Hemoglobin-degrading, aspartic proteases of blood-feeding parasites - Substrate specificity revealed by homology models

Brinkworth, Ross I., Prociv, Paul, Loukas, Alexander and Brindley, Paul J. (2001) Hemoglobin-degrading, aspartic proteases of blood-feeding parasites - Substrate specificity revealed by homology models. Journal of Biological Chemistry, 276 42: 38844-38851. doi:10.1074/jbc.M101934200

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Author Brinkworth, Ross I.
Prociv, Paul
Loukas, Alexander
Brindley, Paul J.
Title Hemoglobin-degrading, aspartic proteases of blood-feeding parasites - Substrate specificity revealed by homology models
Journal name Journal of Biological Chemistry   Check publisher's open access policy
ISSN 0021-9258
Publication date 2001-10-18
Sub-type Article (original research)
DOI 10.1074/jbc.M101934200
Open Access Status File (Publisher version)
Volume 276
Issue 42
Start page 38844
End page 38851
Total pages 8
Editor H. Taber
Place of publication Bethesda MD
Publisher American Society for Biochemistry & Molecular Biology
Language eng
Subject C1
320299 Immunology not elsewhere classified
730101 Infectious diseases
Abstract Blood-feeding parasites, including schistosomes, hookworms, and malaria parasites, employ aspartic proteases to make initial or early cleavages in ingested host hemoglobin. To better understand the substrate affinity of these aspartic proteases, sequences were aligned with and/or three-dimensional, molecular models were constructed of the cathepsin D-like aspartic proteases of schistosomes and hookworms and of plasmepsins of Plasmodium falciparum and Plasmodium vivax, using the structure of human cathepsin D bound to the inhibitor pepstatin as the template. The catalytic subsites S5 through S4' were determined for the modeled parasite proteases. Subsequently, the crystal structure of mouse renin complexed with the nonapeptidyl inhibitor t-butyl-CO-His-Pro-Phe-His-Leu [CHOHCH2]Leu-Tyr-Tyr-Ser-NH2 (CH-66) was used to build homology models of the hemoglobin-degrading peptidases docked with a series of octapeptide substrates. The modeled octapeptides included representative sites in hemoglobin known to be cleaved by both Schistosoma japonicum cathepsin D and human cathepsin D, as well as sites cleaved by one but not the other of these enzymes. The peptidase-octapeptide substrate models revealed that differences in cleavage sites were generally attributable to the influence of a single amino acid change among the P5 to P4' residues that would either enhance or diminish the enzymatic affinity. The difference in cleavage sites appeared to be more profound than might be expected from sequence differences in the enzymes and hemoglobins. The findings support the notion that selective inhibitors of the hemoglobin-degrading peptidases of blood-feeding parasites at large could be developed as novel anti-parasitic agents.
Keyword Biochemistry & Molecular Biology
Hookworm Ancylostoma-caninum
Human Cathepsin-d
Cysteine Proteinase
Q-Index Code C1

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Medicine Publications
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Created: Wed, 15 Aug 2007, 02:47:25 EST