Biochemical purification and pharmacological inhibition of a mammalian prolyl hydroxylase acting on hypoxia-inducible factor
Biochemical purification and pharmacological inhibition of a mammalian prolyl hydroxylase acting on hypoxia-inducible factor
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DOI：
10.1073/pnas.192342099
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发表时间：
2002-10-15
影响因子：
11.1
通讯作者：
Kaelin, WG
中科院分区：
文献类型：
--
作者：
Ivan, M;Haberberger, T;Kaelin, WG
von Hippel-Lindau基因的产物pVHL靶向异源二聚体转录因子缺氧诱导因子（HIF）的α亚基，用于在氧存在下的聚泛素化。pVHL与HIF的结合受HIF α家族成员中存在的肽基序内保守脯氨酰残基的酶促羟基化控制。通过使用生化纯化策略，我们已经确定了秀丽隐杆线虫Egl 9的人类同源物作为HIF脯氨酰羟化酶。此外，我们研究了活性的低分子量抑制剂的前胶原脯氨酰4-羟化酶的HIF羟化酶的潜在抑制剂的结构多样的集合。该系列的模型化合物稳定了多种细胞中的HIF，导致其下游靶点血管内皮生长因子的产生增加。
The product of the von Hippel-Lindau gene, pVHL, targets the alpha subunits of the heterodimeric transcription factor hypoxia-inducible factor (HIF) for polyubiquitination in the presence of oxygen. The binding of pVHL to HIF is governed by the enzymatic hydroxylation of conserved prolyl residues within peptidic motifs present in the HIFalpha family members. By using a biochemical purification strategy, we have identified a human homolog of Caenorhabditis elegans Egl9 as a HIF prolyl hydroxylase. In addition, we studied the activity of a structurally diverse collection of low molecular weight inhibitors of procollagen prolyl 4-hydroxylase as potential inhibitors of the HIF hydroxylase. A model compound of this series stabilized HIF in a variety of cells, leading to the increased production of its downstream target, vascular endothelial growth factor.