Serine

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Serine
Skeletal formula L-Serin - L-Serine.svg
Skeletal formula
Skeletal formula of L-serine
Serine at physiological pH Serine at 7.4 pH.png
Serine at physiological pH
L-serine zwitterion
Serine-from-xtal-view-1-3D-bs-17.png
Serine-from-xtal-view-1-3D-sf.png
Names
IUPAC name
Serine
Other names
2-Amino-3-hydroxypropanoic acid
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.000.250 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • L:206-130-6
KEGG
PubChem CID
UNII
  • InChI=1S/C3H7NO3/c4-2(1-5)3(6)7/h2,5H,1,4H2,(H,6,7)/t2-/m0/s1 Yes check.svgY
    Key: MTCFGRXMJLQNBG-REOHCLBHSA-N Yes check.svgY
  • D/L:Key: MTCFGRXMJLQNBG-UHFFFAOYSA-N
  • D:Key: MTCFGRXMJLQNBG-UWTATZPHSA-N
  • L:C([C@@H](C(=O)O)N)O
  • D/L Zwitterion:C([C@@H](C(=O)[O-])[NH3+])O
Properties [1]
C3H7NO3
Molar mass 105.093 g·mol−1
Appearancewhite crystals or powder
Density 1.603 g/cm3 (22 °C)
Melting point 246 °C (475 °F; 519 K) decomposes
soluble
Acidity (pKa)2.21 (carboxyl), 9.15 (amino) [2]
Supplementary data page
Serine (data page)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Serine (symbol Ser or S) [3] [4] is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH+
3 form under biological conditions), a carboxyl group (which is in the deprotonated −COO−
 form under biological conditions), and a side chain consisting of a hydroxymethyl group, classifying it as a polar amino acid. It can be synthesized in the human body under normal physiological circumstances, making it a nonessential amino acid. It is encoded by the codons UCU, UCC, UCA, UCG, AGU and AGC.

Occurrence

L-Serine (left) and D-serine (right) in zwitterionic form at neutral pH Betain-Serin.png
L-Serine (left) and D-serine (right) in zwitterionic form at neutral pH

This compound is one of the proteinogenic amino acids. Only the L-stereoisomer appears naturally in proteins. It is not essential to the human diet, since it is synthesized in the body from other metabolites, including glycine. Serine was first obtained from silk protein, a particularly rich source, in 1865 by Emil Cramer. [5] Its name is derived from the Latin for silk, sericum . Serine's structure was established in 1902. [6] [7]

Biosynthesis

The biosynthesis of serine starts with the oxidation of 3-phosphoglycerate (an intermediate from glycolysis) to 3-phosphohydroxypyruvate and NADH by phosphoglycerate dehydrogenase (EC 1.1.1.95). Reductive amination (transamination) of this ketone by phosphoserine transaminase (EC 2.6.1.52) yields 3-phosphoserine (O-phosphoserine) which is hydrolyzed to serine by phosphoserine phosphatase (EC 3.1.3.3). [8] [9]

In bacteria such as E. coli these enzymes are encoded by the genes serA (EC 1.1.1.95), serC (EC 2.6.1.52), and serB (EC 3.1.3.3). [10]

Serine biosynthesis Serine biosynthesis.svg
Serine biosynthesis

Serine hydroxymethyltransferase (SMHT) also catalyzes the biosynthesis of glycine (retro-aldol cleavage) from serine, transferring the resulting formalddehyde synthon to 5,6,7,8-tetrahydrofolate. However, that reaction is reversible, and will convert excess glycine to serine. [11] SHMT is a pyridoxal phosphate (PLP) dependent enzyme. [8]

Synthesis and reactions

Industrially, L-serine is produced from glycine and methanol catalyzed by hydroxymethyltransferase. [12]

Racemic serine can be prepared in the laboratory from methyl acrylate in several steps: [13]

Synthesis of dl-serine.svg

Hydrogenation of serine gives the diol serinol:

HOCH2CH(NH2)CO2H + 2 H2 → HOCH2CH(NH2)CH2OH + 2 H2O

Biological function

Metabolic

Cysteine synthesis from serine. Cystathionine beta synthase catalyzes the upper reaction and cystathionine gamma-lyase catalyzes the lower reaction. Cysteine biosynthesis.svg
Cysteine synthesis from serine. Cystathionine beta synthase catalyzes the upper reaction and cystathionine gamma-lyase catalyzes the lower reaction.

