Bestatin-based chemical biology strategy reveals distinct roles for malaria M1- and M17-family aminopeptidases
| Autor: | James C. Whisstock, Geetha Velmourougane, Dustin Brisson, Michael Klemba, Michael B. Harbut, Özlem Önder, Sheena McGowan, Gilana Reiss, Doron C. Greenbaum, Seema Dalal |
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| Rok vydání: | 2011 |
| Předmět: |
Models
Molecular Proteolysis Molecular Sequence Data Plasmodium falciparum Chemical biology Protein Array Analysis Molecular Probe Techniques Vacuole Biology Aminopeptidases Substrate Specificity Hemoglobins Leucyl Aminopeptidase Leucine Peptide Library parasitic diseases medicine Parasite hosting Amino Acid Sequence Enzyme Inhibitors chemistry.chemical_classification Oligopeptide Multidisciplinary medicine.diagnostic_test medicine.disease biology.organism_classification Malaria Enzyme chemistry Biochemistry PNAS Plus Molecular Probes Multigene Family Peptides Protein Processing Post-Translational |
| Popis: | 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 Plasmodium 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 life cycle, prior to the onset of Hb degradation suggesting that Pf-LAP has an essential role outside of Hb digestion. |
| Databáze: | OpenAIRE |
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