title: Structure and substrate fingerprint of aminopeptidase P from Plasmodium falciparum.
abstract: Malaria is one of the world's most prevalent parasitic diseases, with over 200 million cases annually. Alarmingly, the spread of drug-resistant parasites threatens the effectiveness of current antimalarials and has made the development of novel therapeutic strategies a global health priority. Malaria parasites have a complicated lifecycle, involving an asymptomatic 'liver stage' and a symptomatic 'blood stage'. During the blood stage, the parasites utilise a proteolytic cascade to digest host hemoglobin, which produces free amino acids absolutely necessary for parasite growth and reproduction. The enzymes required for hemoglobin digestion are therefore attractive therapeutic targets. The final step of the cascade is catalyzed by several metalloaminopeptidases, including aminopeptidase P (APP). We developed a novel platform to examine the substrate fingerprint of APP from Plasmodium falciparum (PfAPP) and to show that it can catalyze the removal of any residue immediately prior to a proline. Further, we have determined the crystal structure of PfAPP and present the first examination of the 3D structure of this essential malarial enzyme. Together, these analyses provide insights into potential mechanisms of inhibition that could be used to develop novel antimalarial therapeutics.
authors.affiliation: Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton Campus, Melbourne, VIC 3800, Australia.
authors.forename: Nyssa
authors.initials: N
authors.lastname: Drinkwater
authors.affiliation: Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton Campus, Melbourne, VIC 3800, Australia.
authors.forename: Komagal Kannan
authors.initials: KK
authors.lastname: Sivaraman
authors.affiliation: Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton Campus, Melbourne, VIC 3800, Australia.
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Bamert
authors.affiliation: Department of Bioorganic Chemistry, Faculty of Chemistry, Wroclaw University of Technology, Wroclaw, Poland.
authors.forename: Wioletta
authors.initials: W
authors.lastname: Rut
authors.affiliation: Department of Bioorganic Chemistry, Faculty of Chemistry, Wroclaw University of Technology, Wroclaw, Poland.
authors.forename: Khadija
authors.initials: K
authors.lastname: Mohamed
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville Campus, Parkville, VIC 3052, Australia.
authors.forename: Natalie B
authors.initials: NB
authors.lastname: Vinh
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville Campus, Parkville, VIC 3052, Australia.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Scammells
authors.affiliation: Department of Bioorganic Chemistry, Faculty of Chemistry, Wroclaw University of Technology, Wroclaw, Poland.
authors.forename: Marcin
authors.initials: M
authors.lastname: Drag
authors.affiliation: Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton Campus, Melbourne, VIC 3800, Australia.
authors.forename: Sheena
authors.initials: S
authors.lastname: McGowan
mesh_terms: D000626:Aminopeptidases / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D018360:Crystallography, X-Ray; D019281:Dimerization; D004926:Escherichia coli / Q000201:enzymology; D008958:Models, Molecular; D010963:Plasmodium falciparum / Q000201:enzymology*; D011487:Protein Conformation; D059748:Proteolysis; D013379:Substrate Specificity
chemical_list: D000626:Aminopeptidases; C022750:X-Pro aminopeptidase
keywords: Plasmodium falciparum; aminopeptidase; crystallography; malaria; protease inhibitor; substrate specificity