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Proteolysis of human hemoglobin by schistosome cathepsin D

Brindley, Paul J; Kalinna, Bernd; Wong, Joanna Y M; Bogitsh, Burton; King, Lynette J; Smyth, Danielle J; Verity, Christiana K; Abbenante, Giovanni; Brinkworth, Ross I; Fairlie, David P; Smythe, Mark L; Milburn, Peter J; Bielefeldt-Ohmann, Helle; Zheng, Yuan; McManus, Donald P

Description

Schistosomes feed on human blood. They employ proteases to degrade hemoglobin from ingested erythrocytes, using the residues released for amino acid metabolism. However, the identity and the role of the participating protease(s) are unclear and controversial. Confocal microscopy localized schistosomal cathepsin D to the parasite gastrodermis, and revealed elevated protease expression in females. At sub-cellular level, cathepsin D was localized to superficial digestive vacuoles of the gut and to...[Show more]

dc.contributor.authorBrindley, Paul J
dc.contributor.authorKalinna, Bernd
dc.contributor.authorWong, Joanna Y M
dc.contributor.authorBogitsh, Burton
dc.contributor.authorKing, Lynette J
dc.contributor.authorSmyth, Danielle J
dc.contributor.authorVerity, Christiana K
dc.contributor.authorAbbenante, Giovanni
dc.contributor.authorBrinkworth, Ross I
dc.contributor.authorFairlie, David P
dc.contributor.authorSmythe, Mark L
dc.contributor.authorMilburn, Peter J
dc.contributor.authorBielefeldt-Ohmann, Helle
dc.contributor.authorZheng, Yuan
dc.contributor.authorMcManus, Donald P
dc.date.accessioned2015-12-10T23:22:59Z
dc.identifier.issn0166-6851
dc.identifier.urihttp://hdl.handle.net/1885/66752
dc.description.abstractSchistosomes feed on human blood. They employ proteases to degrade hemoglobin from ingested erythrocytes, using the residues released for amino acid metabolism. However, the identity and the role of the participating protease(s) are unclear and controversial. Confocal microscopy localized schistosomal cathepsin D to the parasite gastrodermis, and revealed elevated protease expression in females. At sub-cellular level, cathepsin D was localized to superficial digestive vacuoles of the gut and to cisternae of the gastrodermal rough endoplasmic reticulum. Schistosome cathepsin D, expressed in insect cells, autoactivated at pH 3.6 to a ∼40 kDa form that cleaved the substrates o-aminobenzoyl-Ile-Glu-Phe-nitroPhe-Arg-leu-NH2 and hemoglobin. The NH2-terminal residues of mature cathepsin D of Schistosoma japonicum and Schistosoma mansoni were Asn1 and Gly1, respectively, revealing that the proregion peptide was comprised of 35 residues. The proteases cleaved hemoglobin at pH 2.5-4.6, releasing numerous fragments. S. Japonicum cathepsin D cleaved at 13 sites, S. mansoni cathepsin D at 15 sites. Early cleavage sites were αPhe33-Leu34 and βPhe41-Phe42, while others included αLeu109-Ala-110 and βLeu14-Trp15, demonstrating a preference for bulky hydrophobic residues at P1 and P1′. Most of the schistosomal cathepsin D cleavage sites were discrete from those of human cathepsin D. The gastrodermal location, elevated expression in females, acidic pH optima, similar substrate preferences in two species, and the discrete substrate preferences compared with human cathepsin D together provide compelling support for the hypothesis that schistosomal cathepsin D plays an integral role in hemoglobin proteolysis, and might be selectively targeted by drugs based on protease inhibition.
dc.publisherElsevier
dc.sourceMolecular and Biochemical Parasitology
dc.subjectKeywords: 2 aminobenzoic acid derivative; alanine; cathepsin D; hemoglobin; leucine; oligopeptide; tryptophan; unclassified drug; amino acid metabolism; animal tissue; article; cell vacuole; confocal microscopy; controlled study; drug targeting; hydrophobicity; ins Aspartic protease; Cathepsin D; Gastrodermis; Hemoglobin; Proteolysis; Schistosome
dc.titleProteolysis of human hemoglobin by schistosome cathepsin D
dc.typeJournal article
local.description.notesImported from ARIES
local.description.refereedYes
local.identifier.citationvolume112
dc.date.issued2001
local.identifier.absfor110106 - Medical Biochemistry: Proteins and Peptides (incl. Medical Proteomics)
local.identifier.ariespublicationMigratedxPub1338
local.type.statusPublished Version
local.contributor.affiliationBrindley, Paul J, University of Queensland
local.contributor.affiliationKalinna, Bernd, University of Queensland
local.contributor.affiliationWong, Joanna Y M, University of Queensland
local.contributor.affiliationBogitsh, Burton, University of Queensland
local.contributor.affiliationKing, Lynette J, University of California
local.contributor.affiliationSmyth, Danielle J, University of Queensland
local.contributor.affiliationVerity, Christiana K, University of Queensland
local.contributor.affiliationAbbenante, Giovanni, University of Queensland
local.contributor.affiliationBrinkworth, Ross I, University of Queensland
local.contributor.affiliationFairlie, David P, University of Queensland
local.contributor.affiliationSmythe, Mark L, University of Queensland
local.contributor.affiliationMilburn, Peter J, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationBielefeldt-Ohmann, Helle, University of Queensland
local.contributor.affiliationZheng, Yuan, University of Queensland
local.contributor.affiliationMcManus, Donald P, University of Queensland
local.description.embargo2037-12-31
local.bibliographicCitation.issue1
local.bibliographicCitation.startpage103
local.bibliographicCitation.lastpage112
local.identifier.doi10.1016/S0166-6851(00)00351-0
dc.date.updated2015-12-10T10:35:54Z
local.identifier.scopusID2-s2.0-0035862794
CollectionsANU Research Publications

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