Figure 1.

The GPI biosynthetic pathway.A, formation of the complete GPI precursor and its attachment to proteins. The pathway shown here is from what is known in Saccharomyces cerevisiae. Not all steps have been elucidated in Candida albicans. However, homologs of most of the enzymes and their subunits are also present in C. albicans and the final GPI product is similar. GPI biosynthesis begins at the cytoplasmic face of the ER when GlcNAc from UDP-GlcNAc is transferred to PI by the action of a GlcNAc transferase (GPI-GnT). GlcNAc-PI is de-N-acetylated by the action of Gpi12 and then flipped into the ER lumen by the action of an unknown flippase. The first step on the lumenal face involves acylation (palmitoyl) by an acyltransferase, Gwt1. Subsequently four Man residues and three EtNP residues are transferred by the action of different mannosyltransferases (MT-I to MT-IV) and EtNP transferases (EtNPT-I to EtNPT-III), respectively, to generate the complete precursor (CP). The donor for the mannoses is Dol-P-Man and for EtNP is ethanolaminephosphate. The most likely sequential pathway alone is shown. Once CP is produced, it is amide linked to the C-terminal end of proteins by the action of a transamidase (GPIT). For this, GPIT cleaves the C-terminal GPI attachment signal sequence (SS) of proteins and attaches the EtNP on Man-3 of the CP to the newly generated carboxylate terminus. Inset: The nature of the GPI attachment signal sequence is conserved. The amino acids of the GPI attachment signal sequence are not conserved, but their nature is. These common features, mentioned in the figure, make it easy to identify them either manually or using bioinformatic tools. GPI attachment occurs at the ω residue. B, the known intra-subunit transcriptional cross talk within the C. albicans GPI-GnT and cross-talk with other biochemical pathways in the cell. Intersubunit transcriptional regulations within the GPI-GnT are unique to C. albicans and have not been reported in any other organism. Activations are represented by black arrows within the dotted circle representing the enzyme complex and the red flatheaded arrows represent repression within the GPI-GnT. Gpi15 activates the expression of both Gpi2 and Gpi19 while Eri1 represses both. Gpi15 and Eri1 mutually activate one another. Gpi2 and Gpi19 mutually inhibit the expression of one another and independently activate the expression of Gpi15. The roles of other GPI-GnT subunits in this schema are not yet elucidated. Cross-talk with other biochemical pathways is observed at this step. CaGpi19 and Erg11 (in sterol biosynthetic pathway) are mutually transcriptionally activated. Since Erg11 is the target of azoles, this affects the response of the cells to azole antifungals. CaGpi2 and CaEri1, in different ways, control filamentation via the Cyr1-cAMP-PKA pathway. CaGpi2 activates cAMP-PKA signaling for filamentation while CaEri1 represses it. The red flatheaded arrows represent inhibition and the blue arrows represent activation.