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J. Biol. Chem., Vol. 276, Issue 9, 6566-6575, March 2, 2001
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From the Max-Planck-Institut für Biologie, Corrensstrasse 38, Tübingen 72076, Federal Republic of Germany
Phosphomannose isomerase (PMI) catalyzes the
reversible interconversion of fructose 6-phosphate and mannose
6-phosphate, which is the first step in the biosynthesis of activated
mannose donors required for the biosynthesis of various
glycoconjugates. Leishmania species synthesize
copious amounts of mannose-containing glycolipids and glycoproteins,
which are involved in virulence of these parasitic protozoa. To
investigate the role of PMI for parasite glycoconjugate synthesis, we
have cloned the PMI gene (lmexpmi) from Leishmania mexicana, generated gene deletion mutants
( The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EMBL Data Bank with accession number(s) AJ300464.
The Role of Phosphomannose Isomerase in Leishmania
mexicana Glycoconjugate Synthesis and Virulence*
lmexpmi), and analyzed their phenotype.
lmexpmi mutants lack completely the high PMI activity
found in wild type parasites, but are, in contrast to fungi, able to
grow in media deficient for free mannose. The mutants are unable to
synthesize phosphoglycan repeats
[-6-Gal
1-4Man
1-PO4-] and mannose-containing
glycoinositolphospholipids, and the surface expression of the
glycosylphosphatidylinositol-anchored dominant surface glycoprotein
leishmanolysin is strongly decreased, unless the parasite growth medium
is supplemented with mannose. The lmexpmi mutant is
attenuated in infections of macrophages in vitro and of
mice, suggesting that PMI may be a target for
anti-Leishmania drug development. L. mexicana
lmexpmi provides the first conditional mannose-controlled system for parasite glycoconjugate assembly with
potential applications for the investigation of their biosynthesis, intracellular sorting, and function.
*
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: Tel.: 49-7071-601-238;
Fax: 49-7071-601-235; E-mail: thomas.ilg@tuebingen.mpg.de.
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