ArticleThe Journal of biological chemistry2016
Unexpected Activity of a Novel Kunitz-type Inhibitor: INHIBITION OF CYSTEINE PROTEASES BUT NOT SERINE PROTEASES.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 40 citations in OpenAlex.
- Evolution of the reproductive interactome and the origins of postmating-prezygotic reproductive divergence.BMC biology · 2026Article
- In vitro co-culture ofVirulence · 2025Article
- Antibody detection against Kunitz-type protein inInternational journal of veterinary science and medicine · 2023Article
- Article
- Molecular Characterization of Kunitz-Type Protease Inhibitors from Blister Beetles (Coleoptera, Meloidae).Biomolecules · 2022Article
- Targeting Secreted Protease/Anti-Protease Balance as a Vaccine Strategy against the HelminthVaccines · 2022Article
- Pathogenicity and virulence of the liver flukesVirulence · 2021Article
- Antigen-specific response of CD4Veterinary research · 2021Article
- Structure-Activity Relationship and Molecular Docking of a Kunitz-Like Trypsin Inhibitor, Kunitzin-AH, from the Skin Secretion ofPharmaceutics · 2021Article
- Complementary transcriptomic and proteomic analyses reveal the cellular and molecular processes that drive growth and development of Fasciola hepatica in the host liver.BMC genomics · 2021Article
- An atypical and functionally diverse family of Kunitz-type cysteine/serine proteinase inhibitors secreted by the helminth parasite Fasciola hepatica.Scientific reports · 2020Article
- Evolutionary Aspects of the Structural Convergence and Functional Diversification of Kunitz-Domain Inhibitors.Journal of molecular evolution · 2020Review
- Fasciola hepatica serine protease inhibitor family (serpins): Purposely crafted for regulating host proteases.PLoS neglected tropical diseases · 2020Article
- Bioinformatics analysis and characterization of a secretory cystatin from Thelohanellus kitauei.AMB Express · 2020Article
- A Vaccine Based on Kunitz-Type Molecule Confers Protection AgainstFrontiers in immunology · 2020Article
- A Kunitz-type peptide fromThe journal of venomous animals and toxins including tropical diseases · 2020Article
- Review
- A Novel Kunitzin-Like Trypsin Inhibitor Isolated from Defensive Skin Secretion ofBiomolecules · 2019Article
- Comparison of recombinant cathepsins L1, L2, and L5 as ELISA targets for serodiagnosis of bovine and ovine fascioliasis.Parasitology research · 2018Article
- Green mamba peptide targets type-2 vasopressin receptor against polycystic kidney disease.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Kunitz-type (KT) protease inhibitors are low molecular weight proteins classically defined as serine protease inhibitors. We identified a novel secreted KT inhibitor associated with the gut and parenchymal tissues of the infective juvenile stage of Fasciola hepatica, a helminth parasite of medical and veterinary importance. Unexpectedly, recombinant KT inhibitor (rFhKT1) exhibited no inhibitory activity toward serine proteases but was a potent inhibitor of the major secreted cathepsin L cysteine proteases of F. hepatica, FhCL1 and FhCL2, and of human cathepsins L and K (Ki = 0.4-27 nm). FhKT1 prevented the auto-catalytic activation of FhCL1 and FhCL2 and formed stable complexes with the mature enzymes. Pulldown experiments from adult parasite culture medium showed that rFhKT1 interacts specifically with native secreted FhCL1, FhCL2, and FhCL5. Substitution of the unusual P1 Leu(15) within the exposed reactive loop of FhKT1 for the more commonly found Arg (FhKT1Leu(15)/Arg(15)) had modest adverse effects on the cysteine protease inhibition but conferred potent activity against the serine protease trypsin (Ki = 1.5 nm). Computational docking and sequence analysis provided hypotheses for the exclusive binding of FhKT1 to cysteine proteases, the importance of the Leu(15) in anchoring the inhibitor into the S2 active site pocket, and the inhibitor's selectivity toward FhCL1, FhCL2, and human cathepsins L and K. FhKT1 represents a novel evolutionary adaptation of KT protease inhibitors by F. hepatica, with its prime purpose likely in the regulation of the major parasite-secreted proteases and/or cathepsin L-like proteases of its host.
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