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J Biol Chem, Vol. 275, Issue 20, 14958-14963, May 19, 2000
From the Department of Medical and Molecular Parasitology, New York
University School of Medicine, New York, New York 10010
We previously reported that
S-adenosylmethionine (AdoMet), a key molecule in
methylation reactions and polyamine biosynthesis, enhances axenic
culture of the AIDS-associated opportunistic fungal pathogen
Pneumocystis carinii. Here we report that AdoMet is
absolutely required for continuous growth. Two transporters are
present, one high affinity, Km = 4.5 µM, and one low affinity, Km = 333 µM. The physiologically relevant high affinity transporter has a pH optimum of 7.5 and no related natural compounds compete for uptake. Transport is 98% inhibited at 4 °C, 24%
inhibited by 20 mM sodium azide, and 95% inhibited by the
combination of 20 mM sodium azide and 1 mM
salicylhydroxamic acid; thus transport is active and dependent on both
a cytochrome chain and an alternative oxidase. In vitro,
AdoMet is used at a rate of 1.40 × 107 molecules
cell
S-Adenosylmethionine and Pneumocystis
carinii*
,
1 min1. AdoMet synthetase activity was
not detected by a sensitive radiolabel incorporation assay capable of
detecting 0.1% of the activity in rat liver. In addition, the AdoMet
plasma concentration of rats is inversely correlated with the number of
P. carinii in the lungs. These findings demonstrate that
P. carinii is an AdoMet auxotroph. The uptake and
metabolism of this compound are rational chemotherapeutic targets.
*
This work was supported in part by United States Public
Health Service Grants R01 AI41947 and R01 AI43757.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 Medical and
Molecular Parasitology, New York University School of Medicine, 341 East 25th St., New York, NY 10010. Tel.: 212-263-6956; Fax:
212-263-6956; E-mail: merals01@popmail.med.nyu.edu.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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