Morris and his colleagues found GAF was present in homogenates of wild-type Drosophila melanogaster, but not in certain eye- color mutants which lack xanthurenic acid.
Commenting on the finding, Richard Carter, lecturer at the Institute of Cell, Animal and Population Biology at the University of Edinburgh, in Scotland, said: “In terms of malaria biology, this is a significant finding. It has identified the essential molecular key which directs malaria parasites to progress from the stages in the vertebrate host to begin their development in the mosquito vector.“
It was a lucky break, he added, that the molecule identified turned out to be in a well-studied area of insect biochemistry and genetics.
In a News and Views article in the same issue of Nature, Carter, together with Lisa Ranford-Cartwright of the same institute, said one crucial experiment will be to test the infectivity of human malaria parasites to eye-color mutants of Anopheles mosquitoes that cannot produce xanthurenic acid.
“Should they be refractory to infection with human malaria parasites, the role of xanthurenic acid as the 'ignition key' to transmission of malaria through mosquitoes will be effectively proved,“ they added.
Morris said his biology colleagues currently are carrying out these experiments. He told BioWorld International: “We are also working on ways of quantifying xanthurenic acid, so that we can be absolutely certain that the correct concentration, which we have demonstrated is needed in the lab, is present in vivo in the individual mosquito.
“In addition, we want to find out what xanthurenic acid binds to, and where on the gametocyte is the receptor that it activates, if indeed its action is receptor-mediated. We want to know whether we can interfere with that process, either at the receptor level or at the second-messenger level.“
The team is examining synthetic analogues of xanthurenic acid to help it determine how the molecule's structure is linked to its function. Morris added, “We expect that we may be able to find an antagonist that will bind to any putative receptor for xanthurenic acid on the gametocyte and so block it.“
Looking into the future, Morris and his colleagues suggest in Nature that it may one day be possible to use mutant mosquitoes that lack functional genes necessary for the production of xanthurenic acid as a form of biological control for malaria. *