title: Crystal structure of Schistosoma mansoni arginase, a potential drug target for the treatment of schistosomiasis.
abstract: The X-ray crystal structure of arginase from Schistosoma mansoni (SmARG) and the structures of its complexes with several amino acid inhibitors have been determined at atomic resolution. SmARG is a binuclear manganese metalloenzyme that catalyzes the hydrolysis of l-arginine to form l-ornithine and urea, and this enzyme is upregulated in all forms of the parasite that interact with the human host. Current hypotheses suggest that parasitic arginases could play a role in host immune evasion by depleting pools of substrate l-arginine that would otherwise be utilized for NO biosynthesis and NO-dependent processes in the immune response. Although the amino acid sequence of SmARG is only 42% identical with that of human arginase I, residues important for substrate binding and catalysis are strictly conserved. In general, classical amino acid inhibitors such as 2(S)-amino-6-boronohexanoic acid (ABH) tend to bind more weakly to SmARG than to human arginase I despite identical inhibitor binding modes in each enzyme active site. The identification of a patch on the enzyme surface capable of accommodating the additional Cα substitutent of an α,α-disubstituted amino acid inhibitor suggests that such inhibitors could exhibit higher affinity and biological activity. The structures of SmARG complexed with two different α,α-disubstituted derivatives of ABH are presented and provide a proof of concept for this approach in the enhancement of enzyme-inhibitor affinity.
authors.affiliation: Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania , Philadelphia, Pennsylvania 19104-6323, United States.
authors.forename: Yang
authors.initials: Y
authors.lastname: Hai
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Edwards
authors.forename: Michael C
authors.initials: MC
authors.lastname: Van Zandt
authors.forename: Karl F
authors.initials: KF
authors.lastname: Hoffmann
authors.forename: David W
authors.initials: DW
authors.lastname: Christianson
mesh_terms: D000818:Animals; D001119:Arginase / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D018360:Crystallography, X-Ray; D016503:Drug Delivery Systems; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000627:therapeutic use; D015801:Helminth Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D006801:Humans; D017434:Protein Structure, Tertiary; D012550:Schistosoma mansoni / Q000201:enzymology* / Q000235:genetics; D012555:Schistosomiasis mansoni / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D040681:Structural Homology, Protein
chemical_list: D004791:Enzyme Inhibitors; D015801:Helminth Proteins; D001119:Arginase