The AtlasAmino acidsPolar, uncharged
SerineSer · S
A small amino acid made from glucose that feeds the folate cycle, builds the brain’s fats and, when it runs short, lets the nervous system poison itself with the wrong lipid.
Molecule · Ser · 7 heavy atoms
Serine
C3H7NO3105.09 g/mol
A small amino acid made from glucose that feeds the folate cycle, builds the brain’s fats and, when it runs short, lets the nervous system poison itself with the wrong lipid.
Built fromthe charted ones open their own entry
- Codes
- Ser · S
- Formula
- C3H7NO3
- Molar mass
- 105.09 g/mol
- Systematic name
- (2S)-2-amino-3-hydroxypropanoic acid
- Side chain
- Hydroxymethyl: one carbon and a hydroxyl; small, polar and uncharged.
- Class
- Polar, uncharged
- In the diet
- Dispensable
- Carbon skeleton
- Glucogenic
- pKa
- α-COOH 2.21 · α-NH3+ 9.15
- Isoelectric point
- pH 5.68
- Hydropathy
- -0.8 (Kyte–Doolittle)
- Codons
UCUUCCUCAUCGAGUAGC- Main transporters
- SLC1A4 (ASCT1)
pKa and isoelectric point: Nelson and Cox, Lehninger Principles of Biochemistry, table of amino acid properties (free amino acid, 25 °C). Hydropathy: Kyte and Doolittle, J Mol Biol 1982. Essentiality: Reeds, J Nutr 2000. Formula and mass computed from the structure.
In brief
What it is
An amino acid with a single carbon carrying a hydroxyl group: small, polar and uncharged. The body makes it from 3-phosphoglycerate, an intermediate of glycolysis, in three steps 1,2.
Why it matters
Serine is the main source of one-carbon units for folate metabolism, and so of nucleotides and methylation 3; the precursor of glycine, cysteine, D-serine and the sphingolipids and phospholipids of membranes 1; and, as a target for kinases, one of the cell’s main phosphorylation sites 4.
Where it runs short
Inherited defects in serine synthesis cause microcephaly, seizures and developmental delay in children, and polyneuropathy in adults 2. In diabetic mice, low serine drove peripheral neuropathy through the build-up of toxic 1-deoxysphingolipids 5.
Where it turns
There is no known toxicity of excess dietary serine at food levels; in cancer, though, many tumours depend on serine, and in mice restricting dietary serine and glycine slowed some of them 6.
When serine runs short, the enzyme that should use it takes alanine instead, and makes a lipid the body cannot break down.
The molecule
Serine is alanine with a hydroxyl on its side chain. That hydroxyl is the business end: it is where kinases attach phosphate, so serine is one of the three amino acids, with threonine and tyrosine, through which much of cell signalling runs 4. In serine proteases a serine hydroxyl, activated by a neighbouring histidine, is what cuts the target protein 7.
Move across the chart to read the charge at any pH.
Computed from its pKa values (α-carboxyl 2.21, α-amino 9.15) by the Henderson–Hasselbalch equation, for the free amino acid in water at 25 °C. Inside a folded protein the same groups can shift by a unit or more. The faint lines are the other amino acids.
Kyte–Doolittle hydropathy index: positive values avoid water and tend to be buried inside a folded protein, negative values sit on its surface. Each letter is an amino acid; choose one to open it.
| 1st ↓ 2nd → | U | C | A | G | 3rd |
|---|---|---|---|---|---|
| U | UUUPhe | UCUSer | UAUTyr | UGUCys | U |
| UUCPhe | UCCSer | UACTyr | UGCCys | C | |
| UUALeu | UCASer | UAAStop | UGAStop | A | |
| UUGLeu | UCGSer | UAGStop | UGGTrp | G | |
| C | CUULeu | CCUPro | CAUHis | CGUArg | U |
| CUCLeu | CCCPro | CACHis | CGCArg | C | |
| CUALeu | CCAPro | CAAGln | CGAArg | A | |
| CUGLeu | CCGPro | CAGGln | CGGArg | G | |
| A | AUUIle | ACUThr | AAUAsn | AGUSer | U |
| AUCIle | ACCThr | AACAsn | AGCSer | C | |
| AUAIle | ACAThr | AAALys | AGAArg | A | |
| AUGMet | ACGThr | AAGLys | AGGArg | G | |
| G | GUUVal | GCUAla | GAUAsp | GGUGly | U |
| GUCVal | GCCAla | GACAsp | GGCGly | C | |
| GUAVal | GCAAla | GAAGlu | GGAGly | A | |
| GUGVal | GCGAla | GAGGlu | GGGGly | G |
Where it comes from
The body makes serine from 3-phosphoglycerate, a product of glycolysis, by three enzymes: phosphoglycerate dehydrogenase, the first and rate-limiting step, phosphoserine aminotransferase and phosphoserine phosphatase 2,8.
