the plasmodium falciparum malaria m1 alanyl aminopeptidase (pfa-m1) insights of catalytic mechanism and function from md simulations恶性疟原虫疟疾m1丙氨酰氨肽酶(pfa-m1)见解md模拟的催化机理和功能.pdfVIP

The Plasmodium falciparum Malaria M1 Alanyl Aminopeptidase (PfA-M1): Insights of Catalytic Mechanism and Function from MD Simulations 1,2 2 3 1,2 Peter M. Jones , Mark W. Robinson , John P. Dalton , Anthony M. George * 1 School of Medical and Molecular Biosciences, Sydney, New South Wales, Australia, 2 i3 Institute, University of Technology Sydney, Sydney, New South Wales, Australia, 3 Institute of Parasitology, McGill University, Montreal, Quebec, Canada Abstract Malaria caused by several species of Plasmodium is major parasitic disease of humans, causing 1–3 million deaths worldwide annually. The widespread resistance of the human parasite to current drug therapies is of major concern making the identification of new drug targets urgent. While the parasite grows and multiplies inside the host erythrocyte it degrades the host cell hemoglobin and utilizes the released amino acids to synthesize its own proteins. The P. falciparum malarial M1 alanyl-aminopeptidase (PfA-M1) is an enzyme involved in the terminal stages of hemoglobin digestion and the generation of an amino acid pool within the parasite. The enzyme has been validated as a potential drug target since inhibitors of the enzyme block parasite growth in vitro and in vivo. In order to gain further understanding of this enzyme, molecular dynamics simulations using data from a recent crystal structure of PfA-M1 were performed. The results elucidate the pentahedral coordination of the catalytic Zn in these metallo-proteases and provide new insights into the roles of this cation and important active site residues in ligand