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A bestatin-based chemical biology strategy reveals distinct roles for malaria M1- and M17-family aminopeptidases (3T8V, 3T8W)

Monash University
DC Greenbaum (Aggregated by) M Klemba (Aggregated by) Sheena McGowan (Aggregated 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=info:doi10.4225/03/57428d3d67ef1&rft.title=A bestatin-based chemical biology strategy reveals distinct roles for malaria M1- and M17-family aminopeptidases (3T8V, 3T8W)&rft.identifier=http://doi.org/10.4225/03/57428d3d67ef1&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=DC Greenbaum&rft.creator=M Klemba&rft.creator=Sheena McGowan&rft.date=2016&rft_rights=&rft_subject=proteolysis&rft_subject=malaria&rft_subject=oligopeptides&rft_subject=imaginglocus&rft.type=dataset&rft.language=English Access the data

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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.

Issued: 2016-12-11

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