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Phosphoserine
Phosphoserine
Phosphoserine
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l-Phosphoserine
Skeletal formula
Skeletal formula
Ball-and-stick model
Ball-and-stick model
Names
IUPAC name
(S)-2-Amino-3-(phosphonooxy)propionic acid
Other names
L-O-Phosphoserine
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.006.352 Edit this at Wikidata
EC Number
  • 206-986-0
KEGG
MeSH Phosphoserine
UNII
  • InChI=1S/C3H8NO6P/c4-2(3(5)6)1-10-11(7,8)9/h2H,1,4H2,(H,5,6)(H2,7,8,9)/t2-/m0/s1 checkY
    Key: BZQFBWGGLXLEPQ-REOHCLBHSA-N checkY
  • InChI=1/C3H8NO6P/c4-2(3(5)6)1-10-11(7,8)9/h2H,1,4H2,(H,5,6)(H2,7,8,9)/t2-/m0/s1
  • O=P(O)(O)OC[C@@H](C(=O)O)N
Properties
C3H8NO6P
Molar mass 185.073 g/mol
Melting point 228 °C (442 °F; 501 K)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
checkY verify (what is checkY☒N ?)

Phosphoserine (abbreviated as SEP or J) is an ester of serine and phosphoric acid. Phosphoserine is a component of many proteins as the result of posttranslational modifications.[1] The phosphorylation of the alcohol functional group in serine to produce phosphoserine is catalyzed by various types of kinases.[2][3] Through the use of technologies that utilize an expanded genetic code, phosphoserine can also be incorporated into proteins during translation.[4][5][6]

It is a normal metabolite found in human biofluids.[7]

Phosphoserine has three potential coordination sites (carboxyl, amine and phosphate group) Determination of the mode of coordination between phosphorylated ligands and metal ions occurring in an organism is a first step to explain the function of the phosphoserine in bioinorganic processes.[8][9]

References

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Phosphoserine

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from Grokipedia
Phosphoserine is a phosphorylated of the L-serine, in which the hydroxyl group on the is esterified with a group, resulting in the C₃H₈NO₆P and the IUPAC name (2S)-2-amino-3-(phosphonooxy)propanoic acid. This non-proteinogenic serves dual critical roles in : as a key metabolic intermediate in the de novo of L-serine via the phosphorylated pathway, where it is produced from phosphohydroxypyruvate by phosphoserine aminotransferase and then hydrolyzed to L-serine by phosphoserine ; and as the most abundant (PTM) in eukaryotic proteins, installed on serine residues by protein kinases to regulate diverse cellular processes including , enzymatic activity, and protein-protein interactions. In the context of L-serine biosynthesis, phosphoserine occupies a pivotal position in the cytosolic phosphorylated pathway, which converts the glycolytic intermediate 3-phosphoglycerate to L-serine through three enzymatic steps, with deficiencies in this pathway linked to severe neurological disorders such as serine deficiency syndromes characterized by seizures and developmental delays. The enzyme phosphoserine phosphatase catalyzes the final dephosphorylation step, ensuring efficient production of L-serine, which is essential for the synthesis of nucleotides, phospholipids, and other amino acids like glycine and cysteine. As a PTM, phosphoserine enables dynamic control of protein function, with approximately 86% of events occurring on serine residues in cells, influencing pathways from progression to . Kinases such as cyclin-dependent kinases add the group in response to cellular signals, while phosphatases remove it, creating reversible switches that are dysregulated in diseases like cancer and neurodegeneration. Advances in genetic encoding, including site-specific incorporation of phosphoserine into recombinant proteins in mammalian cells as of 2024, facilitate structural and functional studies that reveal its role in activating enzymes like the E3 ligase Parkin.

Structure and Nomenclature

Molecular Structure

Phosphoserine has the molecular formula \ceC3H8NO6P\ce{C3H8NO6P} and a molecular weight of 185.07 g/mol. It is the phosphorylated derivative of the amino acid serine, in which a phosphate group is esterified to the hydroxyl group attached to the beta-carbon of serine's side chain. At physiological pH, phosphoserine predominantly exists in its zwitterionic form, featuring a protonated alpha-amino group (\ceNH3+\ce{NH3^{+}}), a deprotonated carboxylate group (\ceCOO−\ce{COO^{-}}), and a dianionic phosphate group (\ce−OPO32−\ce{-OPO3^{2-}}) that is largely deprotonated. The molecule contains a single chiral center at the alpha-carbon. The naturally occurring form is the L-enantiomer, which corresponds to the (2S) , identical to that of L-serine. This stereochemistry can be textually represented by the IUPAC name (2S)-2-amino-3-(phosphonooxy)propanoic acid, highlighting the spatial arrangement where, in the standard , the amino group is on the left at the alpha-carbon. In comparison to serine (\ceC3H7NO3\ce{C3H7NO3}, molecular weight 105.09 g/mol), phosphoserine differs by the addition of the \ce−PO3H2\ce{-PO3H2} group replacing the hydrogen of the side-chain hydroxyl, thereby introducing the ester linkage while preserving the core backbone.

