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Covalent modification of proteins with phosphatidylinositol (PI) was first suggested as a novel mechanism of membrane attachment when it was found that PI-specific phospholipase C (PI-PLC) could release alkaline phosphatase from tissue slices [1-5]. Subsequent compositional analysis of Trypanosoma brucei variant surface glycoprotein (VSG) [6,7], Torpedo acetylcholinesterase [8], erythrocyte acetylcholinesterase [9] and rat brain Thy-l [10] revealed that carbohydrates and ethanolamine were also components ofthe membrane anchor. These findings led to the conclusion that these proteins were attached to the cell surface by a glycosylphosphatidylinositol (GPI) anchor. Since then, over 100 proteins have been found to be GPI-anchored (see [11-13] for reviews). These proteins exist in all eukaryotic species including parasites, Drosophila, yeast and mammals. The functions of the GPI-anchored proteins are also diverse, ranging from enzymes, coat proteins and cell-adhesion molecules to receptors. The initial studies of both GPI structure and biosynthesis were done with African trypanosomes. Because GPI-anchored VSG represents approximately 10% of the total cellular protein in this parasite [14], GPI biosynthesis is very active and GPI precursors and mature anchors are abundant. In vivo radiolabelling studies in which GPI was found associated with VSG within 1 min after translation of the protein established that the glycolipid core is pre-assembled and transferred en bloc to newly synthesized proteins in the endoplasmic reticulum (ER) [15,16]. The isolation and structural elucidation of candidate GPI precursors [17-20] as well as studies with isolated trypanosome membranes have established that the glycolipid is synthesized by the sequential addition of the predicted carbohydrates to PI [21-23]. Although GPI-anchored proteins are not as abundant in yeast and mammalian cells as in parasites, the availability of mutants defective in GPI biosynthesis has made these species invaluable for the study of this pathway. These mutants are listed in Table 1. Particularly useful have been a set of lymphoma cell mutants deficient in the surface expression of the GPI-anchored T-cell antigen Thy1. These mutants, which were isolated using complement-mediated lysis by Dr. Robert Hyman [24,25], fall into six complementation groups. The ThyI protein is produced normally by these cells but is not expressed on the cell surface because of defects in either an enzyme or another component required for biosynthesis of the GPI anchor [26,27]. Our current understanding of the biosynthetic pathway for GPI membrane anchors obtained from studies in parasites, yeast and mammalian cells will be discussed in this review. The aspects of this process which are particular for only one or two of these species will also be considered. Because structure and biosynthesis

Biosynthesis of glycosylphosphatidylinositol membrane anchors