Heparan Sulfate Modulates Kinin Release by Trypanosoma cruzi through the Activity of Cruzipain

Trypanosoma cruzi activates the kinin pathway through the activity of its major cysteine proteinase, cruzipain. Because kininogen molecules may be displayed on cell surfaces by binding to glycosaminoglycans, we examined whether the ability of cruzipain to release kinins from high molecular weight ki...

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Bibliographic Details
Published in:The Journal of biological chemistry 2002-02, Vol.277 (8), p.5875-5881
Main Authors: Lima, Ana Paula C.A., Almeida, Paulo C., Tersariol, Ivarne L.S., Schmitz, Veronica, Schmaier, Alvin H., Juliano, Luiz, Hirata, Isaura Y., Müller-Esterl, Werner, Chagas, Jair R., Scharfstein, Julio
Format: Article
Language:English
Subjects:
Amino Acid Motifs
Amino Acid Sequence
Animals
cruzipain
Cysteine Endopeptidases - metabolism
Enzyme Activation - drug effects
heparan sulfate
Heparitin Sulfate - pharmacology
Kinetics
kininogen
Kininogens - metabolism
kinins
Kinins - metabolism
Peptide Fragments - chemistry
Peptide Fragments - metabolism
proteoglycans
Protozoan Proteins
Substrate Specificity
Trypanosoma cruzi
Trypanosoma cruzi - drug effects
Trypanosoma cruzi - enzymology
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Summary:Trypanosoma cruzi activates the kinin pathway through the activity of its major cysteine proteinase, cruzipain. Because kininogen molecules may be displayed on cell surfaces by binding to glycosaminoglycans, we examined whether the ability of cruzipain to release kinins from high molecular weight kininogen (HK) is modulated by heparan sulfate (HS). Kinetic assays show that HS reduces the cysteine proteinase inhibitory activity (Kiapp) of HK about 10-fold. Conversely, the catalytic efficiency of cruzipain on kinin-related synthetic fluorogenic substrates is enhanced up to 6-fold in the presence of HS. Analysis of the HK breakdown products generated by cruzipain indicated that HS changes the pattern of HK cleavage products. Direct measurements of bradykinin demonstrated an up to 35-fold increase in cruzipain-mediated kinin liberation in the presence of HS. Similarly, kinin release by living trypomastigotes increased up to 10-fold in the presence of HS. These studies suggest that the efficiency of T. cruzi to initiate kinin release is potently enhanced by the mutual interactions between cruzipain, HK, and heparan sulfate proteoglycans.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M108518200