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J. Biol. Chem., Vol. 277, Issue 5, 3219-3225, February 1, 2002
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From the Departments of Immucillins are logically designed
transition-state analogue inhibitors of mammalian purine nucleoside
phosphorylase (PNP) that induce purine-less death of Plasmodium
falciparum in cultured erythrocytes (Kicska, G. A., Tyler,
P. C., Evans, G. B., Furneaux, R. H., Schramm, V. L., and Kim, K. (2002) J. Biol. Chem. 277, 3226-3231). PNP is present at high levels in human erythrocytes and in P. falciparum, but the Plasmodium enzyme
has not been characterized. A search of the P. falciparum
genome data base yielded an open reading frame similar to the PNP from
Escherichia coli. PNP from P. falciparum
(P. falciparum PNP) was cloned, overexpressed in E. coli, purified, and characterized. The primary amino acid
sequence has 26% identity with E. coli PNP, has 20%
identity with human PNP, and is phylogenetically unique among known
PNPs with equal genetic distance between PNPs and uridine
phosphorylases. Recombinant P. falciparum PNP is
catalytically active for inosine and guanosine but is less active for
uridine. The immucillins are powerful inhibitors of P. falciparum PNP. Immucillin-H is a slow onset tight binding inhibitor with a Ki* value of 0.6 nM.
Eight related immucillins are also powerful inhibitors with
dissociation constants from 0.9 to 20 nM. The
Km/Ki* value for immucillin-H is 9000, making this inhibitor the most powerful yet reported for
P. falciparum PNP. The PNP from P. falciparum
differs from the human enzyme by a lower Km for
inosine, decreased preference for deoxyguanosine, and reduced
affinity for the immucillins, with the exception of
5'-deoxy-immucillin-H. These properties of P. falciparum
PNP are consistent with a metabolic role in purine salvage and provide
an explanation for the antibiotic effect of the immucillins on P. falciparum cultured in human erythrocytes.
The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EBI Data Bank with accession number(s) AF426159.
Transition State Analogue Inhibitors of Purine Nucleoside
Phosphorylase from Plasmodium falciparum*
,
**, and
Biochemistry, ¶ Medicine
(Division of Infectious Diseases), and Microbiology and
Immunology, Albert Einstein College of Medicine, Bronx, New York 10461 and the § Carbohydrate Chemistry Team, Industrial Research
Limited, Lower Hutt, New Zealand
*
This work was supported in part by Research Grant GM41916
from the National Institutes of Health and by Medical Scientist Training Program Training Grant GM07288.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of
Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park
Ave., Bronx, NY 10461. Tel.: 718-430-2813; Fax: 718-430-8565; E-mail: vern@aecom.yu.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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