The brain cannot rely on blood serine, which crosses the blood–brain barrier poorly, so astrocytes make it and hand it to neurons through ASCT1 9.
DispensableMade from glucose through 3-phosphoglycerate, so not needed in the diet; the brain depends on making its own 1,9,10.
How much
None set; the body makes it from glucose 10.
Where it is in food
- All protein; but blood serine reaches the brain poorly 9.
In the bottle · enzymatic or extractedIndustrial serine has come mainly from extraction and enzymatic catalysis; direct fermentation from sugar with engineered Corynebacterium glutamicum or Escherichia coli is being developed 11,12.
What the body does with it
Serine is the main entry to one-carbon metabolism. Serine hydroxymethyltransferase converts it to glycine while loading a carbon onto tetrahydrofolate, and those carbons build purines and thymidine for DNA and regenerate methionine for methylation; much of this happens in mitochondria 3.
Serine is also the backbone of membrane lipids. Serine palmitoyltransferase joins it to palmitate to begin every sphingolipid, and it forms the head group of phosphatidylserine 1,13. A racemase converts L-serine into D-serine, a co-agonist of NMDA receptors at synapses 14,15.
Many cancers lean on serine. In 2011 the first enzyme of serine synthesis, PHGDH, was found to be raised in 70% of oestrogen-receptor-negative breast cancers and required by those cells to grow 16. In mouse models of intestinal cancer and lymphoma, a diet without serine and glycine extended survival, though tumours driven by KRAS responded less 6.
In three sentences each
The one-carbon donor
Serine hydroxymethyltransferase splits serine into glycine and a one-carbon unit carried by folate, the main source of the carbons used to build purines and thymidine and to make methionine 3.
How it is made, moved and broken down
When serine runs short, serine palmitoyltransferase starts using alanine. The products, 1-deoxysphingolipids, lack the hydroxyl that cells need to break sphingolipids down, so they accumulate. Variants in the enzyme that favour alanine cause hereditary sensory and autonomic neuropathy type 1, and lowering serine in cells shifted their lipid profile towards that pattern 13.
Carbon skeleton · glucogenicSerine is converted to glycine and one-carbon units, and its carbon skeleton counts as glucogenic 3.
- 3-Phosphoglycerate
- Phosphoglycerate dehydrogenasePHGDH · NAD⁺
- 3-Phosphohydroxypyruvate
- Phosphoserine aminotransferasePSAT1 · vitamin B6
- Phosphoserine
- Phosphoserine phosphatasePSPH
- Serine
- Serine + THF
- Serine hydroxymethyltransferaseSHMT1, SHMT2 · vitamin B6
- Glycine + methylene-THF
- Serine racemaseSRR · vitamin B6
- D-Serine
- Serine palmitoyltransferaseSPTLC1, SPTLC2 · vitamin B6
- Sphingolipids (or, with alanine, 1-deoxysphingolipids)
How it crosses membranes
- SLC1A4 · ASCT1astrocytes and neurons — carries serine from astrocytes to neurons; recessive mutations cause microcephaly and hypomyelination 9
Where it matters most
When it goes wrong
Inherited
Serine deficiency disorders
PHGDH, PSAT1, PSPH · autosomal recessive
Microcephaly, psychomotor delay and seizures in children, or a progressive polyneuropathy in adults, with low serine in CSF and plasma; they are treatable, so prompt recognition matters 2. Milder cases can present in adolescence as ichthyosis and neuropathy, where high-dose serine and glycine cleared the skin but barely helped the nerves 19.
How it is foundFasting plasma and CSF serine; gene sequencing 2.
Inherited
Neu–Laxova syndrome
PHGDH, PSAT1, PSPH · autosomal recessive
The most severe end of the serine synthesis disorders, with multiple malformations and death before or soon after birth 8,20.
How it is foundPrenatal ultrasound and sequencing 8.
Inherited
ASCT1 deficiency
SLC1A4 · autosomal recessive
Developmental delay, microcephaly and poor myelination, sometimes with seizures, from failure to move serine from astrocytes into neurons 9.
How it is foundExome sequencing 9.
