Structure-activity relationship of synthetic phosphoinositolglycans mimicking metabolic insulin action

被引:81
作者
Frick, W [1 ]
Bauer, A [1 ]
Bauer, J [1 ]
Wied, S [1 ]
Müller, G [1 ]
机构
[1] Hoechst Marion Roussel Deutschland GMBH, DG Metab Dis Res, D-65926 Frankfurt, Germany
关键词
D O I
10.1021/bi9806201
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
Phosphoinositolglycan (PIG) molecules have been implicated to stimulate glucose and lipid metabolism in insulin-sensitive cells and tissues in vitro and in vivo. The structural requirements for this partial insulin-mimetic activity remained unclear so far. For establishment of a first structure-activity relationship, a number of PIG compounds were synthesized consisting of the complete or shortened/mutated glycan moiety derived from the structure of the glycosylphosphatidylinositol (GPI) anchor of the GPI-anchored protein, Gce1p, from yeast. The PIG compounds were divided into four classes according to their insulin-mimetic activity in vitro with the typical representatives: compound 41, HO-SO2-O-6Man alpha 1 (Man alpha 1-2)-2Man alpha 1(6-HSO3)-6Man alpha 1-4GluN beta 1-6(D)inositol-1,2-(cyclic)-phosphate; compound 37, HO-PO(H)O-6Man alpha 1(Man alpha 1-2)-2Man alpha 1-6Man alpha 1-4GluN beta 1-6(D)inositol-1,2-(cyclic)-phosphate; compound 7, HO-PO(H)O-6Man alpha 1-4GluN(1-6(L)inositol-1,2-(cyclic)-phosphate; and compound 1, HO-PO(H)O-6Man alpha 1-4GluN(1-6(L)inositol. Compounds 41 and 37 stimulated lipogenesis up to 90% (at 20 mu M) of the maximal insulin response but with differing concentrations required for 50% activation (EC50 values 2.5 +/- 0.9 vs 4.9 +/- 1.7 mu M) as well as glycogen synthase (4.7 +/- 1 vs 9.5 +/- 1.5 mu M) and glycerol-3-phosphate acyltransferase (3.5 +/- 0.8 vs 8.0 +/- 1.1 mu M). Compound 7 was clearly less potent (20% of the maximal insulin response at 100 mu M), whereas compound 1 was almost inactive. This relative ranking in the insulin-mimetic potency between members of the PIG classes (e.g., 41 > 37 much greater than 7 > 1) was also observed for the (i) activation of glucose transport and glucose transporter isoform 4 translocation in isolated normal and insulin-resistant adipocytes, (ii) inhibition of lipolysis in adipocytes, (iii) stimulation of glucose transport and glycogen synthesis in isolated normal and insulin-resistant diaphragms, and (iv) induction of tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) in diaphragms. The complete glycan core structure (Man(3)-GluN) of typical GPI anchors including a mannose side chain and the inositolphosphate moiety was required for maximal insulin-mimetic activity of the PIG compounds with some variations possible with respect to the type of residues coupled to the terminal mannose/inositol as well as the type of linkages involved. These data argue for the potency and specificity of the interaction of PIG molecules with putative signaling component(s) (presumably at the level of the IRS proteins) in adipose and muscle cells which finally lead to insulin-mimetic metabolic activity even in insulin-resistant states.
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页码:13421 / 13436
页数:16
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