Serine

Serine is a non-essential amino acid that the body makes from 3-phosphoglycerate, an intermediate of glucose breakdown — so its production is directly linked to carbohydrate metabolism. Although rarely discussed in sports nutrition, serine is everywhere in biochemistry. Serine units in proteins are the most common “switch” sites in cell signalling. Serine is the main source of the single-carbon units that feed the folate cycle, which the body needs to make DNA and to supply methyl groups. It’s the starting material for all sphingolipids, important fats in nerve cell membranes and myelin. And its mirror-image form, D-serine, helps switch on NMDA receptors in the brain. Phosphatidylserine (PS), a serine-containing fat, is also sold as a supplement for memory and for reducing the cortisol response to exercise — although the evidence for both is weaker than often claimed.

Classification

• Type: Non-essential amino acid — made from 3-phosphoglycerate, a glucose breakdown intermediate, through three enzyme steps (PHGDH, PSAT1, and PSPH)
• Side chain: A hydroxymethyl group (a carbon carrying a hydroxyl group) — the non-essential counterpart to threonine, which also has a hydroxyl group
• Metabolism: Glucogenic — serine can be converted to pyruvate, which can be used to make glucose or burned for energy; it also donates single-carbon units to the folate cycle
• Versatility: Serine is involved in protein phosphorylation, attaching sugars to proteins, supplying single-carbon units, building phospholipids and sphingolipids, making cysteine and glycine, and — as D-serine — brain signalling

Key Mechanisms

Single-carbon metabolism — feeding the folate cycle:

Serine’s most important metabolic job is donating single-carbon units to the folate cycle, through the enzyme serine hydroxymethyltransferase (SHMT):

Serine + tetrahydrofolate → glycine + 5,10-methylene-tetrahydrofolate (via SHMT, which needs vitamin B6)

This one reaction does two things:

1. It loads a single-carbon unit onto folate, which is then used for:
   • Making thymidine — the “T” building block of DNA, needed every time a cell divides
   • Recycling homocysteine into methionine — after conversion to 5-methyltetrahydrofolate — which keeps up the supply of SAM, the body’s main methyl donor
   • Making purines — the adenine and guanine building blocks of DNA, RNA, and ATP
2. It produces glycine — the main way the body makes its own glycine, which it uses for protein, glutathione (with cysteine and glutamate), creatine, bile acids, and collagen

Serine — mostly made by the body itself — is the main source of the single-carbon units that drive DNA production and methylation, which is why serine and folate are so closely linked.

D-serine and NMDA receptors:

NMDA receptors, central to learning and memory, need two molecules to open:

1. Glutamate, at the main binding site
2. A co-agonist at a second site, called the “glycine site” — which in many brain regions, such as the cortex and hippocampus, is mainly occupied by D-serine rather than glycine

D-serine is made from ordinary L-serine by the enzyme serine racemase. Current evidence suggests that astrocytes, the brain’s support cells, make L-serine from glucose and pass it to neurons, which convert it into D-serine — although exactly which cells make and release D-serine is still debated. Because serine doesn’t enter the brain easily from the blood, the brain relies mainly on making its own. Low D-serine signalling has been linked to schizophrenia, and D-serine has been tested as an add-on treatment, with mixed results.

Phosphatidylserine (PS):

In human cells, phosphatidylserine is made by swapping serine onto the head of other phospholipids — phosphatidylcholine or phosphatidylethanolamine — in the endoplasmic reticulum. PS can also be converted into phosphatidylethanolamine, which in turn can be converted into phosphatidylcholine using SAM.

