Serine/ˈsɪəriːn/(symbolSer orS)[3][4] is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in theprotonated −NH+ 3 form under biological conditions), acarboxyl group (which is in thedeprotonated −COO− form under biological conditions), and a side chain consisting of ahydroxymethyl group, classifying it as apolar amino acid. It can be synthesized in the human body under normal physiological circumstances, making it a nonessential amino acid. It is encoded by thecodons UCU, UCC, UCA, UCG, AGU and AGC.
L-Serine (left) andD-serine (right) in zwitterionic form at neutral pH
This compound is one of theproteinogenic amino acids. Only theL-stereoisomer appears naturally in proteins. It isnot essential to the human diet, since it is synthesized in the body from othermetabolites, includingglycine. Serine was first obtained fromsilk protein, a particularly rich source, in 1865 by Emil Cramer.[5] Its name is derived from theLatin for silk,sericum. Serine's structure was established in 1902.[6][7]
D-Serine, synthesized in neurons byserine racemase fromL-serine (itsenantiomer), serves as a neuromodulator by coactivatingNMDA receptors, making them able to open if they then also bindglutamate.D-serine is a potentagonist at theglycine site (NR1) of canonical diheteromericNMDA receptors. For the receptor to open, glutamate and either glycine orD-serine must bind to it; in addition a pore blocker must not be bound (e.g. Mg2+ or Zn2+).[14] Some research has shown thatD-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 oft-NMDA receptors through the glycine binding site on the GluN3 subunit.[17][18]
D-serine was thought to exist only in bacteria until relatively recently; it was the secondD amino acid discovered to naturally exist in humans, present as a signaling molecule in the brain, soon after the discovery ofD-aspartate. HadD amino acids been discovered in humans sooner, the glycine site on the NMDA receptor might instead be named theD-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]
PureD-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]
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 withL-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 noncommercialInternational Working Group on Neurotransmitter Related Disorders (iNTD).[26]
The classification ofL-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 ofL-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 adjunctivesarcosine to have a medium effect size for negative and total symptoms of schizophrenia.[30] There also is evidence thatL‐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 earlyAlzheimer's disease (AD) diagnosis, due to a relatively high concentration of it in thecerebrospinal 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 oft-NMDA receptors mitigating neuron loss in an animal model oftemporal lobe epilepsy.[34]
D-Serine has been theorized as a potential treatment for sensorineural hearing disorders such ashearing loss andtinnitus.[35]
^"Nomenclature and symbolism for amino acids and peptides (IUPAC-IUB Recommendations 1983)".Pure and Applied Chemistry.56 (5):595–624. 1984.doi:10.1351/pac198456050595..
^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".)
^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.PMID11292060.
^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.PMID17929246.S2CID45669104.
^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.PMID20170643.