Serine is important in metabolism in that it participates in the biosynthesis of purines and pyrimidines. It is the precursor to several amino acids including glycine and cysteine, as well as tryptophan in bacteria. It is also the precursor to numerous other metabolites, including sphingolipids and folate, which is the principal donor of one-carbon fragments in biosynthesis.[ citation needed ]

Signaling

D-Serine, synthesized in neurons by serine racemase from L-serine (its enantiomer), serves as a neuromodulator by coactivating NMDA receptors, making them able to open if they then also bind glutamate. D-serine is a potent agonist at the glycine site (NR1) of canonical diheteromeric NMDA receptors. For the receptor to open, glutamate and either glycine or D-serine must bind to it; in addition a pore blocker must not be bound (e.g. Mg2+ or Zn2+). [14] Some research has shown that D-serine is a more potent agonist at the NMDAR glycine site than glycine itself. [15] [16] However, D-serine has been shown to work as an antagonist/inverse co-agonist of t-NMDA receptors through the glycine binding site on the GluN3 subunit. [17] [18]

Ligands

D-serine was thought to exist only in bacteria until relatively recently; it was the second D amino acid discovered to naturally exist in humans, present as a signaling molecule in the brain, soon after the discovery of D-aspartate. Had D amino acids been discovered in humans sooner, the glycine site on the NMDA receptor might instead be named the D-serine site. [19] Apart from central nervous system, D-serine plays a signaling role in peripheral tissues and organs such as cartilage, [20] kidney, [21] and corpus cavernosum. [22]

Gustatory sensation

Pure D-serine is an off-white crystalline powder with a very faint musty aroma. D-Serine is sweet with an additional minor sour taste at medium and high concentrations. [23]

Clinical significance

Serine deficiency disorders are rare defects in the biosynthesis of the amino acid L-serine. At present three disorders have been reported:

These enzyme defects lead to severe neurological symptoms such as congenital microcephaly and severe psychomotor retardation and in addition, in patients with 3-phosphoglycerate dehydrogenase deficiency to intractable seizures. These symptoms respond to a variable degree to treatment with L-serine, sometimes combined with glycine. [24] [25] Response to treatment is variable and the long-term and functional outcome is unknown. To provide a basis for improving the understanding of the epidemiology, genotype/phenotype correlation and outcome of these diseases their impact on the quality of life of patients, as well as for evaluating diagnostic and therapeutic strategies a patient registry was established by the noncommercial International Working Group on Neurotransmitter Related Disorders (iNTD). [26]

Besides disruption of serine biosynthesis, its transport may also become disrupted. One example is spastic tetraplegia, thin corpus callosum, and progressive microcephaly, a disease caused by mutations that affect the function of the neutral amino acid transporter A.

Research for therapeutic use

The classification of L-serine as a non-essential amino acid has come to be considered as conditional, since vertebrates such as humans cannot always synthesize optimal quantities over entire lifespans. [27] Safety of L-serine has been demonstrated in an FDA-approved human phase I clinical trial with Amyotrophic Lateral Sclerosis, ALS, patients (ClinicalTrials.gov identifier: NCT01835782), [28] [29] but treatment of ALS symptoms has yet to be shown. A 2011 meta-analysis found adjunctive sarcosine to have a medium effect size for negative and total symptoms of schizophrenia. [30] There also is evidence that L‐serine could acquire a therapeutic role in diabetes. [31]

D-Serine is being studied in rodents as a potential treatment for schizophrenia. [32] D-Serine also has been described as a potential biomarker for early Alzheimer's disease (AD) diagnosis, due to a relatively high concentration of it in the cerebrospinal fluid of probable AD patients. [33] D-serine, which is made in the brain, has been shown to work as an antagonist/inverse co-agonist of t-NMDA receptors mitigating neuron loss in an animal model of temporal lobe epilepsy. [34]

