Crystal structure of arginase from Leishmania mexicana and implications for the inhibition of polyamine biosynthesis in parasitic infections

Edward L. D'Antonio, Buddy Ullman, Sigrid C. Roberts, Upasna Gaur Dixit, Mary E. Wilson, Yang Hai, David W. Christianson

Research output: Contribution to journalArticle

32 Citations (Scopus)

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-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.

Original languageEnglish (US)
Pages (from-to)163-176
Number of pages14
JournalArchives of Biochemistry and Biophysics
Volume535
Issue number2
DOIs
StatePublished - 2013

Fingerprint

Leishmania mexicana
Arginase
Parasitic Diseases
Biosynthesis
Polyamines
Crystal structure
Leishmania
Substrates
Microbodies
Protozoa
Leishmaniasis
Cell growth
Enzymes
Manganese
Catalysis
Organelles
Arginine
Cell Survival
Parasites
Salts

Keywords

  • Arginase
  • Leishmaniasis
  • Metalloenzyme
  • X-ray crystallography

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

Cite this

Crystal structure of arginase from Leishmania mexicana and implications for the inhibition of polyamine biosynthesis in parasitic infections. / D'Antonio, Edward L.; Ullman, Buddy; Roberts, Sigrid C.; Dixit, Upasna Gaur; Wilson, Mary E.; Hai, Yang; Christianson, David W.

In: Archives of Biochemistry and Biophysics, Vol. 535, No. 2, 2013, p. 163-176.

Research output: Contribution to journalArticle

D'Antonio, Edward L. ; Ullman, Buddy ; Roberts, Sigrid C. ; Dixit, Upasna Gaur ; Wilson, Mary E. ; Hai, Yang ; Christianson, David W. / Crystal structure of arginase from Leishmania mexicana and implications for the inhibition of polyamine biosynthesis in parasitic infections. In: Archives of Biochemistry and Biophysics. 2013 ; Vol. 535, No. 2. pp. 163-176.
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