PS sits on the inner face of cell membranes and is especially concentrated in the brain. Its roles include:

• Activating protein kinase C: PS, together with calcium, helps anchor protein kinase C (PKC) to the membrane — through PKC’s C2 domain — where it can be fully activated. PKC is involved in many signalling pathways
• An “eat me” signal: when a cell dies through programmed cell death, PS flips to the outer face of its membrane, signalling immune cells to clear it away
• Blood clotting: activated platelets also expose PS on their surface, providing a platform where clotting factors assemble

PS supplements: early studies, mostly using PS extracted from cow brains, found benefits for memory in older adults, and some studies found that PS reduced the cortisol response to exercise. Cow-brain PS was withdrawn over concerns about mad cow disease (BSE), and today’s supplements are made from soy or sunflower. Studies of plant-derived PS for memory have been mixed, and in 2003, the US FDA allowed only a heavily qualified health claim — one that must state that there’s “little scientific evidence” supporting a reduced risk of dementia or cognitive decline. Studies of PS and exercise cortisol have also been mixed, with some showing reductions and others no effect.

Sphingolipids — serine as the starting point:

All sphingolipids, an important class of structural and signalling fats, begin with serine:

Serine + palmitoyl-CoA → 3-ketosphinganine (via serine palmitoyltransferase, the rate-limiting enzyme)

From there, the pathway leads to:

• Ceramide: a signalling fat involved in stress responses, cell death, and insulin resistance
• Myelin sphingolipids: myelin, the insulation around nerve fibers, is about 40% cholesterol by lipid weight, with sphingolipids — especially galactosylceramide and sulfatide, plus some sphingomyelin — among its other key components
• Gangliosides: complex sugar-containing fats important for nerve cell function and communication
• Sphingosine-1-phosphate: a signalling molecule that controls the movement of immune cells — the target of fingolimod, a multiple sclerosis medicine

When serine runs low — deoxysphingolipids: if serine is scarce, or the enzyme is faulty, serine palmitoyltransferase can use alanine or glycine instead, producing “deoxysphingolipids” that are toxic to nerves. This is the cause of a rare inherited nerve disorder, hereditary sensory and autonomic neuropathy type 1 (HSAN1), and in a randomized trial published in 2019, high-dose L-serine slowed its progression. Low serine and raised deoxysphingolipids have also been linked to an eye disease, macular telangiectasia type 2. These are among the few situations where L-serine supplements are used medically.

Making cysteine:

1. Homocysteine + serine → cystathionine (via cystathionine beta-synthase, which needs vitamin B6)
2. Cystathionine → cysteine + alpha-ketobutyrate (via cystathionine gamma-lyase, which also needs vitamin B6)

Serine provides the carbon skeleton and homocysteine (from methionine) provides the sulfur. Since cysteine is the limiting building block for glutathione, this links serine to the body’s antioxidant defenses.

Serine enzymes:

Serine is the key working part of the serine proteases — one of the largest families of protein-cutting enzymes. Their active site uses a “catalytic triad” of serine, histidine, and aspartate, with serine’s hydroxyl group attacking the protein chain. Examples include:

• Digestive enzymes: trypsin, chymotrypsin, and elastase
• Clotting factors: thrombin, factor Xa, and activated protein C
• Immune system enzymes: the complement proteins C1r and C1s
• Clot-dissolving enzymes: plasmin and tissue plasminogen activator (tPA)

Acetylcholinesterase, which breaks down the neurotransmitter acetylcholine, also relies on an active-site serine. Organophosphate nerve agents (such as sarin) and organophosphate pesticides permanently block this serine, causing acetylcholine to build up and nerves to fire uncontrollably.

Cell signalling switches:

Serine is the most commonly phosphorylated amino acid in proteins — far more often than threonine or tyrosine. Almost every major signalling pathway uses serine phosphorylation, switched on by kinases such as PKA, PKC, Akt, and AMPK and off by phosphatases. Examples:

• Akt activation: full activation of Akt, central to insulin signalling and muscle growth, requires phosphorylation at serine 473 (by mTORC2) as well as threonine 308
• Insulin resistance: when IRS-1, a key insulin signalling protein, is phosphorylated at certain serine units — by enzymes activated by nutrient excess (S6K1) and inflammation (JNK) — insulin signalling is dampened. This is one of the molecular links between chronic overeating, inflammation, and insulin resistance

These serine units are built into the proteins themselves, so dietary serine doesn’t control them.

