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 language | English (US) |
|---|---|
| Pages (from-to) | 545-552 |
| Number of pages | 8 |
| Journal | International Journal for Parasitology |
| Volume | 41 |
| Issue number | 5 |
| DOIs | |
| State | Published - Apr 2011 |
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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 journal › Article
}
TY - JOUR
T1 - Inhibition profile of Leishmania mexicana arginase reveals differences with human arginase I
AU - Riley, Eric
AU - Roberts, Sigrid C.
AU - Ullman, Buddy
PY - 2011/4
Y1 - 2011/4
N2 - 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.
AB - 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.
KW - Amino acids
KW - Arginase
KW - Inhibitors
KW - Leishmania
KW - Polyamines
UR - http://www.scopus.com/inward/record.url?scp=79952695042&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79952695042&partnerID=8YFLogxK
U2 - 10.1016/j.ijpara.2010.12.006
DO - 10.1016/j.ijpara.2010.12.006
M3 - Article
C2 - 21232540
AN - SCOPUS:79952695042
VL - 41
SP - 545
EP - 552
JO - International Journal for Parasitology
JF - International Journal for Parasitology
SN - 0020-7519
IS - 5
ER -