Abstract
L-serine is a nonessential amino acid in eukaryotic cells, used for protein synthesis and in producing phosphoglycerides, glycerides, sphingolipids, phosphatidylserine, and methylenetetrahydrofolate. Moreover, L-serine is the precursor of two relevant coagonists of NMDA receptors: glycine (through the enzyme serine hydroxymethyltransferase), which preferentially acts on extrasynaptic receptors and D-serine (through the enzyme serine racemase), dominant at synaptic receptors. The cytosolic “phosphorylated pathway” regulates de novo biosynthesis of L-serine, employing 3-phosphoglycerate generated by glycolysis and the enzymes 3-phosphoglycerate dehydrogenase, phosphoserine aminotransferase, and phosphoserine phosphatase (the latter representing the irreversible step). In the human brain, L-serine is primarily found in glial cells and is supplied to neurons for D-serine synthesis. Serine-deficient patients show severe neurological symptoms, including congenital microcephaly, psychomotor retardation, and intractable seizures, thus highlighting the relevance of de novo production of this amino acid in brain development and morphogenesis. Indeed, the phosphorylated pathway is strictly linked to cancer. Moreover, L-serine has been suggested as a ready-to-use treatment, as also recently proposed for Alzheimer’s disease. Here, we present our current state of knowledge concerning the three mammalian enzymes of the phosphorylated pathway and known mutations related to pathological conditions: although the structure of these enzymes has been solved, how enzyme activity is regulated remains largely unknown. We believe that an in-depth investigation of these enzymes is crucial to identify the molecular mechanisms involved in modulating concentrations of the serine enantiomers and for studying the interplay between glial and neuronal cells and also to determine the most suitable therapeutic approach for various diseases.
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Kent C (1995) Eukaryotic phospholipid biosynthesis. Annu Rev Biochem 64:315–343. https://doi.org/10.1146/annurev.bi.64.070195.001531
Hirabayashi Y, Furuya S (2008) Roles of L-serine and sphingolipid synthesis in brain development and neuronal survival. Prog Lipid Res 47(3):188–203. https://doi.org/10.1016/j.plipres.2008.01.003
Herbig K, Chiang EP, Lee LR, Hills J, Shane B, Stover PJ (2002) Cytoplasmic serine hydroxymethyltransferase mediates competition between folate-dependent deoxyribonucleotide and S-adenosylmethionine biosyntheses. J Biol Chem 277(41):38381–38389. https://doi.org/10.1074/jbc.M205000200
Wang W, Wu Z, Dai Z, Yang Y, Wang J, Wu G (2013) Glycine metabolism in animals and humans: implications for nutrition and health. Amino Acids 45(3):463–477. https://doi.org/10.1007/s00726-013-1493-1
Wolosker H, Sheth KN, Takahashi M et al (1999) Purification of serine racemase: biosynthesis of the neuromodulator D-serine. Proc Natl Acad Sci USA 96(2):721–725. https://doi.org/10.1073/pnas.96.2.721
Yoshida K, Furuya S, Osuka S et al (2004) Targeted disruption of the mouse 3-phosphoglycerate dehydrogenase gene causes severe neurodevelopmental defects and results in embryonic lethality. J Biol Chem 279(5):3573–3577. https://doi.org/10.1074/jbc.C300507200
Furuya S, Yoshida K, Kawakami Y et al (2008) Inactivation of the 3-phosphoglycerate dehydrogenase gene in mice: changes in gene expression and associated regulatory networks resulting from serine deficiency. Funct Integr Genomics 8(3):235–249. https://doi.org/10.1007/s10142-007-0072-5
Tabatabaie L, Klomp LW, Rubio-Gozalbo ME et al (2011) Expanding the clinical spectrum of 3-phosphoglycerate dehydrogenase deficiency. J Inherit Metab Dis 34(1):181–184. https://doi.org/10.1007/s10545-010-9249-5
