Journal ArticleDOI
L-serine synthesis via the phosphorylated pathway in humans
TLDR
It is believed 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.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 diseasesread more
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The Role of D-Amino Acids in Alzheimer's Disease.
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References
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Journal ArticleDOI
Glycine potentiates the NMDA response in cultured mouse brain neurons
J. W. Johnson,P Ascher +1 more
TL;DR: G glycine may facilitate excitatory transmission in the brain through an allosteric activation of the NMDA receptor, and can be observed in outside-out patches as an increase in the frequency of opening of the channels activated by NMDA agonists.
Journal ArticleDOI
Functional genomics reveal that the serine synthesis pathway is essential in breast cancer
Richard Possemato,Kevin Marks,Yoav D. Shaul,Michael E. Pacold,Dohoon Kim,Kıvanç Birsoy,Shalini Sethumadhavan,Hin-Koon Woo,Hyun Gyung Jang,Abhishek K. Jha,Walter W. Chen,Francesca G. Barrett,Nicolas Stransky,Zhi-Yang Tsun,Glenn S. Cowley,Jordi Barretina,Jordi Barretina,Nada Y. Kalaany,Peggy P. Hsu,Kathleen Ottina,Albert M. Chan,Bingbing Yuan,Levi A. Garraway,Levi A. Garraway,David E. Root,Mari Mino-Kenudson,Elena F. Brachtel,Edward M. Driggers,David M. Sabatini +28 more
TL;DR: Results reveal that certain breast cancers are dependent upon increased serine pathway flux caused by PHGDH overexpression and demonstrate the utility of in vivo negative-selection RNAi screens for finding potential anticancer targets.
Journal ArticleDOI
d-Serine is an endogenous ligand for the glycine site of the N-methyl-d-aspartate receptor
Jean-Pierre Mothet,Angèle T. Parent,Angèle T. Parent,Herman Wolosker,Roscoe O. Brady,David J. Linden,Christopher D. Ferris,Michael A. Rogawski,Solomon H. Snyder +8 more
TL;DR: D-serine is an endogenous modulator of the glycine site of NMDA receptors and fully occupies this site at some functional synapses and greatly attenuates NMDA receptor-mediated neurotransmission as assessed by using whole-cell patch-clamp recordings or indirectly by using biochemical assays of the sequelae of NMda receptor- mediated calcium flux.
Journal ArticleDOI
Serine and glycine metabolism in cancer
Ivano Amelio,Francesca Cutruzzolà,Alexey V. Antonov,Massimiliano Agostini,Gerry Melino,Gerry Melino +5 more
TL;DR: A novel anticancer therapy is aiming to target serine and glycine biosynthesis, which are essential metabolites for cancer cells and provide precursors for macromolecules and antioxidant defence.
Journal ArticleDOI
Synaptic and Extrasynaptic NMDA Receptors Are Gated by Different Endogenous Coagonists
Thomas Papouin,Laurent Ladépêche,Laurent Ladépêche,Jérôme Ruel,Jérôme Ruel,Silvia Sacchi,Marilyne Labasque,Marwa Hanini,Laurent Groc,Laurent Groc,Loredano Pollegioni,Jean-Pierre Mothet,Stéphane H. R. Oliet,Stéphane H. R. Oliet +13 more
TL;DR: It is demonstrated that long-term potentiation and NMDA-induced neurotoxicity rely on synaptic NMDARs only, and long- term depression requires both synaptic and extrasynaptic receptors.
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