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A bestatin-based chemical biology strategy reveals distinct roles for malaria M1- and M17-family aminopeptidases

Monash University
Dr Sheena McGowan (Owned by)
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ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Adc&rfr_id=info%3Asid%2FANDS&rft_id=https://mytardis.its.monash.edu.au/experiment/view/636&rft.title=A bestatin-based chemical biology strategy reveals distinct roles for malaria M1- and M17-family aminopeptidases&rft.identifier=experiment/view/636&rft.publisher=Monash University&rft.description=Malaria causes worldwide morbidity and mortality, and while chemotherapy remains an excellent means of malaria control, drug-resistant parasites necessitate the discovery of new antimalarials. Peptidases are a promising class of drug targets and perform several important roles during the P. falciparum erythrocytic life cycle. Herein, we report a multidisciplinary effort combining activity-based protein profiling, biochemical, and peptidomic approaches to functionally analyze two genetically essential P. falciparum metallo-aminopeptidases (MAPs), PfA-M1 and Pf-LAP. Through the synthesis of a suite of activity-based probes (ABPs) based on the general MAP inhibitor scaffold, bestatin, we generated specific ABPs for these two enzymes. Specific inhibition of PfA-M1 caused swelling of the parasite digestive vacuole and prevented proteolysis of hemoglobin (Hb)-derived oligopeptides, likely starving the parasite resulting in death. In contrast, inhibition of Pf-LAP was lethal to parasites early in the lifecycle, prior to the onset of Hb degradation suggesting that Pf-LAP has an essential role outside of Hb digestion.&rft.creator=Dr Sheena McGowan&rft.date=2011&rft_subject=Biochemistry and Cell Biology&rft_subject=Biological Sciences&rft_subject=Medical Biochemistry and Metabolomics&rft_subject=Medical and Health Sciences&rft_subject=Macromolecular Crystallography&rft_subject=Diffraction&rft_subject=Protein Structure&rft_subject=X-Ray&rft_subject=Synchrotron&rft.type=dataset&rft.language=English Access the data

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Creative Commons Attribution-NonCommercial-NoDerivs 2.5 Australia

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Monash University Clayton Campus Building 75 Clayton 3800 Victoria



Brief description

Malaria causes worldwide morbidity and mortality, and while chemotherapy remains an excellent means of malaria control, drug-resistant parasites necessitate the discovery of new antimalarials. Peptidases are a promising class of drug targets and perform several important roles during the P. falciparum erythrocytic life cycle. Herein, we report a multidisciplinary effort combining activity-based protein profiling, biochemical, and peptidomic approaches to functionally analyze two genetically essential P. falciparum metallo-aminopeptidases (MAPs), PfA-M1 and Pf-LAP. Through the synthesis of a suite of activity-based probes (ABPs) based on the general MAP inhibitor scaffold, bestatin, we generated specific ABPs for these two enzymes. Specific inhibition of PfA-M1 caused swelling of the parasite digestive vacuole and prevented proteolysis of hemoglobin (Hb)-derived oligopeptides, likely starving the parasite resulting in death. In contrast, inhibition of Pf-LAP was lethal to parasites early in the lifecycle, prior to the onset of Hb degradation suggesting that Pf-LAP has an essential role outside of Hb digestion.
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  • Local : experiment/view/636