Proline

Proline is an amino acid, one of the building blocks of protein, and it is built differently from the other 19. Its side chain loops back onto its own nitrogen and closes into a ring. That makes proline the only protein amino acid that is a secondary amine.

Where it fits among the groups depends on who you ask. The WHO (World Health Organization) lists proline among the amino acids that can become indispensable under special conditions (conditionally indispensable).

The US National Academies (NASEM) put it in the same group in their classification table. That group is defined as needing a dietary source when the body cannot make enough. Yet the same report calls it dispensable in its safety chapter.

The European Food Safety Authority (EFSA) lists it as dispensable. It also names it among those that can become limiting in some conditions, such as in premature newborns. In plain terms, the body makes its own proline, and most people never need to think about getting it.

Beyond building protein, the body makes proline from glutamate and from ornithine. It uses proline most of all for collagen. A 2024 review calls collagen the most abundant core protein of the extracellular matrix, the scaffold between cells. Per gram, proline plus hydroxyproline are most abundant in collagen and milk proteins, according to a 2011 review.

After proline is built into collagen, an enzyme adds an oxygen-containing hydroxyl group to many of the prolines. That turns them into hydroxyproline, and this step needs vitamin C.

Here is what most readers do not know. The same hydroxylation step is how cells sense oxygen. Enzymes that hydroxylate proline in a protein called HIF decide how long it lasts. The work that uncovered this won the 2019 Nobel Prize in Physiology or Medicine.

Also, the trials behind “proline for skin and joints” test collagen peptides, which are mixtures. We found no randomized trial of proline pills in healthy people, so the trials below credit their results to collagen, never to proline alone.

Health benefits of proline

• ★★Better skin hydration with collagen supplementsHydrolyzed collagen, a mix of amino acids and peptides, raised skin hydration in a review of 26 trials. In 19 trials, 90 days of it also improved elasticity and wrinkles, though the trials had several biases.
• ★★Mixed results for knee pain with collagenIn 4 trials of 507 people with knee osteoarthritis, collagen peptides eased pain more than placebo, though all were at high risk of bias. In 167 active adults with knee pain, 10 g a day did no better than placebo.
• ★★Higher bone density with collagen peptidesA review of trials found higher bone density at the hip and spine, though results differed widely between trials. In women after menopause, 5 g a day for 12 months raised spine and femoral neck bone density.
• ★More lean mass gained with training and collagenIn 53 older men with muscle loss doing resistance training, 15 g of collagen peptides a day raised fat-free mass by 4.2 kg. Placebo raised it by 2.9 kg.
• ★Proline may slow a rare inherited eye diseaseOral proline was tried in four patients with gyrate atrophy, a rare inherited eye disease. Damage was minimized in the youngest and halted in two others, but there was no control group.

Foods high in proline

Soybeans lead our USDA ranking per serving with 1.68 g of proline per cup. A chicken drumstick (1.03 g), ground beef (0.99 g in 4 oz) and shrimp (0.89 g in 3 oz) follow.

Per 100 g, spelt comes first with 1.63 g, then hemp seeds (1.6 g), barley (1.48 g) and pumpkin seeds (1.32 g). Per 100 kcal, shrimp leads (0.88 g), then cod (0.77 g), tuna (0.76 g) and chives (0.72 g), and kale gives 0.5 g. The ranking below shows the full lists.

Proline is in every protein, so enough protein means enough proline. Cereal proteins are called prolamins for their high proline and glutamine content. That fits spelt and barley near the top of the per-100 g list.

Collagen and milk proteins are the richest. Per gram, proline plus hydroxyproline is highest in them, according to a 2011 review. A 2019 trial of collagen hydrolysate describes collagen as high in glycine, proline and hydroxyproline. Protein quality scores are built from the indispensable amino acids, so they say nothing about proline.

How much does a serving give? The National Academies report a mean intake of 5.2 g of proline a day from food and supplements. That is from US survey data for 1988 to 1994, across life stages and genders. The highest median was 7.2 g, in men aged 19 to 30.

By our arithmetic, 1 cup of soybeans (1.68 g) gives about a third of the 5.2 g mean. A chicken drumstick (1.03 g) gives about a fifth.

How proline works

Most of what follows comes from reviews, chemistry, cell work and animal studies, and human trials of proline itself are few.

The main ideas: the body makes proline from glutamate and ornithine, and it crosses the gut on shared carriers. Its ring shapes collagen, vitamin C and oxygen add a hydroxyl group to it inside collagen, and it is broken down back to glutamic acid. Collagen peptides add one more idea, because what you swallow is not what reaches the blood. Here is each one, and what has been seen in people.

The body makes it from glutamate and ornithine

The National Academies’ table lists glutamate as the precursor of proline. According to a 2008 review, the gut makes proline as an end product of glutamine breakdown, through an enzyme called P5C synthase. Proline can also be made from ornithine, though the share of the two routes is not certain.

A 2011 review adds that most mammals, including humans, can make proline from arginine and glutamine or glutamate. But the rate is not enough for newborns, birds and fish. In young pigs fed a proline-free diet, growth improved step by step as proline was added. In seven premature babies fed through a vein, the tracer study on the cards above found almost no proline made from glucose.

The 2008 review also says that raising blood proline makes the body burn more of it and make less. A low-proline diet, or high rates of proline breakdown in burn patients, does not make it produce more.

It crosses the gut on shared carriers

Proline and glycine share carriers. A 2006 review names two transporters, PAT1 (SLC36A1) and the IMINO transporter (SLC6A20). It says they appear to play key roles in taking up glycine and proline, and uses them to explain an inherited disorder called iminoglycinuria.

