Targeting a reductive dehalogenase as a new strategy for controlling mosquito populations

Johns Hopkins University, Baltimore MD

Investigators

Abstract

ABSTRACT Targeting a reductive dehalogenase as a new strategy for controlling mosquito populations The enzyme iodotyrosine deiodinase gained prominence from its role in salvaging iodide from iodotyrosine. This activity is necessary for generating the iodinated hormone thyroxine that is required for all vertebrates. Surprisingly, this enzyme was also found nearly ubiquitous in invertebrates that do not require iodide nor generate thyroxine. Initial studies have suggested that its ability to process a range of halotyrosines (X = I, Br, Cl, not F) remains the same in fruit flies, but its biological role is quite different. The dehalogenase protects flies from the accumulation of endogenous halotyrosine that would otherwise suppress male fertility. Inhibition of the dehalogenase or accumulation of a halotyrosine in vivo significantly decreases fly populations by a mechanism orthogonal to those currently used to mitigate vector-borne disease. Homologs of the dehalogenase are present in most insects and offer a new and potent target for eliminating such vectors if the results from fruit flies extend to other invertebrates. The Anopheles gambiae mosquito was selected as the test organism in our investigations due to its importance as a vector of malaria. Despite a vast amount of research and field work, this disease remains a health priority and its return has recently been reported in the United States. Knowledge gained from fruit flies now guides our experiments on the mosquito. Loss of fertility will be examined after alternative external exposure to halotyrosines and internal suppression of the dehalogenase by chemical and genetic strategies. Analytical chemistry will identify which halotyrosine is generated endogenously and whether halogenation targets tyrosine free in solution or tyrosyl residues within proteins. Initial efforts are also planned to identify the peroxidase responsible for halogenation to build a foundation for broad investigations in the future on the nature and function of an overlooked cycle of halogenation and dehalogenation in insects. The most immediate impact of these studies will derive from a newfound ability to limit mosquito populations and the diseases that they spread.