Inherited
HSAN1 and SPTLC1-related ALS
SPTLC1, SPTLC2 · autosomal dominant
Variants that make serine palmitoyltransferase use alanine cause a sensory and autonomic neuropathy through 1-deoxysphingolipids; variants that free it from its regulators cause juvenile ALS through excess sphingolipid 13,21.
How it is foundPlasma sphingolipid profiling and sequencing 13.
Association
Diabetic neuropathy
Serine and glycine are consistently low in the metabolic syndrome. In mice, diabetes lowered serine, and low serine drove neuropathy through deoxysphingolipids 5. These are animal findings 22.
How it is foundResearch only.
How it is measured
Serine is measured in plasma and CSF in the standard amino acid analysis, compared with age-related reference values 2,23. In research, a serine tolerance test, giving serine and measuring how fast it is cleared, revealed abnormal serine handling in diabetic mice 5.
- Plasma and CSF serineThe biochemical hallmark of the serine synthesis disorders is low serine in CSF and plasma 2.Needs age-specific reference values, since normal levels change with age 2.Late-onset, milder forms are easily missed 19.
- 1-DeoxysphingolipidsThe abnormal lipids made when serine palmitoyltransferase uses alanine; raised in HSAN1 and in macular telangiectasia type 2 13,17.Research and specialist laboratories.
Food, supplements and the evidence
Establishedreplicated in people, for a named outcome
Uncertainsmall, short, mixed, surrogate or preclinical
Sold asthe claim on the label, against the evidence
- Nothing in this column.
What is strange about it
A deficiency treated before birth. In 2004 a fetus found to have PHGDH deficiency showed a falling head circumference by 26 weeks; serine given to the mother restored head growth, and the child was developing normally at four years 24.
Macular telangiectasia type 2, a slow loss of central vision, is linked to low serine and toxic deoxysphingolipids, and is more common in people with type 2 diabetes 17,18. Its first approved treatment, in March 2025, was not a metabolic one but an implant of cells releasing a nerve growth factor into the eye 25.
Serine supplements treat one disorder of serine palmitoyltransferase and should be avoided in the other. In HSAN1 they help by giving the enzyme its proper substrate; in the childhood ALS caused by variants in the same enzyme, which already makes too much sphingolipid, serine is expected to make things worse 13,21.
Where it connects
In the Atlas
Topics on the map
On the map
A star in Conditional amino acids, one of 14. Made from glycolysis, and the entry point to the one-carbon cycle that folate runs — which makes it the link between eating sugar and methylating DNA.
Sources
25 sources, numbered as they are cited. Every one was checked against PubMed or its publisher before it was cited here; the note under each says what it shows and what it does not.
- 1Tabatabaie L, Klomp LW, Berger R, et al. L-serine synthesis in the central nervous system: a review on serine deficiency disorders.doi:10.1016/j.ymgme.2009.10.012 · PMID 19963421
Review of the pathway and its disorders.
- 2van der Crabben SN, Verhoeven-Duif NM, et al. An update on serine deficiency disorders.doi:10.1007/s10545-013-9592-4 · PMID 23463425
Three defects; low CSF and plasma serine; treatable.
- 3Ducker GS, Rabinowitz JD. One-carbon metabolism in health and disease.doi:10.1016/j.cmet.2016.08.009 · PMID 27641100
Serine as the main source of one-carbon units.
- 4Olsen JV, Blagoev B, Gnad F, et al. Global, in vivo, and site-specific phosphorylation dynamics in signaling networks.doi:10.1016/j.cell.2006.09.026 · PMID 17081983
6,600 phosphorylation sites.
- 5Handzlik MK, Gengatharan JM, Frizzi KE, et al. Insulin-regulated serine and lipid metabolism drive peripheral neuropathy.doi:10.1038/s41586-022-05637-6 · PMID 36697822
Mice; serine deficiency, deoxysphingolipids and neuropathy.
- 6Maddocks ODK, Athineos D, Cheung EC, et al. Modulating the therapeutic response of tumours to dietary serine and glycine starvation.doi:10.1038/nature22056 · PMID 28425994
Mouse cancer models.
- 7Brosnan ME, Brosnan JT. Histidine metabolism and function.doi:10.1093/jn/nxaa079 · PMID 33000155
The serine protease catalytic triad.
- 8Acuna-Hidalgo R, Schanze D, Kariminejad A, et al. Neu-Laxova syndrome is a heterogeneous metabolic disorder caused by defects in enzymes of the L-serine biosynthesis pathway.doi:10.1016/j.ajhg.2014.07.012 · PMID 25152457
12 families; all three enzymes.
