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首页> 美国卫生研究院文献>Biochemical Journal >Pyridinedicarboxylates the first mechanism-derived inhibitors for prolyl 4-hydroxylase selectively suppress cellular hydroxyprolyl biosynthesis. Decrease in interstitial collagen and Clq secretion in cell culture.
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Pyridinedicarboxylates the first mechanism-derived inhibitors for prolyl 4-hydroxylase selectively suppress cellular hydroxyprolyl biosynthesis. Decrease in interstitial collagen and Clq secretion in cell culture.

机译：吡啶二羧酸盐是第一个由机理衍生的脯氨酰4-羟化酶抑制剂可选择性抑制细胞羟脯氨酰的生物合成。细胞培养中的间质胶原和Clq分泌减少。

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摘要

Two pyridinedicarboxylates, predicted [Hanauske-Abel (1983) M.D.-Ph.D. Thesis, Philipps Universität Marburg] and later found to be potent reversible inhibitors of purified prolyl 4-hydroxylase [Majaama, Hanauske-Abel, Günzler & Kivirikko (1984) Eur. J. Biochem. 138, 239-245] were investigated with respect to their effect on hydroxyprolyl biosynthesis in the fibroblast/collagen and the macrophage/Clq systems, and the effect was compared with that of the iron chelator 2,2'-dipyridyl, the compound usually employed to inhibit cellular hydroxyprolyl formation. Only the enzyme-mechanism-derived pyridinedicarboxylates were highly selective inhibitors, and only they lacked overt cytotoxicity. Morphologically, their effect was restricted to the site of cellular hydroxyprolyl biosynthesis, i.e. the cisternae of the rough-surfaced endoplasmic reticulum. They were equally effective in the different cell types studied, and human and guinea-pig fibroblasts showed the same sensitivity. The minimal lipophilicity of the pyridinedicarboxylates necessitated high concentrations to achieve suppression of cellular hydroxyprolyl formation, but lipophilic bio-activatable pro-inhibitors may overcome this disadvantage. For the first time, experimental evidence is presented suggesting that, in cell culture, the biosynthesis of interstitial collagens and Clq can be suppressed selectively, identifying the pyridinedicarboxylates as promising pilot compounds for experiments in vivo.
机译：预测有两种吡啶二羧酸盐[Hanauske-Abel（1983）M.D.-Ph.D.论文，PhilippsUniversitätMarburg]，后来发现是纯化的脯氨酰4-羟化酶的有效可逆抑制剂[Majaama，Hanauske-Abel，Günzler和Kivirikko（1984）Eur。 J.生物化学。 [138，239-245]研究了它们对成纤维细胞/胶原蛋白和巨噬细胞/ Clq系统中羟脯氨酰生物合成的影响，并将其与常用的铁螯合剂2,2'-联吡啶进行了比较。抑制细胞羟脯氨酰的形成。只有酶机制衍生的吡啶二羧酸盐是高度选择性的抑制剂，并且只有它们缺乏明显的细胞毒性。从形态上讲，它们的作用限于细胞羟脯氨酰生物合成的位点，即表面粗糙的内质网的池。它们在研究的不同细胞类型中同样有效，人和豚鼠成纤维细胞显示出相同的敏感性。吡啶二羧酸盐的最小亲脂性需要高浓度才能达到抑制细胞羟脯氨酰形成的作用，但是亲脂性可生物激活的前抑制剂可以克服这一缺点。首次，实验证据表明，在细胞培养中，间质胶原和Clq的生物合成可以被选择性抑制，从而确定吡啶二羧酸盐是有希望进行体内实验的先导化合物。

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