van der Crabben SN, Verhoeven-Duif NM, Brilstra EH et al (2013) An update on serine deficiency disorders. J Inherit Metab Dis 36(4):613–619. https://doi.org/10.1007/s10545-013-9592-4
Snell K, Fell DA (1990) Metabolic control analysis of mammalian serine metabolism. Adv Enzyme Regul 30:13–32. https://doi.org/10.1016/0065-2571(90)90006-n
Tabatabaie L, Klomp LW, Berger R, de Koning TJ (2010) L-serine synthesis in the central nervous system: a review on serine deficiency disorders. Mol Genet Metab 99(3):256–262. https://doi.org/10.1016/j.ymgme.2009.10.012
Yang JH, Wada A, Yoshida K et al (2010) Brain-specific Phgdh deletion reveals a pivotal role for L-serine biosynthesis in controlling the level of D-serine, an N-methyl-d-aspartate receptor co-agonist, in adult brain. J Biol Chem 285(53):41380–41390. https://doi.org/10.1074/jbc.M110.187443
El-Hattab AW, Shaheen R, Hertecant J, Galadari HI, Albaqawi BS, Nabil A, Alkuraya FS (2016) On the phenotypic spectrum of serine biosynthesis defects. J Inherit Metab Dis 39(3):373–381. https://doi.org/10.1007/s10545-016-9921-5
Furuya S, Tabata T, Mitoma J et al (2000) L-serine and glycine serve as major astroglia-derived trophic factors for cerebellar Purkinje neurons. Proc Natl Acad Sci USA 97(21):11528–11533. https://doi.org/10.1073/pnas.200364497
Yamasaki M, Yamada K, Furuya S, Mitoma J, Hirabayashi Y, Watanabe M (2001) 3-Phosphoglycerate dehydrogenase, a key enzyme for L-serine biosynthesis, is preferentially expressed in the radial glia/astrocyte lineage and olfactory ensheathing glia in the mouse brain. J Neurosci 21(19):7691–7704. https://doi.org/10.1523/JNEUROSCI.21-19-07691.2001
Shimizu M, Furuya S, Shinoda Y et al (2004) Functional analysis of mouse 3-phosphoglycerate dehydrogenase (Phgdh) gene promoter in developing brain. J Neurosci Res 76(5):623–632. https://doi.org/10.1002/jnr.20102
Johnson JW, Ascher P (1987) Glycine potentiates the NMDA response in cultured mouse brain neurons. Nature 325(6104):529–531. https://doi.org/10.1038/325529a0
Henneberger C, Bard L, King C, Jennings A, Rusakov DA (2013) NMDA receptor activation: two targets for two co-agonists. Neurochem Res 38(6):1156–1162. https://doi.org/10.1007/s11064-013-0987-2
Mothet JP, Parent AT, Wolosker H et al (2000) D-serine is an endogenous ligand for the glycine site of the N-methyl-d-aspartate receptor. Proc Natl Acad Sci USA 97(9):4926–4931. https://doi.org/10.1073/pnas.97.9.4926
Papouin T, Ladépêche L, Ruel J et al (2012) Synaptic and extrasynaptic NMDA receptors are gated by different endogenous coagonists. Cell 150(3):633–646. https://doi.org/10.1016/j.cell.2012.06.029
Wolosker H, Balu DT, Coyle JT (2016) The rise and fall of the D-serine-mediated gliotransmission hypothesis. Trends Neurosci 39(11):712–721. https://doi.org/10.1016/j.tins.2016.09.007
Ferreira JS, Papouin T, Ladépêche L et al (2017) Co-agonists differentially tune GluN2B-NMDA receptor trafficking at hippocampal synapses. Elife 6:e25492. https://doi.org/10.7554/eLife.25492
Meunier CN, Dallérac G, Le Roux N, Sacchi S, Levasseur G, Amar M, Pollegioni L, Mothet JP, Fossier P (2016) D-Serine and glycine differentially control neurotransmission during visual cortex critical period. PLoS ONE 1(3):e0151233. https://doi.org/10.1371/journal.pone.0151233
Li Y, Sacchi S, Pollegioni L, Basu AC, Coyle JT, Bolshakov VY (2013) Identity of endogenous NMDAR glycine site agonist in amygdala is determined by synaptic activity level. Nat Commun 4:1760. https://doi.org/10.1038/ncomms2779
Pollegioni L, Sacchi S (2010) Metabolism of the neuromodulator D-serine. Cell Mol Life Sci 67(14):2387–2404. https://doi.org/10.1007/s00018-010-0307-9
Sacchi S, Caldinelli L, Cappelletti P, Pollegioni L, Molla G (2012) Structure-function relationships in human d-amino acid oxidase. Amino Acids 43(5):1833–1850. https://doi.org/10.1007/s00726-012-1345-4