D-Serine has been theorized as a potential treatment for sensorineural hearing disorders such as hearing loss and tinnitus. [35]

See also

Related Research Articles

<i>N</i>-Methyl-<small>D</small>-aspartic acid Amino acid derivative

N-methyl-D-aspartic acid or N-methyl-D-aspartate (NMDA) is an amino acid derivative that acts as a specific agonist at the NMDA receptor mimicking the action of glutamate, the neurotransmitter which normally acts at that receptor. Unlike glutamate, NMDA only binds to and regulates the NMDA receptor and has no effect on other glutamate receptors. NMDA receptors are particularly important when they become overactive during, for example, withdrawal from alcohol as this causes symptoms such as agitation and, sometimes, epileptiform seizures.

<span class="mw-page-title-main">NMDA receptor</span> Glutamate receptor and ion channel protein found in nerve cells

The N-methyl-D-aspartatereceptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and predominantly Ca2+ ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other two being AMPA and kainate receptors. Depending on its subunit composition, its ligands are glutamate and glycine (or D-serine). However, the binding of the ligands is typically not sufficient to open the channel as it may be blocked by Mg2+ ions which are only removed when the neuron is sufficiently depolarized. Thus, the channel acts as a "coincidence detector" and only once both of these conditions are met, the channel opens and it allows positively charged ions (cations) to flow through the cell membrane. The NMDA receptor is thought to be very important for controlling synaptic plasticity and mediating learning and memory functions.

β-Alanine Chemical compound

β-Alanine is a naturally occurring beta amino acid, which is an amino acid in which the amino group is attached to the β-carbon instead of the more usual α-carbon for alanine (α-alanine). The IUPAC name for β-alanine is 3-aminopropanoic acid. Unlike its counterpart α-alanine, β-alanine has no stereocenter.

Biosynthesis, i.e., chemical synthesis occurring in biological contexts, is a term most often referring to multi-step, enzyme-catalyzed processes where chemical substances absorbed as nutrients serve as enzyme substrates, with conversion by the living organism either into simpler or more complex products. Examples of biosynthetic pathways include those for the production of amino acids, lipid membrane components, and nucleotides, but also for the production of all classes of biological macromolecules, and of acetyl-coenzyme A, adenosine triphosphate, nicotinamide adenine dinucleotide and other key intermediate and transactional molecules needed for metabolism. Thus, in biosynthesis, any of an array of compounds, from simple to complex, are converted into other compounds, and so it includes both the catabolism and anabolism of complex molecules. Biosynthetic processes are often represented via charts of metabolic pathways. A particular biosynthetic pathway may be located within a single cellular organelle, while others involve enzymes that are located across an array of cellular organelles and structures.

<span class="mw-page-title-main">Ligand-gated ion channel</span> Type of ion channel transmembrane protein

Ligand-gated ion channels (LICs, LGIC), also commonly referred to as ionotropic receptors, are a group of transmembrane ion-channel proteins which open to allow ions such as Na+, K+, Ca2+, and/or Cl− to pass through the membrane in response to the binding of a chemical messenger (i.e. a ligand), such as a neurotransmitter.

<span class="mw-page-title-main">Metabotropic glutamate receptor</span> Type of glutamate receptor

The metabotropic glutamate receptors, or mGluRs, are a type of glutamate receptor that are active through an indirect metabotropic process. They are members of the group C family of G-protein-coupled receptors, or GPCRs. Like all glutamate receptors, mGluRs bind with glutamate, an amino acid that functions as an excitatory neurotransmitter.

<span class="mw-page-title-main">Glutamate receptor</span> Cell-surface proteins that bind glutamate and trigger changes which influence the behavior of cells

Glutamate receptors are synaptic and non synaptic receptors located primarily on the membranes of neuronal and glial cells. Glutamate is abundant in the human body, but particularly in the nervous system and especially prominent in the human brain where it is the body's most prominent neurotransmitter, the brain's main excitatory neurotransmitter, and also the precursor for GABA, the brain's main inhibitory neurotransmitter. Glutamate receptors are responsible for the glutamate-mediated postsynaptic excitation of neural cells, and are important for neural communication, memory formation, learning, and regulation.

