Inhibition profile of Leishmania mexicana arginase reveals differences with human arginase I

Eric Riley, Sigrid C. Roberts, Buddy Ullman

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Arginase (ARG), the enzyme that catalyzes the conversion of arginine to ornithine and urea, is the first and committed step in polyamine biosynthesis in Leishmania. The creation of a conditionally lethal Δarg null mutant in Leishmania mexicana has established that ARG is an essential enzyme for the promastigote form of the parasite and that the enzyme provides an important defense mechanism for parasite survival in the eukaryotic host. Furthermore, human ARGI (HsARGI) has also been implicated as a key factor in parasite proliferation. Thus, inhibitors of ARG offer a rational paradigm for drug design. To initiate a search for inhibitors of the L. mexicana ARG (LmARG), recombinant LmARG and HsARGI enzymes were purified from Escherichia coli. Both LmARG and HsARGI were specific for l-arginine and exhibited no activity with either d-arginine or agmatine as possible substrates. LmARG exhibited a Km of 25±4mM for l-arginine, a pH optimum ∼9.0, and was dependent upon the presence of a divalent cation, preferentially manganese. A Km of 13.5±2mM for l-arginine was calculated for the HsARGI. A collection of 37 compounds was evaluated against both enzymes. Twelve of these compounds were identified as being either strong inhibitors of both LmARG and HsARGI or differential inhibitors between the two enzymes. Of the 12 compounds, six were selected for further analysis and the type and extent of inhibition determined.

Original languageEnglish (US)
Pages (from-to)545-552
Number of pages8
JournalInternational Journal for Parasitology
Volume41
Issue number5
DOIs
StatePublished - Apr 2011

Fingerprint

Leishmania mexicana
Arginase
Arginine
Enzymes
Parasites
Agmatine
Ornithine
Drug Design
Leishmania
Divalent Cations
Polyamines
Manganese
Urea
human arginase I
Escherichia coli

Keywords

  • Amino acids
  • Arginase
  • Inhibitors
  • Leishmania
  • Polyamines

ASJC Scopus subject areas

  • Parasitology
  • Infectious Diseases

Cite this

Inhibition profile of Leishmania mexicana arginase reveals differences with human arginase I. / Riley, Eric; Roberts, Sigrid C.; Ullman, Buddy.

In: International Journal for Parasitology, Vol. 41, No. 5, 04.2011, p. 545-552.

Research output: Contribution to journalArticle

Riley, Eric ; Roberts, Sigrid C. ; Ullman, Buddy. / Inhibition profile of Leishmania mexicana arginase reveals differences with human arginase I. In: International Journal for Parasitology. 2011 ; Vol. 41, No. 5. pp. 545-552.
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