Crystal Structure of Schistosoma mansoni Arginase, a Potential Drug Target for the Treatment of Schistosomiasis

Yang Hai, Jennifer Edwards, Michael C. Van Zandt, Karl Francis Hoffmann, David W. Christianson

Research output: Contribution to journalArticlepeer-review

17 Citations (SciVal)
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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.

Original languageEnglish
Pages (from-to)4671-4684
Number of pages14
JournalBiochemistry
Volume53
Issue number28
Early online date09 Jul 2014
DOIs
Publication statusPublished - 22 Jul 2014

Keywords

  • Animals
  • Arginase/antagonists & inhibitors
  • Crystallography, X-Ray
  • Drug Delivery Systems
  • Enzyme Inhibitors/chemistry
  • Helminth Proteins/antagonists & inhibitors
  • Humans
  • Protein Structure, Tertiary
  • Schistosoma mansoni/enzymology
  • Schistosomiasis mansoni/drug therapy
  • Structural Homology, Protein

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