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Title: Crystal Structure of Schistosoma mansoni Arginase, a Potential Drug Target for the Treatment of Schistosomiasis

Authors:
; ; ; ;
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL)
Sponsoring Org.:
USDOE SC OFFICE OF SCIENCE (SC)
OSTI Identifier:
1162525
Report Number(s):
BNL-106469-2014-JA
Journal ID: ISSN 0006--2960
DOE Contract Number:
DE-AC02-98CH10886
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemistry; Journal Volume: 53; Journal Issue: 28
Country of Publication:
United States
Language:
English

Citation Formats

Hai, Y., Edwards, J., Van Zandt, M., Hoffmann, K., and Christianson, D.. Crystal Structure of Schistosoma mansoni Arginase, a Potential Drug Target for the Treatment of Schistosomiasis. United States: N. p., 2014. Web. doi:10.1021/bi5004519.
Hai, Y., Edwards, J., Van Zandt, M., Hoffmann, K., & Christianson, D.. Crystal Structure of Schistosoma mansoni Arginase, a Potential Drug Target for the Treatment of Schistosomiasis. United States. doi:10.1021/bi5004519.
Hai, Y., Edwards, J., Van Zandt, M., Hoffmann, K., and Christianson, D.. Tue . "Crystal Structure of Schistosoma mansoni Arginase, a Potential Drug Target for the Treatment of Schistosomiasis". United States. doi:10.1021/bi5004519.
@article{osti_1162525,
title = {Crystal Structure of Schistosoma mansoni Arginase, a Potential Drug Target for the Treatment of Schistosomiasis},
author = {Hai, Y. and Edwards, J. and Van Zandt, M. and Hoffmann, K. and Christianson, D.},
abstractNote = {},
doi = {10.1021/bi5004519},
journal = {Biochemistry},
number = 28,
volume = 53,
place = {United States},
year = {Tue Jul 22 00:00:00 EDT 2014},
month = {Tue Jul 22 00:00:00 EDT 2014}
}
  • Compressed tissue autoradiography using (75Se)selenomethionine labelled parasites has been used to investigate the migration potential of normal and radiation attenuated cercariae of Schistosoma mansoni in naive guinea pigs. By Day 14 after infection. 44% of normal parasites were detected as reduced silver foci in the liver; this value corresponded well with the number of liver parasites recovered by retrograde perfusion of the hepatic portal system on Day 42 (42% of the challenge). In contrast, cercariae subjected to 50 krad of gamma irradiation failed to migrate out of the skin. The migration capacity of 20 krad irradiated parasites was less severelymore » affected in that about half of the challenge parasites reached the lungs, but virtually none moved to the liver. These data are discussed in relation to the kinetics of immunity induced in guinea pigs by infection or vaccination with normal or radiation attenuated parasites.« less
  • Previous work has shown that cattle can acquire a strong resistance to Schistosoma bovis infection following repeated natural exposure. Partial resistance to a laboratory challenge with S. bovis has also been demonstrated in calves after immunization with an irradiated schistosomular or cercarial vaccine. The aim of the present study was to see whether this type of caccine could protect calves under the very different conditions of natural exposure to S. bovis in the field. Thirty 6- to 9-month-old calves were each immunized with 10,000 irradiated S. bovis schistosomula by intramuscular injection and 8 weeks later were released into an enzooticmore » area along with 30 unvaccinated animals. The calves were followed up for 10 months, during which period protection was evidenced by a lower mortality rate, a slower rate of acquisition of infection, and lower fecal egg counts in the vaccinated calves. Necropsy of the survivors showed 60 to 70% reductions in worm and tissue egg counts of the vaccinated calves as compared to those not vaccinated.« less
  • To examine the antigens of adult Schistosoma mansoni, /sup 35/S-methionine-labelled, detergent-extracted proteins were immunoprecipitated and analyzed on SDS-PAGE. Human infection serum immunoprecipitated 14 polypeptides with M/sub r/'s of 120, 105, 88, 86, 66, 64, 54, 48, 42, 38, 35, 32, 29, and 20 Kd. Upon digestion with endoglycosidase F polypeptides with M/sub r/'s of 120, 105, 54, 48, and 29 appeared to have carbohydrate moieties. Extracts of female and male S. mansoni were analyzed by immunoprecipitation and immunoblotting. Two polypeptides with M/sub r/'s of 86 Kd and 54 Kd were detected only in extracts of males. Polyadenylated RNA was extractedmore » from S. mansoni and translated in rabbit reticulocyte lysates. Among the in vitro translation products, polypeptides with 120, 94, 64, 43, 37, 35, 30, 26 and 22 Kd apparent molecular weights were immunoprecipitated by human infection serum. When the translation products of female worms and male worms were compared, the polypeptides with M/sub r/'s of 94 and 64 Kd were only observed in males.« less
  • Human arginase I is a potential target for therapeutic intervention in diseases linked to compromised L-arginine homeostasis. Here, we report high-affinity binding of the reaction coordinate analogue inhibitors 2(S)-amino-6-boronohexanoic acid (ABH, Kd = 5 nM) and S-(2-boronoethyl)-L-cysteine (BEC, Kd = 270 nM) to human arginase I, and we report x-ray crystal structures of the respective enzyme-inhibitor complexes at 1.29- and 1.94-Angstrom resolution determined from crystals twinned by hemihedry. The ultrahigh-resolution structure of the human arginase I-ABH complex yields an unprecedented view of the binuclear manganese cluster and illuminates the structural basis for nanomolar affinity: bidentate inner-sphere boronate-manganese coordination interactions andmore » fully saturated hydrogen bond networks with inhibitor {alpha}-amino and {alpha}-carboxylate groups. These interactions are therefore implicated in the stabilization of the transition state for L-arginine hydrolysis. Electron density maps also reveal that active-site residue H141 is protonated as the imidazolium cation. The location of H141 is such that it could function as a general acid to protonate the leaving amino group of L-ornithine during catalysis, and this is a revised mechanistic proposal for arginase. This work serves as a foundation for studying the structural and chemical biology of arginase I in the immune response, and we demonstrate the inhibition of arginase activity by ABH in human and murine myeloid cells.« less