Serine Amino Acids: Properties, Function, Benefits, and Sources

What is serine?

In 1865, the German chemist Emil Cramer recognized l-serine (Ser) in silk protein for the first time. It is one of the most common amino acids present in vertebrate proteins. At first, l-serine was thought of as a nutrient that animals and people could do without. Nevertheless, l-serine is an essential amino acid from a metabolic and physiological standpoint. Because of its rapid synthesis rate, which allows for secondary conversion, it is the precursor of other nonessential amino acids like cysteine and glycine. Since no other amino acid can boost cell growth as effectively as l-serine, it has long been recognized that it can sustain cell proliferation.

In the human body, glycine and 3-phosphoglycerate (3-PG) can be converted into L-serine. Thus, it is categorized as a dietary amino acid that is not required but is considered disposable in biochemistry and physiology textbooks. A wide variety of cellular processes rely on L-serine, and it is crucial to the metabolism of all nutrients. Sphingolipids (SL) include ceramides, phosphosphingolipids, and glycosphingolipids are abundant in all cell membranes; L-serine is a substrate for glucose and protein synthesis and a component of phospholipids, especially phosphatidylserine (PS). Additionally, glycine synthesis, the folate and methionine cycles, the production of sulfur-containing amino acids, and neurotransmission all rely on L-serine. Protein polarity and glycoprotein synthesis are both aided by the hydroxyl side-chain of L-serine, which also acts as a principal site for attaching a phosphate group in order to control protein activity. The metabolic importance of its D-isoform, D-serine, is distinct. D-serine functions as a complete glycine agonist, produced and stored within astrocytes. Glutamate stimulates the release of D-serine from astrocytes, enabling D-serine to function as a co-agonist at the glycine binding site of NMDA receptors. Recent findings indicate that the serine-synthesizing enzyme, serine racemase, is also localized in the pyramidal neurons of the cortex and hippocampus, as well as in GABAergic neurons of the striatum.

Serine structure

The molecular formula for serine is C₃H₇NO₃, making it a polar amino acid. Its structure is made up of a carboxyl group (-COOH), a hydroxymethyl side chain (-CH₂OH), and a core α-carbon bound to an amino group (-NH₂). Serine's ability to generate hydrogen bonds and be hydrophilic due to the hydroxyl group on its side chain is essential for its function in protein interactions and enzymatic processes. Serine is found in a zwitterionic state at physiological pH (~7.4), where the side chain is uncharged and the amino group is protonated (-NH₃⁺) while the carboxyl group is deprotonated (-COO^-). This structure adds to serine's significance in cellular operations by enabling it to take part in processes like phosphorylation and enzyme catalysis.

Chemical structures of L-serine. (Yoneda K., et al., 2018)

Serine sources

Serine is a non-essential amino acid obtained from dietary sources or produced by the body from several metabolites, including glycine. Serine is present in soybeans, nuts (notably peanuts, almonds, and walnuts), eggs, chickpeas, lentils, meat, and fish (particularly shellfish). The body synthesizes serine when dietary intake is inadequate. It is metabolized from ketones and glycine, and retroconversion with glycine occurs as well. Similar to other amino acids, when food containing serine is consumed, the molecule is removed in the small intestine and absorbed into the bloodstream. It traverses the body, penetrates the blood-brain barrier, and enters neurons, where it is converted into glycine and various other chemicals. Consequently, the concentration of serine within cells is modulated by various metabolic activities. If insufficient amounts are consumed, more serine is synthesized from numerous sources. When excessive amounts are consumed, only a fraction is transformed into glycine, while the surplus is metabolized into folate and various other proteins.

Serine amino acids at Creative Peptides

Serine pKa

The ionization of the α-carboxyl group (pKa = 2.2) and the α-amino group (pKa ≈ 9.15) at different pH levels are reflected in the pKa values for serine. The carboxyl group is deprotonated (-COO^-) and the amino group is protonated (-NH₃⁺) at physiological pH (~7.4). Because it lacks an ionizable group, the hydroxymethyl group (-CH₂OH) that makes up serine's side chain does not affect the pKa values. Thus, at normal pH, serine is a zwitterion—a non-polar amino acid that can engage in hydrogen bonding and enzyme reactions—because its side chain is also non-polar.