<span class="mw-page-title-main">D-amino acid oxidase</span> Enzyme

D-amino acid oxidase is an enzyme with the function on a molecular level to oxidize D-amino acids to the corresponding α-keto acids, producing ammonia and hydrogen peroxide. This results in a number of physiological effects in various systems, most notably the brain. The enzyme is most active toward neutral D-amino acids, and not active toward acidic D-amino acids. One of its most important targets in mammals is D-Serine in the central nervous system. By targeting this and other D-amino acids in vertebrates, DAAO is important in detoxification. The role in microorganisms is slightly different, breaking down D-amino acids to generate energy.

<span class="mw-page-title-main">Kynurenic acid</span> Chemical compound

Kynurenic acid is a product of the normal metabolism of amino acid L-tryptophan. It has been shown that kynurenic acid possesses neuroactive activity. It acts as an antiexcitotoxic and anticonvulsant, most likely through acting as an antagonist at excitatory amino acid receptors. Because of this activity, it may influence important neurophysiological and neuropathological processes. As a result, kynurenic acid has been considered for use in therapy in certain neurobiological disorders. Conversely, increased levels of kynurenic acid have also been linked to certain pathological conditions.

β-Methylamino-<small>L</small>-alanine Chemical compound

β-Methylamino-L-alanine, or BMAA, is a non-proteinogenic amino acid produced by cyanobacteria. BMAA is a neurotoxin. Its potential role in various neurodegenerative disorders is the subject of scientific research.

<span class="mw-page-title-main">Amino acid synthesis</span> The set of biochemical processes by which amino acids are produced

Amino acid biosynthesis is the set of biochemical processes by which the amino acids are produced. The substrates for these processes are various compounds in the organism's diet or growth media. Not all organisms are able to synthesize all amino acids. For example, humans can synthesize 11 of the 20 standard amino acids. These 11 are called the non-essential amino acids.

<span class="mw-page-title-main">NMDA receptor antagonist</span> Class of anesthetics

NMDA receptor antagonists are a class of drugs that work to antagonize, or inhibit the action of, the N-Methyl-D-aspartate receptor (NMDAR). They are commonly used as anesthetics for humans and animals; the state of anesthesia they induce is referred to as dissociative anesthesia.

<span class="mw-page-title-main">Quisqualic acid</span> Chemical compound

Quisqualic acid is an agonist of the AMPA, kainate, and group I metabotropic glutamate receptors. It is one of the most potent AMPA receptor agonists known. It causes excitotoxicity and is used in neuroscience to selectively destroy neurons in the brain or spinal cord. Quisqualic acid occurs naturally in the seeds of Quisqualis species.

<span class="mw-page-title-main">Dimethylglycine</span> Chemical compound

Dimethylglycine (DMG) is a derivative of the amino acid glycine with the structural formula (CH3)2NCH2COOH. It can be found in beans and liver, and has a sweet taste. It can be formed from trimethylglycine upon the loss of one of its methyl groups. It is also a byproduct of the metabolism of choline.

<span class="mw-page-title-main">Gavestinel</span> Chemical compound

Gavestinel (GV-150,526) was an investigational drug developed by GlaxoSmithKline for acute intracerebral hemorrhage, which in 2001 failed to show an effect in what was at the time, the largest clinical trial in stroke that had been conducted.

<span class="mw-page-title-main">HA-966</span> Chemical compound

HA-966 or (±)-3-amino-1-hydroxy-pyrrolidin-2-one is a molecule used in scientific research as a glycine receptor and NMDA receptor antagonist / low efficacy partial agonist. It has neuroprotective and anticonvulsant, anxiolytic, antinociceptive and sedative / hypnotic effects in animal models. Pilot human clinical trials in the early 1960s showed that HA-966 appeared to benefit patients with tremors of extrapyramidal origin.

<span class="mw-page-title-main">Bitopertin</span> Chemical compound

Bitopertin is a glycine reuptake inhibitor which was under development by Roche as an adjunct to antipsychotics for the treatment of persistent negative symptoms or suboptimally controlled positive symptoms associated with schizophrenia. Research into this indication has been largely halted as a result of disappointing trial results. As of 2024, it is under development for the management of erythropoietic protoporphyria.