Dietary Intake

Serine has no Recommended Dietary Allowance — it’s non-essential, the body makes it from glucose, and almost every protein food provides it.

Serine is spread across all protein foods. Eggs have the highest share of serine in their protein (7.4%) — egg yolk contains phosvitin, a protein that’s about half serine and one of the most heavily phosphorylated proteins known. Dairy, soy, and legumes come next, at about 5–6%, while meat and fish are about 3.5–4.5%. Any diet with enough protein provides plenty of serine.

Helps With

• Supplying single-carbon units to the folate cycle, for making DNA and methyl groups
• Making D-serine, which helps activate NMDA receptors for learning and memory
• Making phosphatidylserine, for cell membranes, signalling, and blood clotting
• Making sphingolipids, including key components of myelin
• Making cysteine and glycine
• Enzyme activity, as the key working part of serine proteases
• Cell signalling, as the most common phosphorylation site in proteins

Serine for Athletes and Active People

Serine itself isn’t something athletes need to think about — the body makes plenty, and protein foods provide more. The serine-related supplement marketed to athletes is phosphatidylserine.

Phosphatidylserine and cortisol: cortisol rises during hard exercise as part of the normal stress response. Some small studies using 600–800mg of PS a day found smaller cortisol and ACTH increases after intense exercise, and a few reported less muscle soreness or better mood, but other studies found no effect. There’s no clear evidence that PS improves training adaptations or performance. If you want to try it, use a product from a reputable, third-party-tested brand, and be realistic about the likely benefit.

Glycine for connective tissue: serine is the body’s main source of its own glycine, the most abundant amino acid in collagen. Eating enough protein supports this; gelatin or collagen with vitamin C before training is a separate option with emerging evidence for tendons and ligaments (see our vitamin C page).

Learning skills: learning new movement skills depends on NMDA receptor-driven changes at synapses, which need D-serine. But the brain makes its own serine and D-serine, so diet or supplements don’t influence this in healthy people.

Insulin sensitivity: the serine phosphorylation of IRS-1 described above is one way chronic overeating and inflammation impair insulin sensitivity. Regular exercise works in the opposite direction, improving insulin sensitivity — one of the best-established health benefits of training.

Serine Deficiency

Dietary serine deficiency doesn’t occur in healthy people — the body makes serine from glucose continuously.

Inherited serine deficiency disorders: rare genetic defects in the enzymes that make serine (PHGDH, PSAT1, or PSPH) leave the body, and especially the brain, short of serine despite a normal diet. They range from Neu-Laxova syndrome, a severe and usually fatal condition before or shortly after birth, to milder forms with an unusually small head, developmental delay, seizures, and stiff or weak limbs. Treatment with high-dose L-serine (sometimes with glycine), started as early as possible, can control seizures and improve development — clear evidence that the brain depends on serine, even though it’s classed as non-essential.

Deoxysphingolipid disorders: as described above, low serine or faulty serine palmitoyltransferase can produce toxic deoxysphingolipids, causing hereditary sensory and autonomic neuropathy type 1, and contributing to macular telangiectasia type 2.

L-serine and ALS: in Guam, an unusually high rate of an ALS-like disease among the Chamorro people was linked to eating cycad seeds, which contain the toxin BMAA. One hypothesis is that BMAA can be mistakenly built into proteins in place of serine, and that extra L-serine might compete with it. This idea is debated, but L-serine has been tested in people with ALS: in a 2017 safety trial, doses of up to 30g a day were well tolerated, and larger trials have followed. It’s not an established treatment.