Murtas G, Sacchi S, Valentino M, Pollegioni L (2017) Biochemical properties of human d-amino acid oxidase. Front Mol Biosci 4:88. https://doi.org/10.3389/fmolb.2017.00088
Pollegioni L, Sacchi S, Murtas G (2018) Human d-amino acid oxidase: structure, function, and regulation. Front Mol Biosci 5:107. https://doi.org/10.3389/fmolb.2018.00107
Papouin T, Henneberger C, Rusakov DA, Oliet SHR (2017) Astroglial versus neuronal D-serine: fact checking. Trends Neurosci 40(9):517–520. https://doi.org/10.1016/j.tins.2017.05.007
Wolosker H, Balu DT, Coyle JT (2017) Astroglial versus neuronal D-serine: check your controls! Trends Neurosci 40(9):520–522. https://doi.org/10.1016/j.tins.2017.06.010
Meunier C, Wang N, Yi C et al (2017) Contribution of astroglial Cx43 hemichannels to the modulation of glutamatergic currents by D-serine in the mouse prefrontal cortex. J Neurosci 37(37):9064–9075. https://doi.org/10.1523/JNEUROSCI.2204-16.2017
Rosenberg D, Kartvelishvily E, Shleper M, Klinker CM, Bowser MT, Wolosker H (2010) Neuronal release of D-serine: a physiological pathway controlling extracellular D-serine concentration. FASEB J 24(8):2951–2961. https://doi.org/10.1096/fj.09-147967
Martineau M, Parpura V, Mothet JP (2014) Cell-type specific mechanisms of D-serine uptake and release in the brain. Front Synaptic Neurosci 6:12. https://doi.org/10.3389/fnsyn.2014.00012
Wolosker H (2011) Serine racemase and the serine shuttle between neurons and astrocytes. Biochim Biophys Acta 1814(11):1558–1566. https://doi.org/10.1016/j.bbapap.2011.01.001
Neame S, Safory H, Radzishevsky I et al (2019) The NMDA receptor activation by D-serine and glycine is controlled by an astrocytic Phgdh-dependent serine shuttle. Proc Natl Acad Sci USA 116(41):20736–20742. https://doi.org/10.1073/pnas.1909458116
Bennett M (2009) Positive and negative symptoms in schizophrenia: the NMDA receptor hypofunction hypothesis, neuregulin/ErbB4 and synapse regression. Aust N Z J Psychiatry 43(8):711–721. https://doi.org/10.1080/00048670903001943
Heresco-Levy U, Shoham S, Javitt DC (2013) Glycine site agonists of the N-methyl-d-aspartate receptor and Parkinson's disease: a hypothesis. Mov Disord 28(4):419–424. https://doi.org/10.1002/mds.25306
Zhang J, Li Y, Xu J, Yang Z (2014) The role of N-methyl-d-aspartate receptor in Alzheimer's disease. J Neurol Sci 339(1–2):123–129. https://doi.org/10.1016/j.jns.2014.01.041
Sasabe J, Chiba T, Yamada M et al (2007) D-serine is a key determinant of glutamate toxicity in amyotrophic lateral sclerosis. EMBO J 26(18):4149–4159. https://doi.org/10.1038/sj.emboj.7601840
Abe T, Suzuki M, Sasabe J et al (2014) Cellular origin and regulation of D- and L-serine in in vitro and in vivo models of cerebral ischemia. J Cereb Blood Flow Metab 34(12):1928–1935. https://doi.org/10.1038/jcbfm.2014.164
Suzuki M, Sasabe J, Miyoshi Y et al (2015) Glycolytic flux controls D-serine synthesis through glyceraldehyde-3-phosphate dehydrogenase in astrocytes. Proc Natl Acad Sci USA 112(17):E2217–E2224. https://doi.org/10.1073/pnas.1416117112
Mitoma J, Furuya S, Hirabayashi Y (1998) A novel metabolic communication between neurons and astrocytes: non-essential amino acid L-serine released from astrocytes is essential for developing hippocampal neurons. Neurosci Res 30(2):195–199. https://doi.org/10.1016/s0168-0102(97)00113-2
Amelio I, Cutruzzolá F, Antonov A, Agostini M, Melino G (2014) Serine and glycine metabolism in cancer. Trends Biochem Sci 39(4):191–198. https://doi.org/10.1016/j.tibs.2014.02.004
DeBerardinis RJ (2011) Serine metabolism: some tumors take the road less traveled. Cell Metab 14(3):285–286. https://doi.org/10.1016/j.cmet.2011.08.004
