A humble hexose monophosphate pathway metabolite regulates short- and long-term control of lipogenesis.
A humble hexose monophosphate pathway metabolite regulates short- and long-term control of lipogenesis.
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一种不起眼的单磷酸己糖途径代谢物调节脂肪生成的短期和长期控制。
DOI：
10.1073/pnas.1132039100
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发表时间：
2003
影响因子：
11.1
通讯作者：
Veech,RichardL
中科院分区：
文献类型：
--
作者：
Veech,RichardL
大多数现代生物学家和当代生物化学教科书都将糖酵解途径和脂肪合成作为所有相关事实已知的历史。Kosaku Uyeda和他的小组在最近一期的PNAS上发表的一篇文章（1）将对脂肪生成调控的新见解与英雄蛋白质化学以及酶学和分子生物学的优雅结合结合起来。本文描述了一种被忽视的单磷酸己糖途径的代谢产物5-磷酸木酮糖（Xu-5-P）如何激活蛋白磷酸酶2A来介导糖酵解途径中碳水化合物喂养的急性效应，以及脂肪酸和甘油三酯合成所需的酶的协调长期控制。在20世纪90年代早期，鉴定了命名为SREBP的转录因子，其是一种固醇应答元件结合蛋白，其调节编码胆固醇生物合成的许多关键酶的基因的转录，所述关键酶包括羟甲基戊二酰（HMG）-CoA合酶（EC 4.1. 3.5）、HMG-CoA还原酶（EC 1.1. 1.88）、法呢基-二磷酸合酶（EC 2.5. 1.10）和低密度脂蛋白受体蛋白（综述见参考文献2）。SREBP还调节编码葡糖激酶（EC 2.7. 1.12），一种负责催化肝糖酵解第一步的酶。SREBP的加工受蛋白水解的调节，其机制类似于淀粉样前体蛋白的加工。SREBP的裂解需要称为SCAP的活化蛋白，并且负责胆固醇对固醇合成的反馈抑制。还发现，除了影响固醇合成之外，SREBP还调节编码脂肪酸生物合成所必需的酶的一些基因的表达。这些发现导致了这样的结论，即SREBP协调膜的两个主要组成部分，脂肪酸和胆固醇的合成。然而，很快，更多的数据出现了。
Most modern biologists and contemporary textbooks of biochemistry present the glycolytic pathway and the synthesis of fats as history where all of the relevant facts are known. An article in a recent issue of PNAS by Kosaku Uyeda and his group (1) combines new insights into the regulation of lipogenesis with heroic protein chemistry and an elegant combination of enzymology and molecular biology. This paper describes how a small and ignored metabolite of the hexose monophosphate pathway, xylulose 5-phosphate (Xu-5-P), activates protein phosphatase 2A to mediate the acute effects of carbohydrate feeding on the glycolytic pathway, as well as the coordinate long-term control of the enzymes required for fatty acid and triglyceride synthesis.It has long been known that feeding of cholesterol suppresses cholesterol synthesis. In the early 1990s a transcription factor designated as SREBP, a sterol response element binding protein, was identified that regulated the transcription of the genes encoding a number of the key enzymes of cholesterol biosynthesis, including hydroxymethylglutaryl (HMG)-CoA synthase (EC 4.1. 3.5), HMG-CoA reductase (EC 1.1. 1.88), farnesyl-diphosphate synthase (EC 2.5. 1.10), and the low-density lipoprotein receptor protein (for review, see ref. 2). SREBP also regulates the transcription of the gene encoding glucokinase (EC 2.7. 1.12), an enzyme responsible for catalysis of the first step of hepatic glycolysis. The processing of SREBP is regulated by proteolysis by mechanisms analogous to those involved in the processing of amyloid precursor protein. Cleavage of SREBP requires an activating protein designated SCAP and is responsible for the feedback inhibition of cholesterol on sterol synthesis. It was also found that, in addition to affecting sterol synthesis, SREBP also modulates the expression of some of the genes encoding enzymes necessary for fatty acid biosynthesis. These findings led to the conclusion that SREBP coordinates the synthesis of the two major building blocks of membranes, fatty acids and cholesterol. Soon, however, more data were to emerge.