Atypical N-terminal extensions confer novel regulatory properties on GTP cyclohydrolase isoforms in Drosophila melanogaster
Atypical N-terminal extensions confer novel regulatory properties on GTP cyclohydrolase isoforms in Drosophila melanogaster
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DOI：
10.1074/jbc.m602196200
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发表时间：
2006-11-03
影响因子：
4.8
通讯作者：
O'Donnell, Janis M.
中科院分区：
文献类型：
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作者：
Funderburk, Christopher D.;Bowling, Kevin M.;O'Donnell, Janis M.
辅助因子四氢生物蝶呤在信号分子多巴胺、血清素和一氧化氮的调节中起关键作用。辅助因子合成缺陷与几种人类遗传性疾病有关。辅因子池的调控责任在于其生物合成途径中的第一个酶，GTP环水解酶i。因为生物体必须能够快速响应环境和发育线索来调节这些信号分子的输出，复杂的调控机制对于信号调节至关重要。哺乳动物GTP环水解酶通过相关的调节蛋白受到终产物抑制，并通过磷酸化受到正调节，尽管靶残基未知。GTP环水解酶由高度保守的同十聚体催化核和被认为是调控位点的非保守n端结构域组成。我们首次在任何生物体中证明该蛋白的n端臂具有调节功能。我们确定了通过n端结构域介导的酶的两种不同的调节模式。第一种是最终产物反馈抑制，催化上类似于哺乳动物酶，不同之处在于辅因子的反馈抑制需要n端臂上的序列，而不是单独的调节蛋白。第二种是N端臂与活性位点之间的一种新的抑制相互作用，这种相互作用可以通过N端丝氨酸残基的磷酸化来缓解。这两种机制都允许下游信号通路所需的辅助因子产生的急性和高反应性调节。
The cofactor tetrahydrobiopterin plays critical roles in the modulation of the signaling molecules dopamine, serotonin, and nitric oxide. Deficits in cofactor synthesis have been associated with several human hereditary diseases. Responsibility for the regulation of cofactor pools resides with the first enzyme in its biosynthetic pathway, GTP cyclohydrolase I. Because organisms must be able to rapidly respond to environmental and developmental cues to adjust output of these signaling molecules, complex regulatory mechanisms are vital for signal modulation. Mammalian GTP cyclohydrolase is subject to end-product inhibition via an associated regulatory protein and to positive regulation via phosphorylation, although target residues are unknown. GTP cyclohydrolase is composed of a highly conserved homodecameric catalytic core and non-conserved N-terminal domains proposed to be regulatory sites. We demonstrate for the first time in any organism that the N-terminal arms of the protein serve regulatory functions. We identify two different modes of regulation of the enzyme mediated through the N-terminal domains. The first is end-product feedback inhibition, catalytically similar to that of the mammalian enzyme, except that feedback inhibition by the cofactor requires sequences in the N-terminal arms rather than a separate regulatory protein. The second is a novel inhibitory interaction between the N-terminal arms and the active sites, which can be alleviated through the phosphorylation of serine residues within the N termini. Both mechanisms allow for acute and highly responsive regulation of cofactor production as required by downstream signaling pathways.