Naming Conventions

The systematic name for phosphoserine, as defined by the International Union of Pure and Applied Chemistry (IUPAC), is (2S)-2-amino-3-(phosphonooxy)propanoic acid, reflecting its configuration as the L-enantiomer with the group esterified to the side-chain hydroxyl. This emphasizes the propanoic acid backbone, the amino group at the alpha carbon, and the phosphonooxy substituent at the beta position. Commonly, phosphoserine is referred to as O-phosphoserine to specify the oxygen-linked phosphate on the serine residue, or alternatively as phosphono-L-serine, highlighting the phosphonic acid-like functionality. The naming conventions originated in the mid-20th century, following its isolation from protein hydrolysates in the 1950s, which built upon earlier detections in specific phosphoproteins like phosvitin from the 1930s and aligned with the emerging understanding of protein phosphorylation. These terms distinguish it from serine itself and underscore its role as a modified amino acid. In scientific literature, particularly in biochemistry and , phosphoserine is abbreviated as pSer (lowercase 'p' denoting ) or Ser(P), where the parenthesis indicates the phosphate attachment to the serine . These abbreviations facilitate concise representation in protein sequences and databases. In workflows, such as analysis, phosphoserine is denoted as an extension of the one-letter code for serine ('S'), often with a shift of +79.966 Da or specific to identify the modification site. The standard and biologically relevant form of phosphoserine is O-phosphoserine, with the phosphate esterified to the hydroxyl oxygen of the beta-carbon ; this contrasts with rare or hypothetical variants like N-phosphoserine (on the alpha-amino ) or C-phosphoserine (on the carboxyl group), which are unstable under physiological conditions and not observed in natural . The O-linked isomer predominates in eukaryotic and prokaryotic systems due to the specificity of kinases and phosphatases that target the side-chain alcohol.

Physical and Chemical Properties

Physical Characteristics

Phosphoserine is typically observed as a white to off-white crystalline solid. Due to the presence of its ionic , carboxyl, and amino groups, phosphoserine exhibits high in , approximately 71 g/L at 20°C, while displaying low in organic solvents such as and acetone. The compound lacks a distinct melting point and decomposes in the temperature range of 170–190°C. Its ionization states in are determined by pKa values of approximately 2.1 for the α-carboxylic acid group, 5.6 for the secondary dissociation of the group, and 9.7 for the α-ammonium group. For the naturally occurring L-enantiomer, the specific optical rotation is [α]_D^{20} = +5° (c = 2, H₂O), reflecting its chiral center at the α-carbon. These physical characteristics arise directly from the molecule's polar functional groups, which enhance hydrophilicity and contribute to its zwitterionic nature in neutral pH environments.

Reactivity and Stability

Phosphoserine, as a phosphate monoester, exhibits reactivity primarily through its phosphate group, which is susceptible to hydrolysis under acidic or basic conditions. The general hydrolysis reaction involves nucleophilic attack by water on the phosphorus atom, yielding serine and inorganic phosphate: R-O-PO32−+H2O→R-OH+HPO42−\text{R-O-PO}_3^{2-} + \text{H}_2\text{O} \rightarrow \text{R-OH} + \text{HPO}_4^{2-} This process is catalyzed by acid or base, with the dianionic form predominant at neutral pH showing exceptional stability, estimated at a half-life of approximately 101210^{12} years at 25°C. Hydrolysis rates accelerate significantly at pH extremes; for instance, in strong acid (pH < 2), protonation of the phosphate facilitates P-O bond cleavage, while in alkaline conditions (pH > 10), the monoanionic form undergoes faster breakdown via associative mechanisms. The moiety also enables ionic interactions, forming salts with monovalent cations such as sodium, as seen in commercially available sodium O-phospho-L-serine. Additionally, the oxygen atoms of the group can coordinate with divalent metals like Ca²⁺ and Mg²⁺, forming complexes that influence solubility and reactivity; for example, calcium phosphoserine exhibits a defined with the metal bridged via phosphate oxygens. Stability of phosphoserine is high at physiological (around 7), where non-enzymatic is negligible, allowing persistence in biological contexts. , however, it remains sensitive to enzymatic by phosphatases, which rapidly remove the phosphate under cellular conditions. Compared to other phosphoamino acids, phosphoserine is more chemically stable than the labile phosphohistidine, which undergoes facile due to its P-N bond.

Biosynthesis and Metabolism

Enzymatic Formation

Phosphoserine is primarily formed enzymatically through the phosphorylation of serine residues within proteins, a process mediated by serine/threonine-specific protein kinases classified under EC 2.7.11.-. These kinases transfer the γ-phosphate group from ATP to the hydroxyl side chain of serine, yielding phosphoserine and ADP in an ATP-dependent reaction that requires Mg²⁺ as a divalent metal cofactor to bind and position ATP in the active site, stabilizing the transition state for phosphoryl transfer. The catalytic mechanism involves a ternary complex where ATP and the protein substrate bind sequentially or in random order depending on the kinase, with the rate-limiting step often being either phosphoryl transfer or product release; for instance, in protein kinase A (PKA, EC 2.7.11.11), MgADP release is rate-determining. Mitogen-activated protein kinases (MAPKs), such as p38 MAPK, exemplify this class by phosphorylating serine residues in response to cellular signals, contributing to the dynamic regulation of protein function. The general reaction for protein phosphorylation is: Ser-OH+ATP→kinase, Mg2+Ser-O-PO32−+ADP\text{Ser-OH} + \text{ATP} \xrightarrow{\text{kinase, Mg}^{2+}} \text{Ser-O-PO}_3^{2-} + \text{ADP}
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