Possemato R, Marks KM, Shaul YD et al (2011) Functional genomics reveal that the serine synthesis pathway is essential in breast cancer. Nature 476(7360):346–350. https://doi.org/10.1038/nature10350
Pollari S, Käkönen SM, Edgren H et al (2011) Enhanced serine production by bone metastatic breast cancer cells stimulates osteoclastogenesis. Breast Cancer Res Treat 125(2):421–430. https://doi.org/10.1007/s10549-010-0848-5
Yang Y, Wu J, Cai J et al (2015) PSAT1 regulates cyclin D1 degradation and sustains proliferation of non-small cell lung cancer cells. Int J Cancer 136(4):E39–E50. https://doi.org/10.1002/ijc.29150
Ojala P, Sundström J, Grönroos JM, Virtanen E, Talvinen K, Nevalainen TJ (2002) mRNA differential display of gene expression in colonic carcinoma. Electrophoresis 23(11):1667–1676. https://doi.org/10.1002/1522-2683(200206)23:11<1667:AID-ELPS1667>3.0.CO;2-0
Friederichs J, Rosenberg R, Mages J et al (2005) Gene expression profiles of different clinical stages of colorectal carcinoma: toward a molecular genetic understanding of tumor progression. Int J Colorectal Dis 20(5):391–402. https://doi.org/10.1007/s00384-004-0722-1
Martens JW, Nimmrich I, Koenig T et al (2005) Association of DNA methylation of phosphoserine aminotransferase with response to endocrine therapy in patients with recurrent breast cancer. Cancer Res 65(10):4101–4117. https://doi.org/10.1158/0008-5472.CAN-05-0064
Li X, Xun Z, Yang Y (2016) Inhibition of phosphoserine phosphatase enhances the anticancer efficacy of 5-fluorouracil in colorectal cancer. Biochem Biophys Res Commun 477(4):633–639. https://doi.org/10.1016/j.bbrc.2016.06.112
Sato K, Masuda T, Hu Q et al (2017) Phosphoserine phosphatase is a novel prognostic biomarker on chromosome 7 in colorectal cancer. Anticancer Res 37(5):2365–2371. https://doi.org/10.21873/anticanres.11574
Grant GA (2018) d-3-phosphoglycerate dehydrogenase. Front Mol Biosci 5:110. https://doi.org/10.3389/fmolb.2018.00110
Grant GA (2012) Contrasting catalytic and allosteric mechanisms for phosphoglycerate dehydrogenases. Arch Biochem Biophys 519(2):175–185. https://doi.org/10.1016/j.abb.2011.10.005
Grant GA (1989) A new family of 2-hydroxyacid dehydrogenases. Biochem Biophys Res Commun 165(3):1371–1374. https://doi.org/10.1016/0006-291x(89)92755-1
Ulane R, Ogur M (1972) Genetic and physiological control of serine and glycine biosynthesis in Saccharomyces. J Bacteriol 109(1):34–43
Ali V, Hashimoto T, Shigeta Y, Nozaki T (2004) Molecular and biochemical characterization of d-phosphoglycerate dehydrogenase from Entamoeba histolytica. A unique enteric protozoan parasite that possesses both phosphorylated and nonphosphorylated serine metabolic pathways. Eur J Biochem 271(13):2670–2681. https://doi.org/10.1111/j.1432-1033.2004.04195.x
Singh RK, Raj I, Pujari R, Gourinath S (2014) Crystal structures and kinetics of Type III 3-phosphoglycerate dehydrogenase reveal catalysis by lysine. FEBS J 281(24):5498–5512. https://doi.org/10.1111/febs.13091
Baek JY, Jun DY, Taub D, Kim YH (2003) Characterization of human phosphoserine aminotransferase involved in the phosphorylated pathway of L-serine biosynthesis. Biochem J 373(Pt 1):191–200. https://doi.org/10.1042/BJ20030144
Cho HM, Jun DY, Bae MA, Ahn JD, Kim YH (2000) Nucleotide sequence and differential expression of the human 3-phosphoglycerate dehydrogenase gene. Gene 245(1):193–201. https://doi.org/10.1016/s0378-1119(00)00009-3
Unterlass JE, Wood RJ, Baslé A et al (2017) Structural insights into the enzymatic activity and potential substrate promiscuity of human 3-phosphoglycerate dehydrogenase (PHGDH). Oncotarget 8(61):104478–104491. https://doi.org/10.18632/oncotarget.22327
Fan J, Teng X, Liu L et al (2015) Human phosphoglycerate dehydrogenase produces the oncometabolite d-2-hydroxyglutarate. ACS Chem Biol 10(2):510–516. https://doi.org/10.1021/cb500683c