Chemical structures and pK_a of the investigated amino acids. (Xu X., et al., 2021)

Serine charge

At the isoelectric point (pI) (pH = 5.68), L-Ser mostly resides in its zwitterionic form. When the pH of a solution is below the isoelectric point (pI), L-Ser resides in its cationic form (-NH₃⁺, -COOH), whereas it assumes an anionic form (-NH₂, -COO⁻) at elevated pH levels. Consequently, at elevated pH levels, L-Ser acts as a potent nucleophile and can establish a bond with an electron-deficient molecule. Nanoparticles, owing to their elevated surface-to-volume ratio, experience either defects or chemical interactions among coordinatively unsaturated surface species to attain stability. Fe³⁺/Fe²⁺ present on the surface of Fe₃O₄ nanoparticles are not entirely coordinated with neighboring oxygen atoms and interact with L-Ser to enhance their stability. L-Ser at pH > 9.15 primarily occurs in its anionic form (COO− and NH₂), which acts as a potent nucleophile capable of forming a connection with Fe³⁺/Fe²⁺.

Effect pH on charge of L-Serine. (Belachew N., et al., 2017)

Serine phosphorylation

One important post-translational alteration is serine phosphorylation, which is carried out by serine/threonine kinases with ATP as the phosphate donor. This process adds a phosphate group to the hydroxyl group of the side chain of serine. Kinases and phosphatases govern this reversible process, which is essential for cell cycle activities, metabolic control, protein function regulation, and cellular signaling. Cells are able to react dynamically to stimuli such as hormones, growth factors, and stress because serine phosphorylation changes the structure, activity, and connections of proteins. Its role in cellular homeostasis is demonstrated by its centrality to pathways such as insulin signaling and the MAPK cascade. A number of studies have provided compelling evidence that elevated Ser/Thr phosphorylation of IRS proteins, especially insulin receptor substrate (IRS)-1, plays a significant negative regulatory impact on insulin function. Depending on the residues that are phosphorylated, IRS proteins can either detach from the IR or become inhibitors of the IR kinase (IRK). This can happen when Ser/Thr phosphorylation occurs in certain residues on IRS proteins. IRS proteins can also be phosphorylated at specific sites on Tyr. Consequently, insulin resistance may develop if IRS proteins are too phosphorylated on Ser/Thr, rather than responding to a signal that promotes Tyr phosphorylation. Over seventy Ser/Thr residues are present in IRS proteins, suggesting that they could be phosphorylation targets. In order to reduce insulin signaling, several serine kinases have been discovered that phosphorylate IRS: JNK (Ser307), PKCθ (Ser1101), PKCζ (Ser323), PKCα (Ser307), salt inducible kinase (Ser794), MAPK (Ser616), mTor/S6K-1 (Ser616/Ser636), and many more.

Serine/Threonine phosphorylation of IRS-1. (Olivares-Reyes J A., et al., 2009)

Serine vs threonine

Serine and threonine are polar amino acids characterized by hydroxyl groups on their side chains, enabling them to establish hydrogen bonds and engage in phosphorylation processes. The primary distinction between them is that serine possesses a smaller hydroxymethyl group (–CH₂OH), whereas threonine contains a hydroxyethyl group (–CH(OH)CH₃) with an extra methyl group (–CH₃), rendering it marginally larger. Both amino acids are hydrophilic and often located on the protein surface; however, threonine is essential, requiring dietary intake, whereas serine is non-essential and can be produced from glycine. Notwithstanding these distinctions, both amino acids possess analogous pKa values and exist in a neutral, zwitterionic state at physiological pH (~7.4).

Copper is inhibited from corrosion in a 0.5 M HCl solution by glutamic acid, serine, and threonine. As a result, the cathodic current density for copper corrosion is significantly reduced, and Ecorr becomes more negative. The nitrogen and oxygen atoms work together to form a barrier that prevents molecules from penetrating the copper, which in turn inhibits corrosion. The presence of oxygen atoms with negative charge centers influences the enhanced inhibitory efficacy of glutamic acid.

