Parasite and mammalian GPI biosynthetic pathways can be distinguished using synthetic substrate analogues

被引:72
作者
Smith, TK
Sharma, DK
Crossman, A
Dix, A
Brimacombe, JS
Ferguson, MAJ
机构
[1] UNIV DUNDEE,DEPT BIOCHEM,DUNDEE DD1 4HN,SCOTLAND
[2] UNIV DUNDEE,DEPT CHEM,DUNDEE DD1 4HN,SCOTLAND
基金
英国惠康基金;
关键词
glycosylphosphatidylinositol; Hela; Leishmania; mannosyltransferase; Trypanosome;
D O I
10.1093/emboj/16.22.6667
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Glycosylphosphatidylinositol (GPI) structures are attached to many cell surface glycoproteins in lower and higher eukaryotes. GPI structures are particularly abundant in trypanosomatid parasites where they can be found attached to complex phosphosaccharides, as well as to glycoproteins, and as mature surface glycolipids. The high density of GPI structures at all life-cycle stages of African trypanosomes and Leishmania suggests that the GPI biosynthetic pathway might be a reasonable target for the development of anti-parasite drugs. In this paper we show that synthetic analogues of early GPI intermediates having the 2-hydroxyl group of the D-myo-inositol residue methylated are recognized and mannosylated by the GPI biosynthetic pathways of Trypanosoma brucei and Leishmania major but not by that of human (HeLa) cells. These findings suggest that the discovery and development of specific inhibitors of parasite GPI biosynthesis are attainable goals. Moreover, they demonstrate that inositol acylation is required for mannosylation in the HeLa cell GPI biosynthetic pathway, whereas it is required far ethanolamine phosphate addition in the T. brucei GPI biosynthetic pathway.
引用
收藏
页码:6667 / 6675
页数:9
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