title: Crystal structure of arginase from Leishmania mexicana and implications for the inhibition of polyamine biosynthesis in parasitic infections.
abstract: Arginase from parasitic protozoa belonging to the genus Leishmania is a potential drug target for the treatment of leishmaniasis because this binuclear manganese metalloenzyme catalyzes the first committed step in the biosynthesis of polyamines that enable cell growth and survival. The high resolution X-ray crystal structures of the unliganded form of Leishmania mexicana arginase (LmARG) and four inhibitor complexes are now reported. These complexes include the reactive substrate analogue 2(S)-amino-6-boronohexanoic acid (ABH) and the hydroxylated substrate analogue nor-N(ω)-hydroxy-l-arginine (nor-NOHA), which are the most potent arginase inhibitors known to date. Comparisons of the LmARG structure with that of the archetypal arginase, human arginase I, reveal that all residues important for substrate binding and catalysis are strictly conserved. However, three regions of tertiary structure differ between the parasitic enzyme and the human enzyme corresponding to the G62 - S71, L161 - C172, and I219 - V230 segments of LmARG. Additionally, variations are observed in salt link interactions that stabilize trimer assembly in LmARG. We also report biological studies in which we demonstrate that localization of LmARG to the glycosome, a unique subcellular organelle peculiar to Leishmania and related parasites, is essential for robust pathogenesis.
authors.affiliation: Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, PA 19104-6323, USA.
authors.forename: Edward L
authors.initials: EL
authors.lastname: D'Antonio
authors.forename: Buddy
authors.initials: B
authors.lastname: Ullman
authors.forename: Sigrid C
authors.initials: SC
authors.lastname: Roberts
authors.forename: Upasna Gaur
authors.initials: UG
authors.lastname: Dixit
authors.forename: Mary E
authors.initials: ME
authors.lastname: Wilson
authors.forename: Yang
authors.initials: Y
authors.lastname: Hai
authors.forename: David W
authors.initials: DW
authors.lastname: Christianson
mesh_terms: D000614:Aminocaproates / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000977:Antiparasitic Agents / Q000494:pharmacology; D001119:Arginase / Q000037:antagonists & inhibitors / Q000737:chemistry*; D001120:Arginine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D001896:Boron Compounds / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D005260:Female; D006801:Humans; D007894:Leishmania mexicana / Q000187:drug effects / Q000201:enzymology*; D016773:Leishmaniasis, Cutaneous / Q000201:enzymology / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D009952:Ornithine / Q000737:chemistry; D011073:Polyamines / Q000037:antagonists & inhibitors / Q000378:metabolism; D011487:Protein Conformation; D055503:Protein Multimerization; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry*
chemical_list: C121228:2-amino-6-boronohexanoic acid; D000614:Aminocaproates; D000977:Antiparasitic Agents; D001896:Boron Compounds; C404735:N(omega)-hydroxynorarginine; D011073:Polyamines; D015800:Protozoan Proteins; C068309:N(omega)-hydroxyarginine; D001120:Arginine; D009952:Ornithine; D001119:Arginase