<span class="mw-page-title-main">Rapastinel</span> Chemical compound

Rapastinel is a novel antidepressant that was under development by Allergan as an adjunctive therapy for the treatment of treatment-resistant depression. It is a centrally active, intravenously administered amidated tetrapeptide that acts as a novel and selective modulator of the NMDA receptor. The drug is a rapid-acting and long-lasting antidepressant as well as robust cognitive enhancer by virtue of its ability to enhance NMDA receptor-mediated signal transduction and synaptic plasticity.

The International Working Group on Neurotransmitter Related Disorders is an international collaboration of researchers studying neurotransmitter disorders. It has created a patient registry for longitudinal studies.

<span class="mw-page-title-main">D-glycerate dehydrogenase deficiency</span> Rare autosomal recessive human diseases

D-glycerate dehydrogenase deficiency is a rare autosomal metabolic disease where the young patient is unable to produce an enzyme necessary to convert 3-phosphoglycerate into 3-phosphohydroxypyruvate, which is the only way for humans to synthesize serine. This disorder is called Neu–Laxova syndrome in neonates.

References

  1. ↑ Weast RC, ed. (1981). CRC Handbook of Chemistry and Physics (62nd ed.). Boca Raton, FL: CRC Press. p. C-512. ISBN   0-8493-0462-8.
  2. ↑ Dawson, R.M.C., et al., Data for Biochemical Research, Oxford, Clarendon Press, 1959.
  3. ↑ "Nomenclature and Symbolism for Amino Acids and Peptides". IUPAC-IUB Joint Commission on Biochemical Nomenclature. 1983. Archived from the original on 9 October 2008. Retrieved 5 March 2018.
  4. ↑ "Nomenclature and symbolism for amino acids and peptides (IUPAC-IUB Recommendations 1983)", Pure Appl. Chem., 56 (5): 595–624, 1984, doi:10.1351/pac198456050595 .
  5. ↑ Cramer E (1865). "Ueber die Bestandtheile der Seide" [On the constituents of silk]. Journal für praktische Chemie (in German). 96: 76–98. Serine is named on p. 93: "Ich werde den in Frage stehenden Körper unter dem Namen Serin beschreiben." (I will describe the body [i.e., substance] in question by the name "serine".)
  6. ↑ Fischer E, Leuchs H (1902). "Synthese des Serins, der l-Glucosaminsäure und anderer Oxyaminosäuren" [Synthesis of serine, of l-glucosaminic acid, and other oxyamino acids]. Berichte der Deutschen Chemischen Gesellschaft (in German). 35 (3): 3787–3805. doi:10.1002/cber.190203503213.
  7. ↑ "Serine". The Columbia Encyclopedia 6th ed. encyclopedia.com. Retrieved 22 October 2012.
  8. 1 2 Stryer L (1988). Biochemistry (3rd ed.). New York: W.H. Freeman. p.  580. ISBN   978-0-7167-1843-7.
  9. ↑ KEGG EC 3.1.3.3 etc.
  10. ↑ Uniprot: serB
  11. ↑ Lehninger AL, Nelson DL, Cox MM (2000). Principles of Biochemistry (3rd ed.). New York: W. H. Freeman. ISBN   1-57259-153-6.
  12. ↑ Karlheinz Drauz, Ian Grayson, Axel Kleemann, Hans-Peter Krimmer, Wolfgang Leuchtenberger, Christoph Weckbecker (2006). Ullmann's Encyclopedia of Industrial Chemistry . Weinheim: Wiley-VCH. doi:10.1002/14356007.a02_057.pub2. ISBN   978-3527306732.{{cite encyclopedia}}: CS1 maint: multiple names: authors list (link)
  13. ↑ Carter HE, West HD (1940). "dl-Serine". Org. Synth. 20: 81. doi:10.15227/orgsyn.020.0081.
