The GPI biosynthetic pathway as a therapeutic target for African sleeping sickness

Ferguson, Michael A. J.; Brimacombe, J. S.; Brown, Jillian R.; Cross, George A.M.; Dix, Alexander P.; Field, Robert A.; Güther, Maria Lucia S.; Milne, Kenneth G.; Sharma, Deepak; Smith, Terry

doi:10.1016/s0925-4439(99)00058-7

Cited by 136 publications

(96 citation statements)

References 121 publications

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“…1, C-E, and Table 1), suggesting the formation of GlcN-(acyl)PI in T. gondii. This inositol acyltransferase activity, like that of the P. falciparum, S. cerevisiae, and mammalian GPI pathways, acts on GlcN-PI (14,33) and is acyl-CoA-dependent, preferring Pam-CoA over myristyl-CoA or stearoyl-CoA (data not shown).…”

Section: Formation Of Glcn-(acyl)pi-mentioning

confidence: 92%

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The Role of Inositol Acylation and Inositol Deacylation in the Toxoplasma gondii Glycosylphosphatidylinositol Biosynthetic Pathway

Smith

Kimmel

Azzouz

et al. 2007

Journal of Biological Chemistry

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Toxoplasma gondii is a ubiquitous parasitic protozoan that invades nucleated cells in a process thought to be in part due to several surface glycosylphosphatidylinositol (GPI)-anchored proteins, like the major surface antigen SAG1 (P30), which dominates the plasma membrane. The serine protease inhibitors phenylmethylsulfonyl fluoride and diisopropyl fluoride were found to have a profound effect on the T. gondii GPI biosynthetic pathway, leading to the observation and characterization of novel inositol-acylated mannosylated GPI intermediates. This inositol acylation is acyl-CoA-dependent and takes place before mannosylation, but uniquely for this class of inositol-acyltransferase, it is inhibited by phenylmethylsulfonyl fluoride. The subsequent inositol deacylation of fully mannosylated GPI intermediates is inhibited by both phenylmethylsulfonyl fluoride and diisopropyl fluoride. The use of these serine protease inhibitors allows observations as to the timing of inositol acylation and subsequent inositol deacylation of the GPI intermediates. Inositol acylation of the non-mannosylated GPI intermediate D-GlcN␣1-6-D-myo-inositol-1-HPO 4 -sn-lipid precedes mannosylation. Inositol deacylation of the fully mannosylated GPI intermediate allows further processing, i.e. addition of GalNAc side chain to the first mannose. Characterization of the phosphatidylinositol moieties present on both free GPIs and GPI-anchored proteins shows the presence of a diacylglycerol lipid, whose sn-2 position contains almost exclusively an C18:1 acyl chain. The data presented here identify key novel inositol-acylated mannosylated intermediates, allowing the formulation of an updated T. gondii GPI biosynthetic pathway along with identification of the putative genes involved.

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Section: Formation Of Glcn-(acyl)pi-mentioning

confidence: 92%

“…This minimal GPI structure may be embellished with various sidechain modifications, such as additional sugars or ethanolamine phosphates in a species-specific manner (12)(13)(14). In the case of T. gondii a side chain consisting of glucose ␣1-4N-acetylgalactosamine linked to the first mannose has been identified (15).…”

mentioning

confidence: 99%

The Role of Inositol Acylation and Inositol Deacylation in the Toxoplasma gondii Glycosylphosphatidylinositol Biosynthetic Pathway

Smith

Kimmel

Azzouz

et al. 2007

Journal of Biological Chemistry

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“…Folate transport, which involves a glycerolphosphoinositol (GPI)-anchored receptor, is a well-known example of potocytosis (160,205), but Fe 2ϩ , Ca 2ϩ , alkaline phosphatase, and insulin are also transported in this manner (4,85,168). Caveolae-based endocytosis can be employed opportunistically by toxins, viruses, bacteria (227), and trypanosomes (63,232) to gain access to the cell's interior.…”

