Kopp Florian, Komatsu Toru, Nomura Daniel K, Trauger Sunia A, Thomas Jason R, Siuzdak Gary, Simon Gabriel M, Cravatt Benjamin F
Department of Chemical Physiology and The Skaggs Institute for Chemical Biology, La Jolla, CA 92037, USA.
Chem Biol. 2010 Aug 27;17(8):831-40. doi: 10.1016/j.chembiol.2010.06.009.
GDE1 is a mammalian glycerophosphodiesterase (GDE) implicated by in vitro studies in the regulation of glycerophophoinositol (GroPIns) and possibly other glycerophospho (GroP) metabolites. Here, we show using untargeted metabolomics that GroPIns is profoundly (>20-fold) elevated in brain tissue from GDE1(-/-) mice. Furthermore, two additional GroP metabolites not previously identified in eukaryotic cells, glycerophosphoserine (GroPSer) and glycerophosphoglycerate (GroPGate), were also highly elevated in GDE1(-/-) brains. Enzyme assays with synthetic GroP metabolites confirmed that GroPSer and GroPGate are direct substrates of GDE1. Interestingly, our metabolomic profiles also revealed that serine (both L-and D-) levels were significantly reduced in brains of GDE1(-/-) mice. These findings designate GroPSer as a previously unappreciated reservoir for free serine in the nervous system and suggest that GDE1, through recycling serine from GroPSer, may impact D-serine-dependent neural signaling processes in vivo.
GDE1是一种哺乳动物甘油磷酸二酯酶（GDE），体外研究表明它参与甘油磷酸肌醇（GroPIns）以及可能的其他甘油磷酸（GroP）代谢物的调节。在此，我们通过非靶向代谢组学研究发现，GDE1基因敲除（GDE1(-/-)）小鼠脑组织中的GroPIns显著升高（超过20倍）。此外，另外两种之前未在真核细胞中鉴定出的GroP代谢物，甘油磷酸丝氨酸（GroPSer）和甘油磷酸甘油酸（GroPGate），在GDE1(-/-)小鼠的大脑中也高度升高。对合成的GroP代谢物进行酶活性测定证实，GroPSer和GroPGate是GDE1的直接底物。有趣的是，我们的代谢组学分析还显示，GDE1(-/-)小鼠大脑中的丝氨酸（L-丝氨酸和D-丝氨酸）水平显著降低。这些发现表明，GroPSer是神经系统中一种此前未被重视的游离丝氨酸储备库，并且提示GDE1可能通过从GroPSer中回收丝氨酸，在体内影响依赖D-丝氨酸的神经信号传导过程。
