PTERIDINE BIOSYNTHESIS

蝶啶生物合成

• 批准号: 6290518
• 负责人: SHELDON MILSTIEN
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6290518
• 关键词: biosynthesis; brain metabolism; carbon nitrogen hydrolase; cofactor; dopamine; enzyme activity; enzyme feedback; glia; laboratory rat; neurotransmitter metabolism; nitric oxide; nitric oxide synthase; phenylalanine; serotonin; tetrahydrobiopterin; tissue /cell culture; tyrosine 3 monooxygenase; vascular endothelium; vascular smooth muscle

Tetrahydrobiopterin is a required cofactor for the hepatic phenylalanine hydroxylating system. De novo synthesis of tetrahydrobiopterin is regulated mainly by the activity of the first enzyme of the biosynthetic pathway, GTP cyclohydrolase I (GTPCH). The GTPCH feedback regulatory protein (GFRP) forms a complex with GTPCH and confers endproduct feedback sensitivity. GFRP mRNA distribution in rat brain has now been determined and correlated with GTPCH mRNA levels. All aminergic neurons contain both GFRP and GTPCH mRNAs, although the ratio of GFRP to GTPCH mRNA is much greater in serotonergic neurons than in dopaminergic neurons, where it regulates tetrahydrobiopterin and serotonin synthesis. Tetrahydrobiopterin is also required by all forms of nitric oxide synthase and limits production of nitric oxide, endothelial derived relaxing factor, by endothelial cells and vascular smooth muscle cells. Availability of intracellular tetrahydrobiopterin likely plays a role in controlling nitric oxide-dependent vascular tone under normal and pathological conditions. Sphingolipid metabolites, ceramide, spingosine, and sphingsosine-1-phosphate, play important signaling roles in many biological processes, including cell survival and death. We have now found that although ceramide mediates some of the actions of TNF-alpha in the induction of nitric oxide synthase and nitric oxide production in glial cells, TNF-alpha stimulates GTP cyclohydrolase activity and tetrahydrobiopterin synthesis by a ceramide independent mechanism. This is the first indication that these two pathways may be regulated via distinct signaling pathways and by different mechanisms. - tetrahydrobiopterin nitric oxide phenylketonuria athersclerosis sphingolipids

四氢无生蛋白是肝苯丙氨酸羟基系统所需的辅助因子。从头合成四氢无菌蛋白酶的合成主要由生物合成途径的第一种酶，GTP环糖水溶性酶I（GTPCH）的活性调节。 GTPCH反馈调节蛋白（GFRP）与GTPCH形成复合物，并赋予最终产品反馈敏感性。现在已经确定了大鼠脑中的GFRP mRNA分布并与GTPCH mRNA水平相关。尽管血清素能神经元的GFRP与GFRP与GTPCH mRNA的比率大于多巴胺能神经元中，但所有AMINAMERGIC神经元均包含GFRP和GTPCH mRNA，尽管它调节了四氢蛋白蛋白蛋白蛋白蛋白和血清素的合成。各种形式的一氧化氮合酶还需要四氢无菌蛋白酶，并限制了一氧化氮的产生，内皮细胞和血管平滑肌细胞的内皮衍生弛豫因子。细胞内四氢异物蛋白的可用性可能在正常和病理条件下控制一氧化氮依赖性血管张力方面起作用。鞘脂代谢物，神经酰胺，香丁苷和肝氨酸-1-磷酸盐在许多生物过程中起着重要的信号传导作用，包括细胞存活和死亡。现在，我们发现，尽管神经酰胺介导了TNF-α在神经胶质细胞中诱导一氧化氮合酶和一氧化氮的产生中的某些作用，但TNF-α，TNF-α刺激GTP环戊醛酶活性和四氢无生物蛋白酶蛋白质的合成，而陶瓷蛋白具有独立机制。这是第一个迹象表明，这两种途径可以通过不同的信号通路和不同的机制来调节。 - 四氢无生蛋白一氧化氮苯酮蛋白尿素蛋白酶鞘脂鞘脂