  14. ↑ Liu Y, Hill RH, Arhem P, von Euler G (2001). "NMDA and glycine regulate the affinity of the Mg2+-block site in NR1-1a/NR2A NMDA receptor channels expressed in Xenopus oocytes". Life Sciences. 68 (16): 1817–1826. doi:10.1016/S0024-3205(01)00975-4. PMID   11292060.
  15. ↑ MacKay MA, Kravtsenyuk M, Thomas R, Mitchell ND, Dursun SM, Baker GB (6 February 2019). "D-Serine: Potential Therapeutic Agent and/or Biomarker in Schizophrenia and Depression?". Frontiers in Psychiatry. 10: 25. doi: 10.3389/fpsyt.2019.00025 . ISSN   1664-0640. PMC   6372501 . PMID   30787885. D-Serine is more potent than glycine as a coagonist at the NMDA receptor, has a regional distribution in the brain that is similar to that of NMDA receptors and appears to be more closely associated with synaptic NMDA receptors than glycine (which is more closely associated with non-synaptic NMDA receptors).
  16. ↑ Wolosker H, Balu DT (9 June 2020). "D-Serine as the gatekeeper of NMDA receptor activity: implications for the pharmacologic management of anxiety disorders". Translational Psychiatry. 10 (1): 184. doi:10.1038/s41398-020-00870-x. ISSN   2158-3188. PMC   7283225 . PMID   32518273. D-Serine is functionally a more potent activator of synaptic NMDARs than glycine, and mounting evidence suggests that it serves as the major NMDAR co-agonist in limbic brain regions implicated in neuropsychiatric disorders.
  17. ↑ Pilli J, Kumar SS (2012-10-11). "Triheteromeric N-methyl-D-aspartate receptors differentiate synaptic inputs onto pyramidal neurons in somatosensory cortex: involvement of the GluN3A subunit". Neuroscience. 222: 75–88. doi:10.1016/j.neuroscience.2012.07.020. ISSN   1873-7544. PMID   22814002. S2CID   23158971.
  18. ↑ Beesley S, Kumar SS (2023-11-01). "The t-N-methyl-d-aspartate receptor: Making the case for d-Serine to be considered its inverse co-agonist". Neuropharmacology. 238: 109654. doi: 10.1016/j.neuropharm.2023.109654 . ISSN   1873-7064. PMID   37437688.
  19. ↑ Mothet JP, Parent AT, Wolosker H, Brady RO, Linden DJ, Ferris CD, Rogawski MA, Snyder SH (Apr 2000). "D-Serine is an endogenous ligand for the glycine site of the N-methyl-D-aspartate receptor". Proceedings of the National Academy of Sciences of the United States of America. 97 (9): 4926–4931. Bibcode:2000PNAS...97.4926M. doi: 10.1073/pnas.97.9.4926 . PMC   18334 . PMID   10781100.
  20. ↑ Takarada T, Hinoi E, Takahata Y, Yoneda Y (May 2008). "Serine racemase suppresses chondrogenic differentiation in cartilage in a Sox9-dependent manner". Journal of Cellular Physiology. 215 (2): 320–328. doi:10.1002/jcp.21310. PMID   17929246. S2CID   45669104.
  21. ↑ Ma MC, Huang HS, Chen YS, Lee SH (Nov 2008). "Mechanosensitive N-methyl-D-aspartate receptors contribute to sensory activation in the rat renal pelvis". Hypertension. 52 (5): 938–944. doi: 10.1161/HYPERTENSIONAHA.108.114116 . PMID   18809793.
  22. ↑ Ghasemi M, Rezania F, Lewin J, Moore KP, Mani AR (Jun 2010). "D-Serine modulates neurogenic relaxation in rat corpus cavernosum". Biochemical Pharmacology. 79 (12): 1791–1796. doi:10.1016/j.bcp.2010.02.007. PMID   20170643.
  23. ↑ Kawai M, Sekine-Hayakawa Y, Okiyama A, Ninomiya Y (Dec 2012). "Gustatory sensation of L- and D-amino acids in humans". Amino Acids. 43 (6): 2349–2358. doi:10.1007/s00726-012-1315-x. PMID   22588481. S2CID   17671611.
