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Originally published In Press as doi:10.1074/jbc.M105905200 on November 13, 2001

J. Biol. Chem., Vol. 277, Issue 5, 3219-3225, February 1, 2002
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Transition State Analogue Inhibitors of Purine Nucleoside Phosphorylase from Plasmodium falciparum*

Gregory A. KicskaDagger , Peter C. Tyler§, Gary B. Evans§, Richard H. Furneaux§, Kami Kim||**, and Vern L. SchrammDagger Dagger Dagger

From the Departments of Dagger  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

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.

* 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.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EBI Data Bank with accession number(s) AF426159.

** A Burroughs Wellcome New Investigator in Molecular Parasitology.

Dagger Dagger 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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