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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Structure of glycerol-3-phosphate dehydrogenase, an essential monotopic membrane enzyme involved in respiration and metabolism
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Structure of glycerol-3-phosphate dehydrogenase, an essential monotopic membrane enzyme involved in respiration and metabolism

机译：甘油-3-磷酸脱氢酶的结构，甘油三磷酸脱氢酶是参与呼吸和代谢的必不可少的单分子膜酶

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摘要

Sn-glycerol-3-phosphate dehydrogenase (GlpD) is an essential membrane enzyme, functioning at the central junction of respiration, glycolysis, and phospholipid biosynthesis. Its critical role is indicated by the multitiered regulatory mechanisms that stringently controls its expression and function. Once expressed, GlpD activity is regulated through lipid-enzyme interactions in Esche-richia coli. Here, we report seven previously undescribed structures of the fully active E. coli GlpD, up to 1.75 A resolution. In addition to elucidating the structure of the native enzyme, we have determined the structures of GIpD complexed with substrate analogues phosphoenolpyruvate, glyceric acid 2-phosphate, glyceraldehyde-3-phosphate, and product, dihydroxyacetone phosphate. These structural results reveal conformational states of the enzyme, delineating the residues involved in substrate binding and catalysis at the glycerol-3-phosphate site. Two probable mechanisms for catalyzing the dehydrogenation of glycerol-3-phosphate are envisioned, based on the conformational states of the complexes. To further correlate catalytic dehydrogenation to respiration, we have additionally determined the structures of GlpD bound with ubiqui-none analogues menadione and 2-n-heptyl-4-hydroxyquinoline N-oxide, identifying a hydrophobic plateau that is likely the ubiquinone-binding site. These structures illuminate probable mechanisms of catalysis and suggest how GlpD shuttles electrons into the respiratory pathway. Glycerol metabolism has been implicated in insulin signaling and perturbations in glycerol uptake and catabolism are linked to obesity in humans. Homologs of GlpD are found in practically all organisms, from prokaryotes to humans, with >45% consensus protein sequences, signifying that these structural results on the prokaryotic enzyme may be readily applied to the eukaryotic GlpD enzymes.
机译：Sn-甘油-3-磷酸脱氢酶（GlpD）是必不可少的膜酶，在呼吸，糖酵解和磷脂生物合成的中心连接处起作用。严格控制其表达和功能的多层调节机制表明了其关键作用。一旦表达，GlpD活性通过大肠杆菌中的脂质-酶相互作用来调节。在这里，我们报告了全活性大肠杆菌GlpD的七个先前未描述的结构，分辨率高达1.75A。除了阐明天然酶的结构外，我们还确定了与底物类似物磷酸烯醇丙酮酸，2-磷酸甘油酸，3-磷酸甘油醛和产物二羟基丙酮磷酸酯复合的GIpD的结构。这些结构结果揭示了酶的构象状态，描绘了在3-磷酸甘油位点上参与底物结合和催化的残基。基于配合物的构象状态，设想了两种可能的催化3-磷酸甘油酯脱氢的机理。为了进一步将催化脱氢与呼吸相关，我们还确定了与泛醌类似物甲萘醌和2-正庚基-4-羟基喹啉N-氧化物结合的GlpD的结构，确定了可能是泛醌结合位点的疏水平台。这些结构阐明了可能的催化机制，并暗示了GlpD如何将电子传递到呼吸途径中。甘油代谢与胰岛素信号有关，甘油摄入和分解代谢的紊乱与人类肥胖有关。在从原核生物到人类的几乎所有生物中都发现了GlpD的同源物，共有> 45％的共有蛋白序列，这表明原核酶的这些结构结果可能很容易应用于真核GlpD酶。

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