Abstract
BackgroundAcetylcholinesterase (AChE) is an important metabolic enzyme of schistosomes present in the musculature and on the surface of the blood stage where it has been implicated in the modulation of glucose scavenging from mammalian host blood. As both a target for the antischistosomal drug metrifonate and as a potential vaccine candidate, AChE has been characterised in the schistosome species Schistosoma mansoni, S. haematobium and S. bovis, but not in S. japonicum. Recently, using a schistosome protein microarray, a predicted S. japonicum acetylcholinesterase precursor was significantly targeted by protective IgG1 immune responses in S. haematobium-exposed individuals that had acquired drug-induced resistance to schistosomiasis after praziquantel treatment.ResultsWe report the full-length cDNA sequence and describe phylogenetic and molecular structural analysis to facilitate understanding of the biological function of AChE (SjAChE) in S. japonicum. The protein has high sequence identity (88 %) with the AChEs in S. mansoni, S. haematobium and S. bovis and has 25 % sequence similarity with human AChE, suggestive of a highly specialised role for the enzyme in both parasite and host. We immunolocalized SjAChE and demonstrated its presence on the surface of adult worms and schistosomula, as well as its lower expression in parenchymal regions. The relatively abundance of AChE activity (90 %) present on the surface of adult S. japonicum when compared with that reported in other schistosomes suggests SjAChE may be a more effective drug or immunological target against this species. We also demonstrate that the classical inhibitor of AChE, BW285c51, inhibited AChE activity in tegumental extracts of paired worms, single males and single females by 59, 22 and 50 %, respectively, after 24 h incubation with 200 μM BW284c51.ConclusionsThese results build on previous studies in other schistosome species indicating major differences in the enzyme between parasite and mammalian host, and provide further support for the design of an anti-schistosome intervention targeting AChE.
Highlights
Acetylcholinesterase (AChE) is an important metabolic enzyme of schistosomes present in the musculature and on the surface of the blood stage where it has been implicated in the modulation of glucose scavenging from mammalian host blood
All residues within the AChE protein sequence that are currently known to be important for substrate binding and catalytic activity, i.e. those comprising the peripheral anionic site [27], the catalytic triad substrate inhibition of acetylcholinesterase residues involved in signal transduction from the surface to the catalytic center [28], and those lining the catalytic gorge [29], are conserved across all Schistosoma species
After comparisons with other species and the schistosome sequences published by Bentley et al [30], we demonstrated that the catalytic and peripheral active site residues in S. japonicum, S. mansoni, S. haematobium and S. bovis are all conserved, especially when taking into consideration the accepted standard primary AChE (1EA5_A) sequence from the ray Torpedo californica
Summary
Acetylcholinesterase (AChE) is an important metabolic enzyme of schistosomes present in the musculature and on the surface of the blood stage where it has been implicated in the modulation of glucose scavenging from mammalian host blood. As both a target for the antischistosomal drug metrifonate and as a potential vaccine candidate, AChE has been characterised in the schistosome species Schistosoma mansoni, S. haematobium and S. bovis, but not in S. japonicum. During the blood dwelling stages of schistosomes, acetylcholinesterase (AChE) is present on the parasite tegument membrane [4] and in the musculature [5], both in adults and schistosomula. It has been shown that the basal rate of glucose uptake in adult Schistosoma haematobium and S. bovis is about twice that in S. mansoni [7].
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