Inositol acylation

Lu J, Jayaprakash KN, Schlueter U, Fraser-Reid B. Synthesis of a malaria candidate glycosylphosphatidylinositol (GPI) structure a strategy for fully inositol acylated and phosphorylated GPIs. J Am Chem Soc 2004 126 7540-7547. 

Some anchors contain an additional fatty acid that is ester linked to the 2-hydroxyl group of the w> o-inositol. Examples are human erythrocyte acetylcholinesterase [24], T. brucei PARP [16, 25] (Figure 1C), and a population of the human CD52 antigen [19], In some inositol-acylated proteins this acyl chain is a palmitate whereas in some others (e.g. PARP) mass spectrometry analysis has showed that it is quite heterogeneous, containing a mixture of fatty acids (Figure 1C) [16]. 

Figure 2. Biosynthetic pathways for GPI precursors in T. brucei, human, and yeast. Note that some intermediates in each species have an acylated inositol. In T. brucei, early mannosylated intermediates as well as glycolipid A are in equilibrium with inositol-acylated forms (not shown) [53]. The insect form of T. brucei undergoes neither inositol deacylation nor the last three reactions of the fatty acid remodeling, resulting in a lyso GPI precursor containing an acylated inositol. This lyso GPI is also found in PARP (Figure 1C).

Inositol acylation plays an essential role in the biosynthesis of GPIs in mammals, yeast, and T. brucei (Figure 2). In yeast and mammals (but not T. brucei), inositol... 

Many GPI anchors on proteins in mammals and yeast do not contain acylated inositol. Since biosynthesis of all GPIs appears to require inositol acylation and since the complete GPI precursor appears to be inositol acylated, there must be a mechanism to selectively deacylate the inositol. Recent studies on mammalian cells indicate that deacylation occurs in the ER, immediately after linkage of the acylated GPI precursor to the protein. Deacylation appears to be cell type- and protein-specific [52]. 

L. C. Costello P. Orlean. Inositol acylation of a potential glycosyl phosphoinositol anchor precursor from yeast requires acyl coenzyme A. J Biol Chem, 1992, 267, 8599 8603. 

M. L. Guther M. A. Ferguson. The role of inositol acylation and inositol deacylation in GPI biosynthesis in Trypanosoma brucei. EMBO J, 1995,14, 3080-3093. 

Triacylglycerols and some phosphoglycerols are synthesized by progressive acylation of glycerol 3-phosphate. The pathway bifurcates at phosphatidate, forming inositol phospholipids and cardiolipin on the one hand and triacylglycerol and choline and ethanolamine phospholipids on the other. 

The other phospholipids can be derived from phosphatidates (residue = phosphatidyl). Their phosphate residues are esterified with the hydroxyl group of an amino alcohol choline, ethanolamine, or serine) or with the cyclohexane derivative myo-inositol. Phosphatidylcholine is shown here as an example of this type of compound. When two phosphatidyl residues are linked with one glycerol, the result is cardiolipin (not shown), a phospholipid that is characteristic of the inner mitochondrial membrane. Lysophospholipids arise from phospholipids by enzymatic cleavage of an acyl residue. The hemolytic effect of bee and snake venoms is due in part to this reaction. 

Shvets and co-workers (298) have also prepared chiral 1-O-benzyl-myo-inositols by benzylation of the mannose orthoesters (427) and (428) with subsequent acidic hydrolysis. They were also prepared by partial benzylation of chiral l,2 5,6-di-<9-and 2,3 4,5-di-<9-cyclohexylidene-/ny< -inositols. These chiral monobenzyl ethers are potential intermediates for the synthesis of chiral inositol pentakisphosphates. Reaction of the orthoester (427) [299] with benzoyl chloride or diphenylphospho-chloridate in pyridine at 20 °C gave little reaction, whereas at 80 °C the orthoester group was replaced and both hydroxyl groups of the inositol derivative were acylated (or phosphorylated). 

Dr. Hamilton earlier observed that ether extraction of tissue induced autolysis, liberating active esterases and glycosi-dases, and thus leading to more free IAA than extraction of tissue by polar, and thus, enzyme-denaturing solvents (35). Thus, we knew then that there were enzymes in the tissue capaBTe of hydrolyzing IAA esters. Much later, Kopcewicz demonstrated the presence of an enzyme system which could synthesize lAA-myo-inositol from IAA, ATP, Mg++ and CoASH (43). More recently, Mr. Lech Michalczuk (unpublished) has shown that IAA-CoA will acylate inositol only in the presence of other nucleotides. Thus, the reaction is complex, but there is no doubt that enzymes to make and hydrolyze the IAA esters are present in corn. 

No optically active derivatives of epi-inositol have been prepared. All asymmetrically substituted compounds listed in this Table are racemic. 6 p-aminoben-zoyl-.c p-nitrobenzoyl-. d Derived from the corresponding 5,6-di-O-acylated 1,2 3,4-di-O-isopropylidene-epi-inositols. Change of numbering (but not shift of groups) takes place on removal of the isopropylidene groups. 

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