Molecular structures of amino acids. (Zhang D Q., et al., 2008)

Serine synthesis

Fasting people synthesize serine from 3-PG and glycine, which accounts for around 73% of the serine appearance rate. An enzyme called 3-PG dehydrogenase oxidizes 3-PG to 3-phosphohydroxypyruvate, the initial step in the synthesis of L-serine from 3-PG that is produced during glycolysis or gluconeogenesis. The second process involves the use of 3-phosphoserine aminotransferase to catalyze the transamination of glutamate to 3-phosphoserine. The last stage involves the action of phosphoserine phosphatase to create L-serine and inorganic phosphate by irreversible hydrolysis. The last step is vulnerable to feedback regulation of L-serine synthesis and is thought of as the rate limiting step. The kidneys and brain both have significant 3-PG production of L-serine, particularly in astrocytes. Protein restriction or a carbohydrate-rich diet activate the liver's L-serine synthesis enzymes. Reversible conversion of glycine to serine is catalyzed by the enzyme serine hydroxymethyltransferase. This process involves transferring one carbon atom from 5,10-methylene-tetrahydrofolate (5,10-MTHF) to glycine, resulting in tetrahydrofolate (THF) and L-serine. About 41% of the total glycine flux in healthy adults is produced by serine hydroxymethyltransferase as L-serine.

Assessments of arterial-venous differences indicate that the kidneys are the primary source of L-serine released into the bloodstream during fasting, producing around 4 g (~40 mmol) of L-serine daily under physiological settings. The kidneys produce L-serine in the proximal tubule cells from 3-phosphoglycerate and glycine. The primary sources of 3-PG are gluconeogenic precursors, including pyruvate, lactate, glutamate, glutamine, and aspartate. The significance of gluconeogenesis has been substantiated by a notable reduction in serine outflow from the kidneys following the inhibition of phosphoenolpyruvate carboxykinase, the principal enzyme of gluconeogenesis, by 3-mercaptopicolinate. The transformation of glycine into serine is facilitated by the synergistic function of the glycine cleavage enzyme and serine hydroxymethyltransferase. The route is active during acidosis and functions as a source of ammonia for the excretion of H+ from the body via urine.

L-serine synthesis. (Murtas G., et al., 2020)

Serine metabolism

Serine, which is a glucogenic amino acid, can contribute to the process of gluconeogenesis through two different mechanisms. The enzyme serine dehydratase is responsible for the first step, which involves the direct conversion of L-serine to pyruvate. There is a correlation between increasing the amount of protein in the diet and activating this pathway in the liver. Glycerate kinase, serine-pyruvate transaminase, and glycerate dehydrogenase are the enzymes that are responsible for the conversion of serine into 2-phosphoglycerate in the second pathway. This 2-phosphoglycerate can then join the pathways of glycolysis and gluconeogenesis. In human beings, the glycine pathway and the transsulfuration pathway are the primary pathways by which serine is degraded. A collection of enzymes known as the glycine cleavage system is responsible for the degradation of glycine, which is created from L-serine through a reaction that is catalyzed by glycine hydroxymethyltransferase. This process results in the production of carbon dioxide, ammonia, and 5,10-MTHF. Deamination of glycine by D-aminooxidase results in the formation of glyoxylate, which is then oxidized to produce oxalate, which is then eliminated in the urine. This is a less significant form of glycine breakdown. The pathway known as the transsulfuration pathway, in which L-serine serves as a substrate for the production of cystathionine.

Pathways of serine synthesis and metabolism. (Holeček M., 2022)

Serine functions and applications

(1) As the precursor

Sphingolipids, phosphoglycerides, glycerides, and phosphatidylserine all originate from L-serine. Cultured neuronal cells cannot synthesize sphingolipids and phosphatidylserine without an external source of L-serine. Gangliosides generated from sphingosine are relevant components of membranes and myelin and are involved in cellular differentiation, proliferation, and migration. These phospholipids are key lipid messenger molecules in apoptotic signaling pathways.

(2) For protein synthesis

The percentage of L-serine found in the majority of proteins, such as milk, skeletal muscle, and collagen, falls within the 2–5% range. Its polar side chain with a hydroxyl group makes it primarily surface-bound on proteins, where it aids in hydrophilicity and protein-substance interactions. As an integral component of glycoprotein O-glycosidic bonds, L-serine residues are key locations for the reversible binding of phosphate groups, which modulates protein activity. About 200 hydrolytic enzymes, known as serine hydrolases, including trypsin, chymotrypsin, lipoprotein, and hormone sensitive lipase, include L-serine in their catalytic sites. Casein - the main protein in milk - is considered a phosphoprotein because it contains a large amount of phosphorus, which is attached to the casein via serine ester bonds.