Excessive Serine

No formal upper limit has been set for L-serine. Serine from food is safe, and doses of up to 30g a day were well tolerated in a short-term ALS safety trial, with nausea and digestive upset possible at high doses.

Phosphatidylserine: doses of 100–800mg a day are generally well tolerated; digestive upset and trouble sleeping have been reported at the higher end.

D-serine: high doses caused kidney damage in rats, so D-serine is used only in research settings, with kidney monitoring.

Types and Forms

• L-Serine (free form): the standard amino acid; used medically for inherited serine deficiency and HSAN1, and studied in ALS; not commonly used as a general supplement.
• Phosphatidylserine (PS): the serine-containing phospholipid sold for memory and stress; today’s products are made from soy or sunflower. Evidence is mixed.
• D-Serine: the mirror-image form, which activates NMDA receptors; used only in research, including trials in schizophrenia.

Which form for your goal:

How to Take Serine

Through diet: any diet with enough protein and carbohydrate — which supplies the glucose the body uses to make serine — provides plenty without any special attention.

If you try phosphatidylserine:

• Exercise studies used 600–800mg a day, usually in divided doses
• Memory studies mostly used 100–300mg a day
• Take it with a meal containing some fat
• Choose sunflower-derived PS if you avoid soy

L-serine for medical conditions: only under specialist supervision — treatment doses are far higher than anything in food.

Interactions

Vitamin B6 is needed by SHMT, which converts serine into glycine and loads folate with a single-carbon unit, and by the two enzymes that use serine to make cysteine. Folate carries the single-carbon units serine donates. Vitamin B12 is needed further along the folate cycle, to recycle homocysteine into methionine. Palmitoyl-CoA, made from fat, combines with serine to start sphingolipid production. Homocysteine, from methionine, combines with serine to make cysteine.

Synergy

• Works with folate, vitamin B12, and vitamin B6 in single-carbon metabolism — serine provides the carbon units, folate carries them, and B12 helps pass them on to make methionine.
• Works with glycine — serine is the body’s main source of glycine, and the two can be converted back and forth.
• Works with cysteine and glutamate in glutathione production, through the glycine it supplies.
• Works with palmitoyl-CoA in sphingolipid production.
• Works with homocysteine in making cysteine.
• Phosphatidylserine is interconverted with phosphatidylethanolamine and phosphatidylcholine in maintaining cell membranes.

Antagonistic Interactions

Organophosphate nerve agents and pesticides permanently block the active-site serine of acetylcholinesterase — a poisoning mechanism, not a dietary one.

Nutrient excess and inflammation drive serine phosphorylation of IRS-1, dampening insulin signalling — a regulatory effect, not a consequence of eating serine.

When serine is scarce, serine palmitoyltransferase makes toxic deoxysphingolipids from alanine or glycine instead.

The cyanobacterial toxin BMAA may be built into proteins in place of serine — a hypothesis still under debate.

Food values: USDA FoodData Central, SR Legacy — parmesan, hard (FDC ID 170848); pumpkin and squash seed kernels, dried (170556)*; cheddar, sharp, sliced (170899)*; peanuts, raw (172430)*; turkey breast, roasted (174516); pork top loin chop, broiled (167841); yellowfin tuna, cooked (172006); chicken breast, roasted (171477); ground beef, 80% lean, cooked (171797); tofu, firm, calcium-set (172475); sardines, canned in oil (175139); egg, hard-boiled (173424); almonds (170567)*; Atlantic salmon, farmed, cooked (175168); oats, dry (173904); cottage cheese, low-fat, 2% (172182)*; black beans, cooked (173735); chickpeas, cooked (173757); lentils, cooked (172421); white rice, cooked (168878). * SR Legacy values used as fill-ins for the Foundation Foods entries for pumpkin seeds (2515380), cheddar (328637), peanuts (2515376), almonds (2346393), and cottage cheese (328841), whose amino acid data aren’t included in our tracker. Serine as % of protein is calculated from the same USDA records.