tailieunhanh - Báo cáo khoa học: The activity of Plasmodium falciparum arginase is mediated by a novel inter-monomer salt-bridge between Glu295–Arg404

A recent study implicated a role forPlasmodium falciparumarginase in the systemic depletion of arginine levels, which in turn has been associated with human cerebral malaria pathogenesis. Arginase (EC ) is a multimeric metallo-protein that catalyses the hydrolysis of arginine to ornithine and urea by means of a binuclear spin-coupled Mn 2+ cluster in the active site. A previous report indicated thatP. | ỊFEBS Journal The activity of Plasmodium falciparum arginase is mediated by a novel inter-monomer salt-bridge between Glu295-Arg404 Gordon A. Wells1 Ingrid B. Muller2 Carsten Wrenger2 and Abraham I. Louw1 1 Department of Biochemistry University of Pretoria South Africa 2 Department of BiochemicalParasitology Bernhard Nocht Institute for TropicalMedicine Hamburg Germany Keywords arginase malaria metal modelling trimer Correspondence A. I. Louw Department of Biochemistry University of Pretoria Lynwood Road Pretoria 0002 South Africa Fax 27 0 12 362 5302 Tel 27 0 12 420 2480 E-mail Received 27 January 2009 revised 26 March 2009 accepted 23 April2009 doi A recent study implicated a role for Plasmodium falciparum arginase in the systemic depletion of arginine levels which in turn has been associated with human cerebral malaria pathogenesis. Arginase EC is a multimeric metallo-protein that catalyses the hydrolysis of arginine to ornithine and urea by means of a binuclear spin-coupled Mn2 cluster in the active site. A previous report indicated that P. falciparum arginase has a strong dependency between trimer formation enzyme activity and metal co-ordination. Mutations that abolished Mn2 binding also caused dissociation of the trimer conversely mutations that abolished trimer formation resulted in inactive monomers. By contrast the monomers of mammalian and therefore host arginase are also active. P. falciparum arginase thus appears to be an obligate trimer and interfering with trimer formation may therefore serve as an alternative route to enzyme inhibition. In the present study the mechanism of the metal dependency was explored by means of homology modelling and molecular dynamics. When the active site metals are removed loss of structural integrity is observed. This is reflected by a larger equilibration rmsd for the protein when the active site metal is removed and some loss of secondary structure. .

TÀI LIỆU LIÊN QUAN
TỪ KHÓA LIÊN QUAN