Pheromone Study IDs Synthase That Could Produce Sandfly Bait, Prevent Leishmaniasis

Scientists at the University of Nottingham’s School of Chemistry have analyzed the genome of the sandfly Lutzomyia longipalpis to discover the specific terpene synthase (TPS) enzyme that produces the terpene pheromone sobralene, which the male sandfly uses to attract a mate. The discovery could lead to a method for producing the compound through biocatalysis, and enable the development of commercial traps designed to help target and control the spread of this South American sandfly, which can carry the potentially fatal Leishmania parasite.

Commenting on the discovery, research lead Neil Oldham, said, “Finding this enzyme has been very difficult and we have been hunting for it for over two years. The Lutzomyia genome contains an unusually high number of candidate terpene synthase genes … The beauty of the pheromone approach is that it is very specific for this insect and so the next stage of the project will be to engineer microorganisms to make the enzyme in a way that would produce the pheromone. If we can then find a way to scale this up for commercial use this would be a way to control the populations of these insects and hopefully reduce the spread of Leishmaniasis.”

Oldaham and colleagues reported on their work in PNAS, in a paper titled “A diterpene synthase from the sandfly Lutzomyia longipalpis produces the pheromone sobralene.” In their report the team concluded, “In this study, a diterpene synthase that produces the pheromone component sobralene is identified, heterologously expressed and functionally characterized … It is hoped that these findings may offer a potential route to sustainable production of the isomerically pure compound.”

Over 90 sandfly species are known to transmit Leishmania parasites that are spread to humans through being bitten, but Lutzomyia longipalpis, which is which is native to Brazil, is the major carrier of the disease in South America. “The phlebotomine sandfly Lutzomyia longipalpis is a vector for the Leishmania parasite, the causative pathogen of the neglected tropical disease leishmaniasis,” the authors wrote. The most common form of the disease globally is cutaneous leishmaniasis, which can result in skin ulcers and lesions that leave life-long, disfiguring scars. In more serious cases infected people can become very unwell with fever, weight loss, enlargement of the spleen and liver, and anaemia. The most serious form of the disease, known as visceral leishmaniasis, is invariably fatal within two years if untreated. Most cases of visceral leishmaniasis occur in Brazil, but the disease can be found in large parts of the tropics and subtropics.

Terpene synthases are responsible for the biosynthesis of many chemicals used by plants and microorganisms for defense and communication. However, they noted, “Although many TPSs derived from plants and microorganisms have been identified, far fewer examples from insects are known.” In fact, the team continued, “What has emerged only relatively recently is the understanding that insects are themselves capable of biosynthesizing terpenes without the direct input of plants or microorganisms … our understanding of how these structurally diverse natural products are produced by insects is only now beginning to emerge.

Males of the sandfly, Lutzomyia longipalpis, use terpene pheromones to lure females and other males to mating sites, and the newly reported research identifies the first insect terpene synthase (TPS) from this species. The team was able to produce the enzyme in bacteria. “Examination of the L. longipalpis genome revealed a putative terpene synthase (TPS), which—upon heterologous expression in, and purification from, Escherichia coli—yielded a functional enzyme,” they wrote. “This represents identification of a terpene synthase (TPS) from Lutzomyia and shows that insects are capable of biosynthesizing diterpenes. It offers the potential for sustainable production of this compound through biocatalysis.”

Oldham noted,”… thanks to the persistence of Dr. Charlie Ducker, a talented researcher on the team, we were able to find the one that makes the pheromone.” In their paper, the authors further reported, “It is pleasing to confirm that insects are capable of making diterpenes without reliance upon the enzymatic machinery of plants or microorganisms.” Currently, there is no synthetic chemical route to producing sobralene,” they pointed out, and it is unlikely that sustainable and commercially viable production will be achieved by chemical means. “Having identified a sobralene-producing enzyme, we are now exploring its potential as a viable source of the pheromone for vector control,” they said.

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