Main functions of L-serine. (Holeček M., 2022)

(3) Maintain nervous system

The fact that neurological abnormalities are observed in patients with primary disorders of L-serine synthesis is evidence that the de novo synthesis of L-serine is crucial for the development and function of the central nervous system. The pathogenesis of schizophrenia and several neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, is believed to be influenced by dysregulation of serine metabolism. In a mouse model of Alzheimer's disease, it was recently demonstrated that astrocytes are susceptible to glycolysis impairment. This impairment results in a decrease in both L- and D-serine synthesis, as well as alterations to synaptic plasticity and memory. The use of L-serine supplements in the treatment of CNS injuries (such as those caused by cerebral ischemia, stroke, and trauma) has been studied. Research on amyotrophic lateral sclerosis has indicated that L-serine may have therapeutic effects. It has been suggested that D-serine could be used in conjunction with antipsychotics to treat schizophrenia.

L-serine's neurological function. (Phone Myint S M M., et al., 2023)

(4) Reduce diabetes incidence

In beta-cell biology, the varied lipid family known as sphingolipids regulates insulin folding and controls cell death. Condensation of L-serine with palmitoyl-CoA initiates sphingolipid production. Researchers in one study looked at how L-serine affected blood glucose homeostasis and the development of autoimmune diabetes in female NOD mice. Taking L-serine supplements on a regular basis lowers the risk of diabetes and insulitis. Mice given L-serine also showed less HOMA-IR, lower blood glucose levels, and better glucose tolerance testing. Taking L-serine caused a modest drop in body weight, which was accompanied by a decrease in caloric and food consumption. According to mass spectrometry results, L-serine had no influence on sphingolipids in the pancreas. Thus, the evidence points to L-serine as a potential therapeutic supplement for the management of Type 1 Diabetes and the maintenance of normal blood glucose levels.

L-serine supplementation decreases diabetes incidence. (Holm L J., et al., 2018)

(5) Mitigate inflammation

Eighty-one weaned piglets, each of whom was twenty-one days old, were given either a basal diet or a basal diet that included 0.2% serine. Early-weaned piglets were used to determine the effects of dietary serine supplementation on intestinal morphology using hematoxylin and eosin staining, the expression of tight junction proteins (TJPs) using immunoblotting and immunofluorescence, the expression of inflammatory cytokines and apoptosis markers using real-time quantitative polymerase chain reaction (RT-qPCR), and the level of antioxidant enzymes using enzyme-linked immunosorbent assay (ELISA) kits. Supplementation with serine led to an increase in daily body weight gain while simultaneously reducing the occurrence of diarrhea. Piglets who were given serine as a supplement had villi and microvilli that were arranged in a regular pattern in both the jejunum and the ileum. In addition, the consumption of serine in the food led to an increase in the expression of TJP, as well as a reduction in apoptosis, inflammation, and oxidative stress in the intestines of early-weaned mice. There is a possibility that the serine might be utilized as a feed supplement in order to minimize gut dysfunction that is brought on by weaning.

Effects of serine on intestinal inflammation in early-weaned piglets. (Zhou X., et al., 2018)

(6) Attenuate alcoholic fatty liver

Research shows that treating hyperhomocysteinemia with a reduced homocysteine level prevents fatty liver from developing, which is a key factor in the development of hepatic steatosis. In the control group, serum homocysteine concentrations were >5-fold higher than in the ethanol group; however, in the group treated with 200 mg/kg L-serine, these values were reduced by 60.0% and 47.5%, respectively, as compared to the ethanol group. Additionally, when compared to the ethanol group, the L-serine group showed a 63.3% reduction in hepatic neutral lipid accumulation in the chronic ethanol trial. In comparison to the ethanol group, L-Serine raised glutathione by 94.0% and S-adenosylmethionine by 30.6%. Intracellular homocysteine and TG concentrations were >2-fold raised when betaine homocysteine methyltransferase, cystathionine β-synthase, or methionine were silenced. However, when L-serine was used to neutralize the effect of L-serine-independent betaine homocysteine methyltransferase, the rise was reversed. These findings prove that L-serine improves alcoholic fatty liver by speeding up the homocysteine metabolism that is dependent on L-serine.

Intracellular tHcy and TG concentrations. (Sim W C., et al., 2015)

References

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