Serine

Source: Wikipedia, the free encyclopedia.
For the French wine grape, see
Sérine. For the toxic substance, see Sarin
.
Serine
Skeletal formula
Skeletal formula
Skeletal formula of L-serine
Serine at physiological pH
Serine at physiological pH
L-serine zwitterion
Names
IUPAC name
Serine
Other names
2-Amino-3-hydroxypropanoic acid
Identifiers
3D model (
JSmol
)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard
 100.000.250 Edit this at Wikidata
EC Number
  • L: 206-130-6
IUPHAR/BPS
KEGG
UNII
  • InChI=1S/C3H7NO3/c4-2(1-5)3(6)7/h2,5H,1,4H2,(H,6,7)/t2-/m0/s1 checkY
    Key: MTCFGRXMJLQNBG-REOHCLBHSA-N checkY
  • 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[2]
C3H7NO3
Molar mass 105.093 g·mol−1
Appearance white 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)[1]
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)

codons
UCU, UCC, UCA, UCG, AGU and AGC.

Occurrence

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

This compound is one of the

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

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

Glycine biosynthesis:

5,10-methylenetetrahydrofolate (mTHF) (hydrolysis).[11] SHMT is a pyridoxal phosphate (PLP) dependent enzyme. Glycine can also be formed from CO2, NH+
4, and mTHF in a reaction catalyzed by glycine synthase.[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]

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.

Serine is important in

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

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] In fact, D-serine is a more potent agonist at the glycine site on the NMDAR 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

References

  1. ^ Dawson, R.M.C., et al., Data for Biochemical Research, Oxford, Clarendon Press, 1959.
  2. ISBN 0-8493-0462-8
    .
  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. 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. doi:10.1002/cber.190203503213
    .
  7. ^ "Serine". The Columbia Encyclopedia 6th ed. encyclopedia.com. Retrieved 22 October 2012.
  8. ^
    ISBN 978-0-7167-1843-7
    .
  9. ^ KEGG EC 3.1.3.3 etc.
  10. ^ Uniprot: serB
  11. ISBN 1-57259-153-6
    .
  12. ISBN 978-3527306732.{{cite encyclopedia}}: CS1 maint: multiple names: authors list (link
    )
  13. doi:10.15227/orgsyn.020.0081
    .
  14. PMID 11292060
    .
  15. 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. 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. S2CID 23158971
    .
  18. PMID 37437688
    .
  19. PMID 10781100
    .
  20. S2CID 45669104
    .
  21. PMID 18809793
    .
  22. PMID 20170643
    .
  23. S2CID 17671611
    .
  24. S2CID 25013468
    .
  25. PMID 19963421
    .
  26. ^ "Patient registry".
  27. S2CID 20271849
    .
  28. PMID 24086518
    .
  29. S2CID 4584977
    .
  30. S2CID 207299820
    .
  31. PMID 31344283
    .
  32. PMID 23729812
    .
  33. PMID 25942042
    .
  34. PMID 33009404
    .
  35. PMID 34975405
    .

External links
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