Lando David, Peet Daniel J, Gorman Jeffrey J, Whelan Dean A, Whitelaw Murray L, Bruick Richard K
Department of Molecular BioSciences (Biochemistry) and the Centre for the Molecular Genetics of Development, Adelaide University SA 5005, Australia.
Genes Dev. 2002 Jun 15;16(12):1466-71. doi: 10.1101/gad.991402.
Mammalian cells adapt to hypoxic conditions through a transcriptional response pathway mediated by the hypoxia-inducible factor, HIF. HIF transcriptional activity is suppressed under normoxic conditions by hydroxylation of an asparagine residue within its C-terminal transactivation domain, blocking association with coactivators. Here we show that the protein FIH-1, previously shown to interact with HIF, is an asparaginyl hydroxylase. Like known hydroxylase enzymes, FIH-1 is an Fe(II)-dependent enzyme that uses molecular O(2) to modify its substrate. Together with the recently discovered prolyl hydroxylases that regulate HIF stability, this class of oxygen-dependent enzymes comprises critical regulatory components of the hypoxic response pathway.
哺乳动物细胞通过由缺氧诱导因子HIF介导的转录反应途径适应缺氧条件。在常氧条件下，HIF转录活性通过其C末端反式激活结构域内天冬酰胺残基的羟基化而受到抑制，从而阻止与共激活因子的结合。我们在此表明，先前显示与HIF相互作用的蛋白质FIH-1是一种天冬酰胺酰羟化酶。与已知的羟化酶一样，FIH-1是一种依赖Fe(II)的酶，它利用分子氧修饰其底物。与最近发现的调节HIF稳定性的脯氨酰羟化酶一起，这类氧依赖性酶构成了缺氧反应途径的关键调节成分。
