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Serine (symbol Ser or S) is an α-
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...
that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − form under biological conditions), and a side chain consisting of a hydroxymethyl group, classifying it as a
polar Polar may refer to: Geography Polar may refer to: * Geographical pole, either of two fixed points on the surface of a rotating body or planet, at 90 degrees from the equator, based on the axis around which a body rotates *Polar climate, the cli ...
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

This compound is one of the naturally occurring 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 Silk is a natural protein fiber, some forms of which can be woven into textiles. The protein fiber of silk is composed mainly of fibroin and is produced by certain insect larvae to form cocoons. The best-known silk is obtained from th ...
protein, a particularly rich source, in 1865 by Emil Cramer. Its name is derived from the
Latin Latin (, or , ) is a classical language belonging to the Italic languages, Italic branch of the Indo-European languages. Latin was originally a dialect spoken in the lower Tiber area (then known as Latium) around present-day Rome, but through ...
for silk, ''sericum''. Serine's structure was established in 1902. Food sources with high L-Serine content among their proteins include eggs, edamame, lamb, liver, pork, salmon, sardines, seaweed, tofu.


Biosynthesis

The biosynthesis of serine starts with the
oxidation Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or ...
of 3-phosphoglycerate (an intermediate from
glycolysis Glycolysis is the metabolic pathway that converts glucose () into pyruvate (). The free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH ...
) to 3-phosphohydroxypyruvate and NADH by phosphoglycerate dehydrogenase (). Reductive amination (transamination) of this ketone by phosphoserine transaminase () yields 3-phosphoserine (''O''-phosphoserine) which is hydrolyzed to serine by phosphoserine phosphatase (). 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). Glycine biosynthesis: Serine hydroxymethyltransferase (SHMT = serine transhydroxymethylase) also catalyzes the reversible conversions of L-serine to glycine (retro-aldol cleavage) and 5,6,7,8-tetrahydrofolate to 5,10-methylenetetrahydrofolate (mTHF) (hydrolysis). SHMT is a
pyridoxal phosphate Pyridoxal phosphate (PLP, pyridoxal 5'- phosphate, P5P), the active form of vitamin B6, is a coenzyme in a variety of enzymatic reactions. The International Union of Biochemistry and Molecular Biology has catalogued more than 140 PLP-dependent ...
(PLP) dependent enzyme. Glycine can also be formed from CO2, , and mTHF in a reaction catalyzed by
glycine synthase The glycine cleavage system (GCS) is also known as the glycine decarboxylase complex or GDC. The system is a series of enzymes that are triggered in response to high concentrations of the amino acid glycine. The same set of enzymes is sometimes r ...
.


Synthesis and industrial production

Industrially, L-serine is produced from glycine and methanol catalyzed by
hydroxymethyltransferase A transferase is any one of a class of enzymes that catalyse the transfer of specific functional groups (e.g. a methyl or glycosyl group) from one molecule (called the donor) to another (called the acceptor). They are involved in hundreds of di ...
. Racemic serine can be prepared in the laboratory from methyl acrylate in several steps: :


Biological function


Metabolic

Serine is important in
metabolism Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run ...
in that it participates in the
biosynthesis Biosynthesis is a multi-step, enzyme-catalyzed process where substrates are converted into more complex products in living organisms. In biosynthesis, simple compounds are modified, converted into other compounds, or joined to form macromolecul ...
of purines and pyrimidines. It is the precursor to several amino acids including glycine and
cysteine Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile. When present as a deprotonated catalytic residue, some ...
, 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.


Signaling

D-Serine, synthesized in neurons by
serine racemase Serine racemase (SR, ) is the first racemase enzyme in human biology to be identified. This enzyme converts L-serine to its enantiomer form, D-serine. D-serine acts as a neuronal signaling molecule by activating NMDA receptors in the brain. Sin ...
from L-serine (its
enantiomer In chemistry, an enantiomer ( /ɪˈnænti.əmər, ɛ-, -oʊ-/ ''ih-NAN-tee-ə-mər''; from Ancient Greek ἐνάντιος ''(enántios)'' 'opposite', and μέρος ''(méros)'' 'part') – also called optical isomer, antipode, or optical anti ...
), serves as a neuromodulator by coactivating
NMDA receptor The ''N''-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other two being AMPA and ...
s, making them able to open if they then also bind glutamate. D-serine is a potent
agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ag ...
at the glycine site (NR1) of the NMDA-type glutamate receptor (NMDAR). 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+). In fact, D-serine is a more potent agonist at the glycine site on the NMDAR than glycine itself. 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. Apart from central nervous system, D-serine plays a signaling role in peripheral tissues and organs such as cartilage, kidney, and corpus cavernosum.


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.


Clinical significance

Serine deficiency disorders are rare defects in the biosynthesis of the amino acid L-serine. At present three disorders have been reported: * 3-phosphoglycerate dehydrogenase deficiency * 3-phosphoserine phosphatase deficiency * Phosphoserine aminotransferase deficiency 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. 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 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. The group studies deficiencies i ...
(iNTD). Besides disruption of serine biosynthesis, its transport may also become disrupted. One example is
spastic tetraplegia, thin corpus callosum, and progressive microcephaly Spastic can refer to: * Spasticity, a feature of altered muscle performance * A historical reference to people with the movement disorders, see cerebral palsy * Spastic (word), a pejorative used against disabled people See also * Scope (charity) ...
, 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. 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), 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. There also is evidence that L‐serine could acquire a therapeutic role in diabetes. D-Serine is being studied in rodents as a potential treatment for schizophrenia. D-Serine also has been described as a potential biomarker for early
Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As ...
(AD) diagnosis, due to a relatively high concentration of it in the
cerebrospinal fluid Cerebrospinal fluid (CSF) is a clear, colorless body fluid found within the tissue that surrounds the brain and spinal cord of all vertebrates. CSF is produced by specialised ependymal cells in the choroid plexus of the ventricles of the ...
of probable AD patients. D-Serine has been theorized as a potential treatment for sensorineural hearing disorders such as
hearing loss Hearing loss is a partial or total inability to hear. Hearing loss may be present at birth or acquired at any time afterwards. Hearing loss may occur in one or both ears. In children, hearing problems can affect the ability to acquire spoken l ...
and tinnitus.


See also

* Isoserine * Homoserine (isothreonine) *
Serine octamer cluster The Serine octamer cluster in physical chemistry is an unusually stable cluster consisting of eight serine molecules (Ser) implicated in the origin of homochirality. This cluster was first discovered in mass spectrometry experiments. Electrospra ...


References


External links


Serine MS Spectrum
{{Lysophospholipid signaling Proteinogenic amino acids Glucogenic amino acids NMDA receptor agonists Glycine receptor agonists Aldols Amino alcohols Inhibitory amino acids