Journal article
Crystal structure of arginase from Leishmania mexicana and implications for the inhibition of polyamine biosynthesis in parasitic infections
Archives of biochemistry and biophysics, Vol.535(2), pp.163-176
07/15/2013
DOI: 10.1016/j.abb.2013.03.015
PMCID: PMC3683356
PMID: 23583962
Abstract
•Crystal structures of LmARG and its complexes with inhibitors have been determined.•The inhibitor nor-NOHA attenuates parasite proliferation, albeit weakly.•LmARG structures will enable the design of selective inhibitors with improved parasite uptake properties.
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-Nω-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.
Details
- Title: Subtitle
- Crystal structure of arginase from Leishmania mexicana and implications for the inhibition of polyamine biosynthesis in parasitic infections
- Creators
- Edward L D’Antonio - Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, PA 19104-6323, USABuddy Ullman - Department of Biochemistry and Molecular Biology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239-3098, USASigrid C Roberts - Pacific University School of Pharmacy, 222 SE 8th Avenue, Hillsboro, OR 97123, USAUpasna Gaur Dixit - Departments of Internal Medicine and Microbiology, University of Iowa and the Veterans’ Affairs Medical Center, 200 Hawkins Drive, Iowa City, IA 52242, USAMary E Wilson - Departments of Internal Medicine and Microbiology, University of Iowa and the Veterans’ Affairs Medical Center, 200 Hawkins Drive, Iowa City, IA 52242, USAYang Hai - Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, PA 19104-6323, USADavid W Christianson - Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, PA 19104-6323, USA
- Resource Type
- Journal article
- Publication Details
- Archives of biochemistry and biophysics, Vol.535(2), pp.163-176
- DOI
- 10.1016/j.abb.2013.03.015
- PMID
- 23583962
- PMCID
- PMC3683356
- NLM abbreviation
- Arch Biochem Biophys
- ISSN
- 0003-9861
- eISSN
- 1096-0384
- Publisher
- Elsevier Inc
- Language
- English
- Date published
- 07/15/2013
- Academic Unit
- Microbiology and Immunology; International Programs; Epidemiology; Internal Medicine
- Record Identifier
- 9984001209402771
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