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J Biol Chem, Vol. 273, Issue 7, 4245-4257, February 13, 1998
From the Department of Biochemistry, University of Melbourne,
Parkville 3052, Victoria, Australia
Glycosylphosphatidylinositol (GPI) glycolipids
are major cell surface constituents in the Leishmania
parasites. Distinct classes of GPI are present as membrane anchors for
several surface glycoproteins and an abundant lipophosphoglycan as well
as being the major glycolipids (GIPLs) in the plasma membrane. In this
study we have identified putative precursors for the protein and
lipophosphoglycan anchors and delineated the complete pathway for GIPL
biosynthesis in Leishmania mexicana promastigotes. Based on
the structural analyses of these GPI intermediates and their
kinetics of labeling in vivo and in cell-free
systems, we provide evidence that the GIPLs are the products of an
independent biosynthetic pathway rather than being excess precursors of
the anchor pathways. First, we show that the similar glycan head groups
of the GIPL and protein/lipophosphoglycan anchor precursors are
assembled on two distinct pools of PI corresponding to
1-O-(C18:0)alkyl-2-stearoyl-PI and
1-O-(C24:0/C26:0)-2-stearoyl-PI, respectively. These PI
species account for 20 and 1% of the total PI pool, respectively,
indicating a remarkable specificity in their selection. Second,
analysis of the flux of intermediates through these pathways in
vivo and in a cell-free system suggests that the GIPL and anchor
pathways are independently regulated. We also show that GIPL
biosynthesis requires fatty acid remodeling, in which the
sn-2 stearoyl chains are replaced with myristoyl or lauroyl
chains. Fatty acid remodeling is dependent on CoA and ATP and occurs on
pre-existing but not on de novo synthesized GIPLs. We
suggest that the compartmentalization of different GPI pathways may be
important in regulating the species and stage-specific expression of
different GPI structures in these parasites.
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