Plasmodium falciparum is dependent on de novo myo‐inositol biosynthesis for assembly of GPI glycolipids and infectivity. Issue 4 (16th January 2014)

• Record Type: Journal Article
• Authors: MacRae, James I.; Lopaticki, Sash; Maier, Alexander G.; Rupasinghe, Thusitha; Nahid, Amsha; Cowman, Alan F.; McConville, Malcolm J.
• Is Part Of: Molecular microbiology. Volume 91:Issue 4(2014)
• Page Start: 762
• Page End: 776
• Publication Date: 2014-01-16
• Subjects: Molecular microbiology -- Periodicals; 572.829
• DOI: 10.1111/mmi.12496
• Languages: English
• ISSNs: 0950-382X

Abstract

<abstract abstract-type="main"> <title>Summary</title> <p>Intra‐erythrocytic stages of the malaria parasite, <italic>P</italic><italic>lasmodium falciparum</italic>, are thought to be dependent on <italic>de novo</italic> synthesis of phosphatidylinositol, as red blood cells (RBC) lack the capacity to synthesize this phospholipid. The <italic>myo</italic>‐inositol headgroup of PI can either be synthesized <italic>de novo</italic> or scavenged from the RBC. An untargeted metabolite profiling of <italic>P</italic><italic>. falciparum</italic> infected RBC showed that trophozoite and schizont stages accumulate high levels of <italic>myo</italic>‐inositol‐3‐phosphate, indicating increased <italic>de novo </italic>biosynthesis of <italic>myo</italic>‐inositol from glucose 6‐phosphate. Metabolic labelling studies with <sup>13</sup>C‐U‐glucose in the presence and absence of exogenous inositol confirmed that <italic>de novo </italic><italic>myo</italic>‐inositol synthesis occurs in parallel with <italic>myo</italic>‐inositol salvage pathways. Unexpectedly, while both endogenous and scavenged <italic>myo</italic>‐inositol was used to synthesize bulk PI, only <italic>de novo</italic>‐synthesized <italic>myo</italic>‐inositol was incorporated into GPI glycolipids. Moreover, gene disruption studies suggested that the <italic>INO1</italic> gene, encoding <italic>myo</italic>‐inositol 3‐phosphate synthase, is essential in asexual parasite stages. Together these findings suggest that <italic>P</italic><italic>. falciparum</italic> asexual stages are critically dependent on <italic>de novo </italic><italic>myo</italic>‐inositol biosynthesis for assembly of a sub‐pool of PI species and GPI biosynthesis. These findings highlight unexpected complexity in phospholipid biosynthesis in <italic>P</italic><italic>. falciparum</italic> and a lack of redundancy in some nutrient salvage versus endogenous biosynthesis pathways.</p> </abstract>