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首页> 外文期刊>Biochemistry >Structure-activity relationship of synthetic phosphoinositolglycans mimicking metabolic insulin action
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Structure-activity relationship of synthetic phosphoinositolglycans mimicking metabolic insulin action

机译：模拟代谢胰岛素作用的合成磷酸肌醇聚糖的构效关系

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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. [References: 82]
机译：磷酸肌醇聚糖（PIG）分子已被证明在体外和体内刺激胰岛素敏感性细胞和组织中的葡萄糖和脂质代谢。到目前为止，对于这种部分模拟胰岛素活性的结构要求仍不清楚。为了建立第一结构-活性关系，合成了许多PIG化合物，这些化合物由完整或缩短/突变的聚糖部分组成，该聚糖部分来自酵母的GPI锚定蛋白Gce1p的糖基磷脂酰肌醇（GPI）锚结构。 PIG化合物根据其体外模拟胰岛素活性分为典型的四类：化合物41，HO-SO2-O-6Man alpha 1（Man alpha 1-2）-2Man alpha 1（6-HSO3） -6Man alpha 1-4GluN beta 1-6（D）肌醇-1,2-（环）-磷酸盐;化合物37，HO-PO（H）O-6Man alpha 1（Man alpha 1-2）-2Man alpha 1-6Man alpha 1-4GluN beta 1-6（D）肌醇-1,2-（环状）-磷酸;化合物7，HO-PO（H）O-6Man alpha 1-4GluN（1-6（L）肌醇-1,2-（环）-磷酸盐;和化合物1，HO-PO（H）O-6Man alpha 1 -4GluN（1-6（L）肌醇。化合物41和37可刺激最大胰岛素反应的脂肪生成高达90％（在20μM时），但激活50％所需的浓度不同（EC50值为2.5 +/- 0.9 vs 4.9 +/- 1.7μM），糖原合酶（4.7 +/- 1 vs 9.5 +/- 1.5μM）和甘油3-磷酸酰基转移酶（3.5 +/- 0.8 vs 8.0 +/- 1.1μM） 。化合物7的效价显然较低（在100μM时最大胰岛素反应的20％），而化合物1几乎没有活性，PIG类成员之间的模拟胰岛素效价的相对排名（例如41> 37大于7> 1）还观察到（i）分离的正常和胰岛素抵抗性脂肪细胞中的葡萄糖转运和葡萄糖转运蛋白同工型4易位，（ii）抑制脂肪细胞中的脂解，（iii）刺激葡萄糖转运和糖原同隔离的正常隔膜和胰岛素抵抗性隔膜中进行研究，以及（iv）隔膜中诱导胰岛素受体底物1（IRS-1）的酪氨酸磷酸化。 PIG化合物的最大胰岛素模拟活性需要典型的GPI锚蛋白（包括甘露糖侧链和肌醇磷酸酯部分）的完整聚糖核心结构（Man（3）-GluN），并且在偶联残基类型方面可能会有一些变化末端甘露糖/肌醇以及涉及的连接类型。这些数据证明了脂肪和肌肉细胞中PIG分子与推定的信号传导成分（可能在IRS蛋白水平）相互作用的效力和特异性，即使在抗胰岛素的情况下，最终也会导致模拟胰岛素的代谢活性状态。 [参考：82]

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