Fuller N, Spadola L, Cowen S et al (2016) An improved model for fragment-based lead generation at AstraZeneca. Drug Discov Today 21(8):1272–1283. https://doi.org/10.1016/j.drudis.2016.04.023
Pacold ME, Brimacombe KR, Chan SH et al (2016) A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate. Nat Chem Biol 12(6):452–458. https://doi.org/10.1038/nchembio.2070
Mullarky E, Lairson LL, Cantley LC, Lyssiotis CA (2016) A novel small-molecule inhibitor of 3-phosphoglycerate dehydrogenase. Mol Cell Oncol 3(4):e1164280. https://doi.org/10.1080/23723556.2016.1164280
Wang Q, Liberti MV, Liu P et al (2017) Rational design of selective allosteric inhibitors of PHGDH and serine synthesis with anti-tumor activity. Cell Chem Biol 24(1):55–65. https://doi.org/10.1016/j.chembiol.2016.11.013
Ravez S, Corbet C, Spillier Q et al (2017) α-Ketothioamide derivatives: a promising tool to interrogate phosphoglycerate dehydrogenase (PHGDH). J Med Chem 60(4):1591–1597. https://doi.org/10.1021/acs.jmedchem.6b01166
Mullarky E, Xu J, Robin AD et al (2019) Inhibition of 3-phosphoglycerate dehydrogenase (PHGDH) by indole amides abrogates de novo serine synthesis in cancer cells. Bioorg Med Chem Lett 29(17):2503–2510. https://doi.org/10.1016/j.bmcl.2019.07.011
Spillier Q, Vertommen D, Ravez S et al (2019) Anti-alcohol abuse drug disulfiram inhibits human PHGDH via disruption of its active tetrameric form through a specific cysteine oxidation. Sci Rep 9(1):4737. https://doi.org/10.1038/s41598-019-41187-0
Spillier Q, Ravez S, Unterlass J et al (2020) Structure-activity relationships (SARs) of α-Ketothioamides as inhibitors of phosphoglycerate dehydrogenase (PHGDH). Pharmaceuticals (Basel) 13(2):E20. https://doi.org/10.3390/ph13020020
Weinstabl H, Treu M, Rinnenthal J et al (2019) Intracellular trapping of the selective phosphoglycerate dehydrogenase (PHGDH) inhibitor BI-4924 disrupts serine biosynthesis. J Med Chem 62(17):7976–7997. https://doi.org/10.1021/acs.jmedchem.9b00718
Guo J, Gu X, Zheng M, Zhang Y, Chen L, Li H (2019) Azacoccone E inhibits cancer cell growth by targeting 3-phosphoglycerate dehydrogenase. Bioorg Chem 87:16–22. https://doi.org/10.1016/j.bioorg.2019.02.037
Zheng M, Guo J, Xu J et al (2019) Ixocarpalactone A from dietary tomatillo inhibits pancreatic cancer growth by targeting PHGDH. Food Funct 10(6):3386–3395. https://doi.org/10.1039/c9fo00394k
Achouri Y, Rider MH, Schaftingen EV, Robbi M (1997) Cloning, sequencing and expression of rat liver 3-phosphoglycerate dehydrogenase. Biochem J 323(Pt 2):365–370. https://doi.org/10.1042/bj3230365
Singh RK, Tomar P, Dharavath S, Kumar S, Gourinath S (2019) N-terminal residues are crucial for quaternary structure and active site conformation for the phosphoserine aminotransferase from enteric human parasite E. histolytica. Int J Biol Macromol 132:1012–1023. https://doi.org/10.1016/j.ijbiomac.2019.04.027
Hester G, Stark W, Moser M, Kallen J, Marković-Housley Z, Jansonius JN (1999) Crystal structure of phosphoserine aminotransferase from Escherichia coli at 2.3 A resolution: comparison of the unligated enzyme and a complex with α-methyl-l-glutamate. J Mol Biol 286(3):829–850. https://doi.org/10.1006/jmbi.1998.2506
Battula P, Dubnovitsky AP, Papageorgiou AC (2013) Structural basis of l-phosphoserine binding to Bacillus alcalophilus phosphoserine aminotransferase. Acta Crystallogr D Biol Crystallogr 69(Pt 5):804–811. https://doi.org/10.1107/S0907444913002096
Basurko MJ, Marche M, Darriet M, Cassaigne A (1999) Phosphoserine aminotransferase, the second step-catalyzing enzyme for serine biosynthesis. IUBMB Life 48(5):525–529. https://doi.org/10.1080/713803557
