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Schistosome egg production is dependent upon the activities of two developmentally regulated tyrosinases
Jennifer M Fitzpatrick1, Yuriko Hirai, Hirohisa Hirai
1Department of Pathology, University of Cambridge, Tennis Court Rd., CB2 1QP, UK.
Abstract:
Egg production is responsible for life cycle progression and host immunopathology during schistosomiasis, with the associated parasite molecules being investigated as potential novel chemotherapeutic targets. Here, we characterize two Schistosoma mansoni products, tyrosinase 1 and tyrosinase 2 (SmTYR1/SmTYR2) and show that their diphenol oxidase enzyme activities are critical for eggshell formation and production. The genes encoding these bifunctional enzymes (monophenol and diphenol oxidases) result from a duplication event that likely occurred before speciation and exist in the parasite's genome as multiple copies, which are linked and localized to chromosomes 4 and W. SmTYR1/SmTYR2 transcription and diphenol oxidase action are developmentally regulated with most enzyme activity localized to the eggshell-producing cells contained within the vitellaria of adult female worms. Importantly, kojic-acid mediated inhibition (IC50=0.5 microM) of SmTYR1/SmTYR2's diphenol oxidase activity during in vitro culture of sexually mature adult worms resulted in a significant decrease in the production of phenotypically normal eggs. Therefore our data suggest that SmTYR1/2 inhibition represents a novel and potentially effective strategy for combating schistosomiasis and furthermore, it may point to new methods for combinatorial control of immunopathology and egg transmission during platyhelminth infection.
Insights
Schistosoma mansoni tyrosinases (SmTYR1/SmTYR2) are crucial for eggshell formation. Inhibiting their diphenol oxidase activity significantly reduces egg production, offering a novel schistosomiasis treatment strategy.
Area of Science:
- Biochemistry
- Parasitology
- Molecular Biology
Background:
- Egg production in Schistosoma mansoni is vital for parasite lifecycle and host immunopathology.
- Parasite molecules involved in egg production are potential targets for novel chemotherapeutics.
Purpose of the Study:
- To characterize Schistosoma mansoni tyrosinase 1 and 2 (SmTYR1/SmTYR2).
- To investigate the role of SmTYR1/SmTYR2 diphenol oxidase activity in eggshell formation and production.
- To evaluate SmTYR1/SmTYR2 inhibition as a potential schistosomiasis control strategy.
Main Methods:
- Characterization of SmTYR1/SmTYR2 enzyme activities.
- Gene duplication and localization analysis.
- Developmental regulation studies of SmTYR1/SmTYR2 transcription and activity.
- In vitro inhibition assays using kojic acid.
Main Results:
- SmTYR1/SmTYR2 possess critical diphenol oxidase activity for eggshell formation.
- These genes result from a duplication event and exist as multiple copies on chromosomes 4 and W.
- Enzyme activity is developmentally regulated, primarily in adult female worm vitellaria.
- Kojic acid inhibition (IC50=0.5 microM) significantly reduced normal egg production in vitro.
Conclusions:
- SmTYR1/SmTYR2 are essential for Schistosoma mansoni egg production.
- Inhibition of SmTYR1/SmTYR2 diphenol oxidase activity is a promising therapeutic strategy against schistosomiasis.
- This approach may offer new methods for controlling parasite immunopathology and transmission.
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