Section: Lpp In Signaling Platformsmentioning

confidence: 99%

Pulmonary phosphatidic acid phosphatase and lipid phosphate phosphohydrolase

Nanjundan

Possmayer

2003

American Journal of Physiology-Lung Cellular and Molecular Phys

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The lung contains two distinct forms of phosphatidic acid phosphatase (PAP). PAP1 is a cytosolic enzyme that is activated through fatty acid-induced translocation to the endoplasmic reticulum, where it converts phosphatidic acid (PA) to diacylglycerol (DAG) for the biosynthesis of phospholipids and neutral lipids. PAP1 is Mg2+ dependent and sulfhydryl reagent sensitive. PAP2 is a six-transmembrane-domain integral protein localized to the plasma membrane. Because PAP2 degrades sphingosine-1-phosphate (S1P) and ceramide-1-phosphate in addition to PA and lyso-PA, it has been renamed lipid phosphate phosphohydrolase (LPP). LPP is Mg2+independent and sulfhydryl reagent insensitive. This review describes LPP isoforms found in the lung and their location in signaling platforms (rafts/caveolae). Pulmonary LPPs likely function in the phospholipase D pathway, thereby controlling surfactant secretion. Through lowering the levels of lyso-PA and S1P, which serve as agonists for endothelial differentiation gene receptors, LPPs regulate cell division, differentiation, apoptosis, and mobility. LPP activity could also influence transdifferentiation of alveolar type II to type I cells. It is considered likely that these lipid phosphohydrolases have critical roles in lung morphogenesis and in acute lung injury and repair.

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“…GPIs are ubiquitous in eukaryotes (1,2), and their primary function is to anchor proteins to the cell membranes (1)(2)(3). Examples include the Trypanosoma brucei variant surface protein, T. cruzi trans-sialidase, Plasmodium falciparum MSP-1 (merozoite surface protein 1) and MSP-2, Leishmania gp63, Thy-1, acetylcholine esterase, CD14, CD52, CD55, and CD59 (3)(4)(5)(6)(7). In parasites, GPIs also occur abundantly as free lipids (not anchored to proteins).…”

mentioning

confidence: 99%

“…GPIs exhibit a wide array of functions (8,9). GPIs from different species differ in the type of acyl/alkyl substituents and the presence of additional sugar moieties on third and/or first mannose and ethanolamine phosphate residues on the carbohydrate moiety, leading to a broad structural diversity that may relate to their diverse biological activity (3).…”

mentioning

confidence: 99%

Plasmodium falciparumGlycosylphosphatidylinositol-induced TNF-α Secretion by Macrophages Is Mediated without Membrane Insertion or Endocytosis

Vijay‐Kumar

Naik

Gowda

2001

Journal of Biological Chemistry

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The glycosylphosphatidylinositols (GPIs) of Plasmodium falciparum are believed to contribute to the pathogenesis of malaria by inducing the secretion of proinflammatory cytokines by macrophages. Previous studies have shown that P. falciparum GPIs elicit toxic immune responses by protein tyrosine kinase (PTK)-and protein kinase C (PKC)-mediated cell signaling pathways, which are activated by the carbohydrate and acyl moieties of the intact GPIs, respectively. In this study, we show that induction of TNF-␣ by P. falciparum GPIs in macrophages is mediated by the recognition of the distal fourth mannose residue. This event is critical but not sufficient for the productive cell signaling; interaction by the acylglycerol moiety of GPIs is also required. These novel interactions are coupled to previously demonstrated PTK and PKC pathways, since the specific inhibitors of these kinases effectively blocked the GPI-induced TNF-␣ production. Surprisingly, sn-2 lyso-GPIs were also able to elicit TNF-␣ secretion. Contrary to the prevailing notion, GPIs are neither inserted to the plasma membranes nor endocytosized. Thus, this study defines the GPI structural requirements and reveals a novel mechanism for the outside-in activation of cell signaling by P. falciparum GPIs in inducing proinflammatory responses.

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The GPI biosynthetic pathway as a therapeutic target for African sleeping sickness

Cited by 136 publications

References 121 publications

The Role of Inositol Acylation and Inositol Deacylation in the Toxoplasma gondii Glycosylphosphatidylinositol Biosynthetic Pathway

The Role of Inositol Acylation and Inositol Deacylation in the Toxoplasma gondii Glycosylphosphatidylinositol Biosynthetic Pathway

Pulmonary phosphatidic acid phosphatase and lipid phosphate phosphohydrolase

Plasmodium falciparumGlycosylphosphatidylinositol-induced TNF-α Secretion by Macrophages Is Mediated without Membrane Insertion or Endocytosis

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