Duncan K, Lewendon A, Coggins JR (1984) The purification of 5-enolpyruvylshikimate 3-phosphate synthase from an overproducing strain of Escherichia coli. FEBS Lett 165(1):121–127. https://doi.org/10.1016/0014-5793(84)80027-7
Sekula B, Ruszkowski M, Dauter Z (2018) Structural analysis of phosphoserine aminotransferase (isoform 1) from Arabidopsis thaliana- the enzyme involved in the phosphorylated pathway of serine biosynthesis. Front Plant Sci 9:876. https://doi.org/10.3389/fpls.2018.00876
Donini S, Ferrari M, Fedeli C et al (2009) Recombinant production of eight human cytosolic aminotransferases and assessment of their potential involvement in glyoxylate metabolism. Biochem J 422(2):265–272. https://doi.org/10.1042/BJ20090748
Peeraer Y, Rabijns A, Collet JF, Van Schaftingen E, De Ranter C (2004) How calcium inhibits the magnesium-dependent enzyme human phosphoserine phosphatase. Eur J Biochem 271(16):3421–3427. https://doi.org/10.1111/j.0014-2956.2004.04277.x
Collet JF, Stroobant V, Van Schaftingen E (1999) Mechanistic studies of phosphoserine phosphatase, an enzyme related to P-type ATPases. J Biol Chem 274(48):33985–33990. https://doi.org/10.1074/jbc.274.48.33985
Kim HY, Heo YS, Kim JH et al (2002) Molecular basis for the local conformational rearrangement of human phosphoserine phosphatase. J Biol Chem 277(48):46651–46658. https://doi.org/10.1074/jbc.M204866200
Haufroid M, Mirgaux M, Leherte L, Wouters J (2019) Crystal structures and snapshots along the reaction pathway of human phosphoserine phosphatase. Acta Crystallogr D Struct Biol 75(Pt 6):592–604. https://doi.org/10.1107/S2059798319006867
Peeraer Y, Rabijns A, Verboven C, Collet JF, Van Schaftingen E, De Ranter C (2003) High-resolution structure of human phosphoserine phosphatase in open conformation. Acta Crystallogr D Biol Crystallogr 59(Pt 6):971–977. https://doi.org/10.1107/s0907444903005407
Collet JF, Gerin I, Rider MH, Veiga-da-Cunha M, Van Schaftingen E (1997) Human l-3-phosphoserine phosphatase: sequence, expression and evidence for a phosphoenzyme intermediate. FEBS Lett 408(3):281–284. https://doi.org/10.1016/s0014-5793(97)00438-9
Veeranna SKT (1990) Phosphoserine phosphatase of human brain: partial purification, characterization, regional distribution, and effect of certain modulators including psychoactive drugs. Neurochem Res 15(12):1203–1210. https://doi.org/10.1007/bf01208581
Goodnough DB, Lutz MP, Wood PL (1995) Separation and quantification of d- and l-phosphoserine in rat brain using N α-(2,4-dinitro-5-fluorophenyl)-l-alaninamide (Marfey's reagent) by high-performance liquid chromatography with ultraviolet detection. J Chromatogr B Biomed Appl 672(2):290–294. https://doi.org/10.1016/0378-4347(95)00221-4
Veiga-da-Cunha M, Collet JF, Prieur B et al (2004) Mutations responsible for 3-phosphoserine phosphatase deficiency. Eur J Hum Genet 12(2):163–166. https://doi.org/10.1038/sj.ejhg.5201083
Hawkinson JE, Acosta-Burruel M, Ta ND, Wood PL (1997) Novel phosphoserine phosphatase inhibitors. Eur J Pharmacol 337(2–3):315–324. https://doi.org/10.1016/s0014-2999(97)01304-6
Wood PL, Hawkinson JE, Goodnough DB (1996) Formation of D-serine from l-phosphoserine in brain synaptosomes. J Neurochem 67(4):1485–1490. https://doi.org/10.1046/j.1471-4159.1996.67041485.x
Arora G, Tiwari P, Mandal RS et al (2014) High throughput screen identifies small molecule inhibitors specific for Mycobacterium tuberculosis phosphoserine phosphatase. J Biol Chem 289(36):25149–25165. https://doi.org/10.1074/jbc.M114.597682
Jaeken J, Detheux M, Van Maldergem L, Foulon M, Carchon H, Van Schaftingen E (1996) 3-Phosphoglycerate dehydrogenase deficiency: an inborn error of serine biosynthesis. Arch Dis Child 74(6):542–545. https://doi.org/10.1136/adc.74.6.542