- 9Damseh N, Simonin A, Jalas C, et al. Mutations in SLC1A4, encoding the brain serine transporter, are associated with developmental delay, microcephaly and hypomyelination.doi:10.1136/jmedgenet-2015-103104 · PMID 26041762
ASCT1 deficiency; serine crosses the barrier poorly.
- 10Reeds PJ. Dispensable and indispensable amino acids for humans.doi:10.1093/jn/130.7.1835S · PMID 10867060
Serine as dispensable.
- 11Zhang X, Xu G, Shi J, et al. Microbial production of L-serine from renewable feedstocks.doi:10.1016/j.tibtech.2018.02.001 · PMID 29500004
Extraction and enzymatic catalysis as current routes.
- 12Xu G, Zhang X, Xiao W, et al. Production of L-serine and its derivative L-cysteine from renewable feedstocks using Corynebacterium glutamicum: advances and perspectives.doi:10.1080/07388551.2023.2170863 · PMID 36944486
Fermentation in development.
- 13Lone MA, Aaltonen MJ, Zidell A, et al. SPTLC1 variants associated with ALS produce distinct sphingolipid signatures through impaired interaction with ORMDL proteins.doi:10.1172/JCI161908 · PMID 35900868
HSAN1 and ALS variants; serine limitation shifts the profile.
- 14Wolosker H, Sheth KN, Takahashi M, et al. Purification of serine racemase: biosynthesis of the neuromodulator D-serine.doi:10.1073/pnas.96.2.721 · PMID 9892700
Rat brain enzyme; PLP-dependent.
- 15Papouin T, Ladépêche L, Ruel J, et al. Synaptic and extrasynaptic NMDA receptors are gated by different endogenous coagonists.doi:10.1016/j.cell.2012.06.029 · PMID 22863013
D-serine at synapses.
- 16Possemato R, Marks KM, Shaul YD, et al. Functional genomics reveal that the serine synthesis pathway is essential in breast cancer.doi:10.1038/nature10350 · PMID 21760589
PHGDH raised in 70% of ER-negative breast cancers.
- 17Wu L, Chen-Li G, Sanabria MDM. Macular telangiectasia type 2: an update.doi:10.1177/03000605261473180 · PMID 42551495
Serine deficiency and deoxysphingolipids in the retina.
- 18Jung M, Bucher F. Type 2 macular telangiectasia: pathogenesis — the interplay between neurodegeneration and metabolic changes.doi:10.1055/a-2936-0118 · PMID 42660511
Fewer than 5% have a serine-pathway mutation; diabetes more common. In German.
- 19Shen Y, Peng Y, Huang P, et al. Juvenile-onset PSAT1-related neuropathy: a milder phenotype of serine deficiency disorder.doi:10.3389/fgene.2022.949038 · PMID 36061210
Two adolescents with PSAT1 variants; serine and glycine cleared the skin, not the neuropathy.
- 20Abdelfattah F, Kariminejad A, Kahlert AK, et al. Expanding the genotypic and phenotypic spectrum of severe serine biosynthesis disorders.doi:10.1002/humu.24067 · PMID 32579715
15 families; a continuum.
- 21Syeda SB, Lone MA, Mohassel P, et al. Recurrent de novo SPTLC2 variant causes childhood-onset amyotrophic lateral sclerosis (ALS) by excess sphingolipid synthesis.doi:10.1136/jnnp-2023-332132 · PMID 38041679
Six patients; serine supplementation should be avoided in SPT-associated ALS.
- 22Hornemann T. Serine deficiency causes complications in diabetes.doi:10.1038/d41586-023-00054-9 · PMID 36697725
Commentary on the mouse findings.
- 23Sharer JD, De Biase I, Matern D, et al. Laboratory analysis of amino acids, 2018 revision: a technical standard of the American College of Medical Genetics and Genomics (ACMG).doi:10.1038/s41436-018-0328-6 · PMID 30459394
Amino acid analysis methods.
- 24de Koning TJ, Klomp LW, van Oppen AC, et al. Prenatal and early postnatal treatment in 3-phosphoglycerate-dehydrogenase deficiency.doi:10.1016/S0140-6736(04)17596-X · PMID 15610810
One case.
- 25Hoy SM. Revakinagene taroretcel: first approval.doi:10.1007/s40291-025-00787-5 · PMID 40540142
First FDA-approved treatment for MacTel type 2, March 2025.
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