  24. ↑ de Koning TJ (April 2006). "Treatment with amino acids in serine deficiency disorders". Journal of Inherited Metabolic Disease . 29 (2): 347–351. doi:10.1007/s10545-006-0269-0. PMID   16763900. S2CID   25013468.
  25. ↑ Tabatabaie L, Klomp LW, Berger R, de Koning TJ (March 2010). "L-Serine synthesis in the central nervous system: a review on serine deficiency disorders". Mol Genet Metab . 99 (3): 256–262. doi:10.1016/j.ymgme.2009.10.012. PMID   19963421.
  26. ↑ "Patient registry".
  27. ↑ Metcalf JS, Dunlop RA, Powell JT, Banack SA, Cox PA (2017). "L-Serine: a Naturally-Occurring Amino Acid with Therapeutic Potential". Neurotoxicity Research. 33 (1): 213–221. doi:10.1007/s12640-017-9814-x. ISSN   1029-8428. PMID   28929385. S2CID   20271849.
  28. ↑ Dunlop RA, Cox PA, Banack SA, Rodgers KJ (2013). "The non-protein amino acid BMAA is misincorporated into human proteins in place of L-serine causing protein misfolding and aggregation". PLOS ONE. 8 (9): e75376. Bibcode:2013PLoSO...875376D. doi: 10.1371/journal.pone.0075376 . PMC   3783393 . PMID   24086518.
  29. ↑ Levine TD, Miller RG, Bradley WG, Moore DH, Saperstein DS, Flynn LE, Katz JS, Forshew DA, Metcalf JS, Banack SA, Cox PA (2017-01-02). "Phase I clinical trial of safety of L-serine for ALS patients". Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. 18 (1–2): 107–111. doi: 10.1080/21678421.2016.1221971 . ISSN   2167-8421. PMID   27589995. S2CID   4584977.
  30. ↑ Singh SP, Singh V (Oct 2011). "Meta-analysis of the efficacy of adjunctive NMDA receptor modulators in chronic schizophrenia". CNS Drugs. 25 (10): 859–885. doi:10.2165/11586650-000000000-00000. PMID   21936588. S2CID   207299820.
  31. ↑ Holm LJ, Buschard K (2019). "L-serine: a neglected amino acid with a potential therapeutic role in diabetes". APMIS. 127 (10): 655–659. doi: 10.1111/apm.12987 . ISSN   0903-4641. PMC   6851881 . PMID   31344283.
  32. ↑ Balu DT, Li Y, Puhl MD, Benneyworth MA, Basu AC, Takagi S, Bolshakov VY, Coyle JT (Jun 2013). "Multiple risk pathways for schizophrenia converge in serine racemase knockout mice, a mouse model of NMDA receptor hypofunction". Proceedings of the National Academy of Sciences of the United States of America. 110 (26): E2400–E2409. Bibcode:2013PNAS..110E2400B. doi: 10.1073/pnas.1304308110 . PMC   3696825 . PMID   23729812.
  33. ↑ Madeira C, Lourenco MV, Vargas-Lopes C, Suemoto CK, Brandão CO, Reis T, Leite RE, Laks J, Jacob-Filho W, Pasqualucci CA, Grinberg LT, Ferreira ST, Panizzutti R (May 5, 2015). "D-Serine levels in Alzheimer's disease: implications for novel biomarker development". Translational Psychiatry. 5 (5): e561. doi:10.1038/tp.2015.52. PMC   4471283 . PMID   25942042.
  34. ↑ Beesley S, Sullenberger T, Crotty K, Ailani R, D'Orio C, Evans K, Ogunkunle EO, Roper MG, Kumar SS (2020-10-02). "D-serine mitigates cell loss associated with temporal lobe epilepsy". Nature Communications. 11 (1): 4966. Bibcode:2020NatCo..11.4966B. doi:10.1038/s41467-020-18757-2. ISSN   2041-1723. PMC   7532172 . PMID   33009404.
  35. ↑ Wang J, Serratrice N, Lee CJ, François F, Sweedler JV, Puel JL, Mothet JP, Ruel J (17 December 2021). "Physiopathological Relevance of D-Serine in the Mammalian Cochlea". Frontiers in Cellular Neuroscience. 15. Frontiers Media SA: 733004. doi: 10.3389/fncel.2021.733004 . ISSN   1662-5102. PMC   8718999 . PMID   34975405.