Méneret A, Wiame E, Marelli C, Lenglet T, Van Schaftingen E, Sedel F (2012) A serine synthesis defect presenting with a Charcot-Marie-Tooth-like polyneuropathy. Arch Neurol 69(7):908–911. https://doi.org/10.1001/archneurol.2011.1526
Shaheen R, Rahbeeni Z, Alhashem A et al (2014) Neu-Laxova syndrome, an inborn error of serine metabolism, is caused by mutations in PHGDH. Am J Hum Genet 94(6):898–904. https://doi.org/10.1016/j.ajhg.2014.04.015
de Koning TJ (2017) Amino acid synthesis deficiencies. J Inherit Metab Dis 40(4):609–620. https://doi.org/10.1007/s10545-017-0063-1
de Koning TJ, Snell K, Duran M, Berger R, Poll-The BT, Surtees R (2003) L-serine in disease and development. Biochem J 371(Pt 3):653–661. https://doi.org/10.1042/BJ20021785
Glinton KE, Benke PJ, Lines MA et al (2018) Disturbed phospholipid metabolism in serine biosynthesis defects revealed by metabolomic profiling. Mol Genet Metab 123(3):309–316. https://doi.org/10.1016/j.ymgme.2017.12.009
Klomp LW, de Koning TJ, Malingré HE et al (2000) Molecular characterization of 3-phosphoglycerate dehydrogenase deficiency–a neurometabolic disorder associated with reduced L-serine biosynthesis. Am J Hum Genet 67(6):1389–1399. https://doi.org/10.1086/316886
Pind S, Slominski E, Mauthe J et al (2002) V490M, a common mutation in 3-phosphoglycerate dehydrogenase deficiency, causes enzyme deficiency by decreasing the yield of mature enzyme. J Biol Chem 277(9):7136–7143. https://doi.org/10.1074/jbc.M111419200
Tabatabaie L, de Koning TJ, Geboers AJ, van den Berg IE, Berger R, Klomp LW (2009) Novel mutations in 3-phosphoglycerate dehydrogenase (PHGDH) are distributed throughout the protein and result in altered enzyme kinetics. Hum Mutat 30(5):749–756. https://doi.org/10.1002/humu.20934
Ni C, Cheng RH, Zhang J et al (2019) Novel and recurrent PHGDH and PSAT1 mutations in Chinese patients with Neu-Laxova syndrome. Eur J Dermatol 29(6):641–646. https://doi.org/10.1684/ejd.2019.3673
Acuna-Hidalgo R, Schanze D, Kariminejad A et al (2014) Neu-Laxova syndrome is a heterogeneous metabolic disorder caused by defects in enzymes of the L-serine biosynthesis pathway. Am J Hum Genet 95(3):285–293. https://doi.org/10.1016/j.ajhg.2014.07.012
Mattos EP, Silva AA, Magalhães JA et al (2015) Identification of a premature stop codon mutation in the PHGDH gene in severe Neu-Laxova syndrome-evidence for phenotypic variability. Am J Med Genet A 167(6):1323–1329. https://doi.org/10.1002/ajmg.a.36930
Bourque DK, Cloutier M, Kernohan KD et al (2019) Neu-Laxova syndrome presenting prenatally with increased nuchal translucency and cystic hygroma: the utility of exome sequencing in deciphering the diagnosis. Am J Med Genet A 179(5):813–816. https://doi.org/10.1002/ajmg.a.61076
Mullarky E, Mattaini KR, Vander Heiden MG, Cantley LC, Locasale JW (2011) PHGDH amplification and altered glucose metabolism in human melanoma. Pigment Cell Melanoma Res 24(6):1112–1115. https://doi.org/10.1111/j.1755-148X.2011.00919.x
Zogg CK (2014) Phosphoglycerate dehydrogenase: potential therapeutic target and putative metabolic oncogene. J Oncol 2014:524101. https://doi.org/10.1155/2014/524101
Mattaini KR, Sullivan MR, Vander Heiden MG (2016) The importance of serine metabolism in cancer. J Cell Biol 214(3):249–257. https://doi.org/10.1083/jcb.201604085
de Koning TJ, Duran M, Dorland L et al (1998) Beneficial effects of L-serine and glycine in the management of seizures in 3-phosphoglycerate dehydrogenase deficiency. Ann Neurol 44(2):261–265. https://doi.org/10.1002/ana.410440219
Pineda M, Vilaseca MA, Artuch R et al (2000) 3-phosphoglycerate dehydrogenase deficiency in a patient with West syndrome. Dev Med Child Neurol 42(9):629–633. https://doi.org/10.1017/s0012162200001171
