T1 - The biosynthesis of GPI anchors

Finally, we exploited the more fastidious nature of the human de-N-acetylase (; ; this study) by combining features that provide specificity for the parasite de-N-acetylase (i.e. β anomeric linkage or 2-O-alkylation of the -myo-inositol residue) with the N-acyl function of the non-specific inhibitor GlcNCONH2-PI to produce GlcNCONH2-β-PI and GlcNCONH2-(2-O-octyl)-PI. These compounds, which are active in vitro, are leads for the design and synthesis of parasite-specific inhibitors that may be active in vivo. Such compounds could impact significantly on the development of trypanocidal drugs, since the GPI biosynthetic pathway has been validated as a therapeutic target against African trypanosomes (; ).

GPI anchor biosynthetic process

GPI anchor biosynthetic process via N-asparaginyl-glycosylphosphatidylinositolethanolamine

About - GPI biosynthesis disorders

Next to be assessed was the ability of GlcNR-PI analogues to inhibit MT-1 and/or later enzymes in the GPI pathway. This was achieved by pre-incubating the trypanosomal cell-free system with the analogues prior to incubation with GlcN-PI and GDP-[3H]Man. GlcNMal-PI and GlcPtu-PI showed little or no inhibition of the mannosylation of GlcN-PI when compared with the control (Figure , lanes 1, 3 and 7). GlcNBn-PI caused significant, but incomplete inhibition, whereas GlcNMe2-PI and Glc NCONH2-PI produced complete inhibition (Figure , lanes 4, 5 and 6). These inhibitory effects cannot be ascribed to non-specific effects, resulting from increased concentrations of synthetic lipid in the system, since pre-incubation with an equivalent concentration of GlcNAc-PI stimulated the biosynthetic pathway (Figure , lane 8).

Chapter 12 Inhibitors of GPI Biosynthesis - ScienceDirect

In this paper we describe the first mechanism-based suicide inhibitor of GPI biosynthesis, and combine features of this molecule with others to produce two parasite-specific suicide substrate inhibitors.

GPI anchor biosynthetic process via N-aspartyl-glycosylphosphatidylinositolethanolamine
GPI anchor biosynthetic process via N-cysteinyl-glycosylphosphatidylinositolethanolamine

Biosynthesis of GPI membrane anchors

brucei has been genetically 5–8 and chemically 9 validated as a drug target.A key early step in the biosynthesis of the GPI anchors is the de- N -acetylation of 2-acetamido-2-deoxy-α- d -glucopyranosyl-(1→6)-phosphatidylinositol 10 [α- d -Glc p NAc-PI ( 1 , Fig.

GPI anchor biosynthetic process via N-glycyl-glycosylphosphatidylinositolethanolamine

What is GPI anchor biosynthesis

Guether, Maria, Lucia S., Ferguson, Michael A.J. (1995) The role of inositol acylation an inositol deacylation in GPI biosynthesis in Trypanosoma brucei. EMBO Journal. 14(13): 3080-93.

GPI anchor biosynthetic process via N-seryl-glycosylphosphatidylinositolethanolamine

Category:GO:0006506 ! GPI anchor biosynthetic process

AB - Biosynthesis of glycosylphosphatidylinositol (GPI) is initiated by transfer of N-acetylglucosamine (GlcNAc) from UDP-GlcNAc to phosphatidylinositol (PI). This chemically simple step is genetically complex because three genes are required in both mammals and yeast. Mammalian PIG-A and PIG-C are homologous to yeast GPI3 and GPI2, respectively; however, mammalian PIG-H is not homologous to yeast GPI1. Here, we report cloning of a human homolog of GPI1 (hGPI1) and demonstrate that four mammalian gene products form a protein complex in the endoplasmic reticulum membrane. PIG-L, which is involved in the second step in GPI synthesis, GlcNAc-PI de-N-acetylation, did not associate with the isolated complex. The protein complex had GPI-GlcNAc transferase (GPI-GnT) activity in vitro, but did not mediate the second reaction, Bovine PI was utilized ~ 100-fold more efficiently than soybean PI as a substrate, and lyse PI was a very inefficient substrate, These results suggest that GPI-GnT recognizes the fatty acyl chains of PI, The unusually complex organization of GPI-GnT may be relevant to selective usage of PI and/or regulation.