Fig 1.
PIP and IP synthesis and regulation in T. brucei.
(A) Structure of PIP2 indicated by the inositol ring (black hexagon), phosphates (red circles), and DAG with fatty acid chain. PLC cleaves PIP2 and produces diacylglycerol and IP3. Black arrows indicate phosphate and inositol. The yellow arrow indicates the site of PLC cleavage, which occurs between DAG and phosphate sn1. The green arrow indicates the directionality of the PLC reaction. (B) The number of genes involved in PIP and IP synthesis, signaling (includes PLC and IP3 receptors), and PIP and IP kinases and phosphatases in eukaryotes and prokaryotes. The size of the black circles indicates the number of genes in each category. (C) Synthesis of PIPs and IPs based on T. brucei predicted and characterized enzymes. Enzymes, whose regulatory functions are discussed here, are indicated in blue. PIP-Pase indicates enzymes that dephosphorylate PIPs at positions 3, 4, or 5 of the inositol ring. It includes PIP5Pase, whose catalytic activity is detailed below in D. Metabolite short names are used for simplicity. (D) Regulation of VSG silencing by PIP5Pase. PIP5Pase dephosphorylates the 5-phosphate (green circle) of PIP3 and prevents this metabolite binding to RAP1, which preserves RAP1 function (and likely other proteins) in ES chromatin organization. Catalytic inactivation of PIP5Pase results in PIP3 binding to RAP1, which affects ES chromatin organization and results in transcription of VSG genes. 1, diacylglycerol kinase; 2, cytidine diphosphate-diacylglycerol synthase; 3, phosphatidylinositol synthase; 70 bp, 70 base pair repeats; Ath, Arabidopsis thaliana; DAG, diacylglycerol; ER, endoplasmic reticulum; ES, expression site; ESAG, expression site associated genes; Hsp, Homo sapiens; I, myo-inositol; IMPase, inositol monophosphatase; IP, inositol phosphate; IP1, D-myo-inositol 1-monophosphate; IP2, D-myo-inositol 1,4-diphosphate; IP3, D-myo-inositol 1,4,5-triphosphate; IP4, D-myo-inositol 1,3,4,5-tetrakisphosphate; IP5, D-myo-inositol 1,2,3,4,5-pentakisphosphate; IP5Pase, inositol polyphosphate 5-phosphatase; IP6, D-myo-inositol 1,2,3,4,5,6-hexakisphosphate; IP6K, inositol hexakisphosphate kinase; IP7, D-myo-inositol 5-diphospho 1,2,3,4,6-pentakisphosphate; IPMK, inositol polyphosphate multikinase; Mtb, Mycobacterium tuberculosis; PIP, phosphatidylinositol phosphate; PIP1, phosphatidylinositol 4-phosphate; PIP2, phosphatidylinositol 4,5-biphosphate; PIP3, phosphatidylinositol 3,4,5-triphosphate; PIP5K, phosphatidylinositol phosphate 5-kinase; PIP5Pase, phosphatidylinositol phosphate 5-phosphatase; PIP-Pase, phosphatidylinositol phosphate phosphatases; PLC, Phospholipase C; PM, plasma membrane; Pol I, RNA polymerase I; PP-IP4, D-myo-inositol 5-diphospho 1,3,4,6-tetrakisphosphate; RAP1, repressor-activator protein 1; Sce, Saccharomyces cerevisiae; sn1, unimolecular nucleophilic substitution; Tbr, T. brucei; Ttm, Thermus thermophilus; VSG, variant surface glycoprotein.
Table 1.
Regulatory roles of PIP and IP enzymes in T. brucei.