Brassier A, Valayannopoulos V, Bahi-Buisson N et al (2016) Two new cases of serine deficiency disorders treated with L-serine. Eur J Paediatr Neurol 20(1):53–60. https://doi.org/10.1016/j.ejpn.2015.10.007
Benke PJ, Hidalgo RJ, Braffman BH et al (2017) Infantile serine biosynthesis defect due to phosphoglycerate dehydrogenase deficiency: variability in phenotype and treatment response, novel mutations, and diagnostic challenges. J Child Neurol 32(6):543–549. https://doi.org/10.1177/0883073817690094
Cavole TR, Perrone E, Lucena de Castro FSC, Alvarez Perez AB, Waitzberg AFL, Cernach MCSP (2020) Clinical, molecular, and pathological findings in a Neu-Laxova syndrome stillborn: a Brazilian case report. Am J Med Genet A. https://doi.org/10.1002/ajmg.a.61559.10.1002/ajmg.a.61559
Poli A, Vial Y, Haye D et al (2017) Phosphoglycerate dehydrogenase (PHGDH) deficiency without epilepsy mimicking primary microcephaly. Am J Med Genet A 173(7):1936–1942. https://doi.org/10.1002/ajmg.a.38217
Takeichi T, Okuno Y, Kawamoto A et al (2018) Reduction of stratum corneum ceramides in Neu-Laxova syndrome caused by phosphoglycerate dehydrogenase deficiency. J Lipid Res 59(12):2413–2420. https://doi.org/10.1194/jlr.P087536
Le Douce J, Maugard M, Veran J et al (2020) Impairment of glycolysis-derived L-serine production in astrocytes contributes to cognitive deficits in Alzheimer's disease. Cell Metab 31(3):503–517.e8. https://doi.org/10.1016/j.cmet.2020.02.004
Hart CE, Race V, Achouri Y et al (2007) Phosphoserine aminotransferase deficiency: a novel disorder of the serine biosynthesis pathway. Am J Hum Genet 80(5):931–937. https://doi.org/10.1086/517888
Ozeki Y, Pickard BS, Kano S et al (2011) A novel balanced chromosomal translocation found in subjects with schizophrenia and schizotypal personality disorder: altered L-serine level associated with disruption of PSAT1 gene expression. Neurosci Res 69(2):154–160. https://doi.org/10.1016/j.neures.2010.10.003
Jaeken J, Detheux M, Fryns JP, Collet JF, Alliet P, Van Schaftingen E (1997) Phosphoserine phosphatase deficiency in a patient with Williams syndrome. J Med Genet 34(7):594–596. https://doi.org/10.1136/jmg.34.7.594
Byers HM, Bennett RL, Malouf EA et al (2016) Novel report of phosphoserine phosphatase deficiency in an adult with myeloneuropathy and limb contractures. JIMD Rep 30:103–108. https://doi.org/10.1007/8904_2015_510
Vincent JB, Jamil T, Rafiq MA et al (2015) Phosphoserine phosphatase (PSPH) gene mutation in an intellectual disability family from Pakistan. Clin Genet 87(3):296–298. https://doi.org/10.1111/cge.12445
Ozeki Y, Sekine M, Fujii K et al (2016) Phosphoserine phosphatase activity is elevated and correlates negatively with plasma D-serine concentration in patients with schizophrenia. Psychiatry Res 237:344–350. https://doi.org/10.1016/j.psychres.2016.01.010
Heese K, Nagai Y, Sawada T (2000) Induction of rat l-phosphoserine phosphatase by amyloid-beta (1–42) is inhibited by interleukin-11. Neurosci Lett 288(1):37–40. https://doi.org/10.1016/s0304-3940(00)01197-6
Rudy CC, Hunsberger HC, Weitzner DS, Reed MN (2015) The role of the tripartite glutamatergic synapse in the pathophysiology of Alzheimer's disease. Aging Dis 6(2):131–148. https://doi.org/10.14336/AD.2014.0423
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This work was supported by a grant from Ministero Università e Ricerca Scientifica PRIN 2017 (Grant 2017H4J3AS) to LP, and from Fondo di Ateneo per la Ricerca to LP and SS.
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Murtas, G., Marcone, G.L., Sacchi, S. et al. L-serine synthesis via the phosphorylated pathway in humans. Cell. Mol. Life Sci. 77, 5131–5148 (2020). https://doi.org/10.1007/s00018-020-03574-z
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DOI: https://doi.org/10.1007/s00018-020-03574-z