The glycerophospho metabolome and its influence on amino acid homeostasis revealed by brain metabolomics of GDE1(-/-) mice.
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.
Kopp
Florian
F
Department of Chemical Physiology and The Skaggs Institute for Chemical Biology, La Jolla, CA 92037, USA.
Komatsu
Toru
T
Nomura
Daniel K
DK
Trauger
Sunia A
SA
Thomas
Jason R
JR
Siuzdak
Gary
G
Simon
Gabriel M
GM
Cravatt
Benjamin F
BF
D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D006706:Homeostasis; D007295:Inositol Phosphates / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry; D055442:Metabolome; D055432:Metabolomics / Q000379:methods*; D051379:Mice; D010727:Phosphoric Diester Hydrolases / Q000172:deficiency* / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D012995:Solubility; D014867:Water / Q000737:chemistry
D000596:Amino Acids; D007295:Inositol Phosphates; D014867:Water; C014575:glycerylphosphoinositol; D012694:Serine; D010727:Phosphoric Diester Hydrolases; C038133:glycerophosphodiester phosphodiesterase
Mol Gen Genet. 1991 Apr;226(1-2):321-7
1851953
J Biol Chem. 2001 Feb 9;276(6):3756-63
11078727
J Chromatogr A. 2006 Aug 25;1125(1):76-88
16759663
Proc Natl Acad Sci U S A. 2000 Apr 11;97(8):3999-4004
10760272
Biochim Biophys Acta. 2007 Mar;1771(3):337-42
16781190
J Exp Med. 1995 Nov 1;182(5):1545-56
7595224
J Neurosci. 2001 Oct 1;21(19):7691-704
11567059
J Biol Chem. 2007 May 11;282(19):14463-75
17371878
Anal Biochem. 2008 Apr 15;375(2):272-81
18243123
Mol Biol Cell. 1997 Mar;8(3):443-53
9188097
Cell Mol Life Sci. 2009 Nov;66(21):3449-67
19669618
Proc Natl Acad Sci U S A. 2000 Oct 10;97(21):11528-33
11016963
J Biol Chem. 2006 Sep 8;281(36):26465-72
16818490
Science. 2005 Sep 30;309(5744):2212-5
16195461
Curr Opin Neurol. 2004 Apr;17(2):197-204
15021249
J Biol Chem. 2005 Oct 28;280(43):36110-7
16141200
Proc Natl Acad Sci U S A. 2008 Aug 5;105(31):11026-31
18667693
Neurochem Res. 2000 May;25(5):553-60
10905615
FEBS Lett. 2006 Dec 22;580(30):6789-96
17141226
J Biol Chem. 2008 Apr 4;283(14):9341-9
18227059
Anal Chem. 2009 Apr 15;81(8):3071-8
19301915
Anal Chem. 2006 Feb 1;78(3):779-87
16448051
J Biol Chem. 2005 Mar 4;280(9):8544-52
15611060
Brain Res. 1994 Jan 21;634(2):291-5
8131079
Anal Chem. 2008 Aug 15;80(16):6382-9
18627180
J Biol Chem. 1983 May 10;258(9):5428-32
6304089
Nature. 2010 Jan 14;463(7278):232-6
20075918
J Biol Chem. 2003 Oct 31;278(44):43595-602
12933806
J Biol Chem. 1984 Mar 10;259(5):3111-6
6321496
FEBS Lett. 2003 Jul 31;548(1-3):69-73
12885409
J Lipid Res. 2009 Aug;50(8):1589-99
19096047
Neurochem Res. 2005 Nov;30(11):1421-7
16341939
Nat Chem Biol. 2009 Jan;5(1):23-5
19011639
Eur J Biochem. 1996 Oct 15;241(2):386-92
8917434
Nature. 2009 Dec 10;462(7274):739-44
19935646
Genetics. 1998 Aug;149(4):1707-15
9691030
ACS Chem Biol. 2009 Aug 21;4(8):617-23
19621937
J Biol Chem. 2009 Sep 11;284(37):24848-56
19596859
Biochemistry. 2004 Nov 16;43(45):14332-9
15533037
Biochemistry. 2007 Dec 18;46(50):14500-13
18031065
Biosci Biotechnol Biochem. 2007 Aug;71(8):1811-8
17690467
J Biol Chem. 2006 Jul 7;281(27):18489-98
16684771
Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1745-50
12576545
Mol Biosyst. 2010 Aug;6(8):1411-8
20393650
Proc Natl Acad Sci U S A. 2000 Apr 25;97(9):4926-31
10781100
Chem Biol. 2006 Oct;13(10):1041-50
17052608
Curr Opin Chem Biol. 2009 Dec;13(5-6):526-31
19744877
Cell. 2009 Sep 18;138(6):1209-21
19766572
Proc Natl Acad Sci U S A. 1999 Nov 9;96(23):13409-14
10557334
Anal Chem. 2007 Aug 15;79(16):6167-73
17630720