In rat intestine, proline uptake went mainly through a sodium-dependent system B and a proton-driven PAT1-like carrier. Collagen eaten as hydrolysate takes another route, as short peptides. Hydroxyproline-containing peptides, mostly Pro-Hyp, show up in human blood after the dose.

Its ring shapes protein, most of all collagen

Proline is the only protein amino acid that is a secondary amine: its side chain connects back to the nitrogen and forms a five-membered ring. The ring lets its peptide bonds sit in both the cis and the trans form. Runs of proline and hydroxyproline form the polyproline helix that is the main structure of collagen.

Per gram, proline plus hydroxyproline are most abundant in collagen and milk proteins. A 2024 review calls collagens the most abundant core proteins of the extracellular matrix, made mainly by fibroblasts (connective tissue cells). A 2011 review adds that the need for proline in whole-body protein synthesis is the greatest of all amino acids.

Vitamin C and oxygen finish the job

After proline is built into collagen, the enzyme prolyl 4-hydroxylase adds a hydroxyl group to many of the prolines and makes hydroxyproline. A 2010 review calls this the most common modification of proteins in humans, best known for stabilizing the collagen triple helix.

Vitamin C is a cofactor: a 1985 review calls ascorbic acid essential for prolyl hydroxylase. In a guinea pig model of scurvy, adding ascorbate reversed defective proline hydroxylation. It did not reverse the drop in collagen production, which the authors tied to weight loss.

Oxygen matters too. Prolyl hydroxylases act as oxygen sensors for the protein HIF, and a 2026 review says low oxygen raises production of the collagen hydroxylases through HIF. William Kaelin, Peter Ratcliffe and Gregg Semenza shared the 2019 Nobel Prize in Physiology or Medicine for discovering how cells sense and adapt to oxygen.

It returns to glutamic acid

The National Academies describe proline as formed from and converted to glutamic acid. Its level in body fluids depends mainly on two enzymes: proline dehydrogenase (also called proline oxidase) and P5C reductase. P5C is the pivot between them. Inherited defects show what happens when they fail.

Type I hyperprolinemia is a proline dehydrogenase deficiency, caused by the PRODH gene on chromosome 22q11.2. That region is deleted in velo-cardio-facial syndrome and linked to schizophrenia susceptibility. Type II is a P5C dehydrogenase deficiency.

A P5C synthetase deficiency gives low proline with high ammonia, and prolidase deficiency causes severe skin ulcers. High hydroxyproline (hyperhydroxyprolinemia) is believed to be a benign disorder with no symptoms.

Collagen peptides: what reaches the blood

Eating collagen or gelatin does not just deliver proline. Healthy volunteers ate 9.4 to 23 g of gelatin hydrolysate. The peptide form of hydroxyproline in their blood peaked at 20 to 60 nmol/mL after 1 to 2 hours. Pro-Hyp was the main peptide.

In four volunteers, peak levels of hydroxyproline-containing peptides rose with the dose, from 6.43 to 20.17 to 32.84 nmol/mL across three doses. The absorption limit was not reached at the highest one.

Cell studies cited in a 2016 trial report found that Pro-Hyp and Hyp-Gly attract skin fibroblasts, and that Pro-Hyp raises hyaluronic acid production. Whether that explains skin results in people is not shown.

In one trial, 15 g of vitamin C-enriched hydrolyzed collagen before leg exercise restored a blood marker of collagen synthesis in middle-aged men. A 30 g dose raised it further. A 2017 review warns that biochemical and physiologic barriers limit what swallowed amino acids can do for wound healing.

What has been seen in people

The human evidence is about collagen, not proline. Meta-analyses favor collagen peptides for skin hydration and for knee osteoarthritis pain, though the trials are small and at high risk of bias. Single trials in people with knee pain and in menopausal women found no change in pain or bone markers.

Vitamin C-enriched gelatin and collagen raised a blood marker of collagen synthesis in two small crossover trials. For proline itself there is one 1985 report in an eye disease. All of these are among the study cards above and in the forms section below.

How much proline do you need?

No daily amount of proline is set, because the body makes it. The WHO table of adult amino acid requirements covers the nine indispensable amino acids only. So do the National Academies’ estimated average requirements and recommended allowances. The site has no Daily Value for proline, because neither the FDA nor the EU has set one.

What people actually eat is on record. In US survey data from 1988 to 1994, mean proline intake from food and supplements was 5.2 g a day across life stages and genders. The highest median was 7.2 g in men aged 19 to 30. The highest 99th percentile was 12.0 g in boys aged 14 to 18, according to the National Academies.

We found no values for children, pregnancy or breastfeeding, because no requirement exists for proline.

Why is proline in the “conditional” group at all? EFSA says the conditionally indispensable amino acids, a list that includes proline, can become limiting in premature neonates. That happens when the body cannot meet the need unless the diet supplies them. A 2011 review adds that the rate of proline synthesis is not enough for newborns.

Proline deficiency: signs and who is at risk

We found no report of proline deficiency from diet alone in healthy people, and no sign or test that doctors use for it. Sources flag premature infants, where a tracer study found almost no proline made from glucose in seven babies on intravenous feeding. They also flag burn patients. In them, a low-proline diet or high rates of proline breakdown do not make the body produce more, according to a 2008 review.

Rare inherited disorders change proline in the body. Type I and type II hyperprolinemia raise it, and a P5C synthetase deficiency lowers it and comes with high ammonia. Prolidase deficiency is a disorder of breaking down peptides that end in proline or hydroxyproline. It causes intellectual disability and severe skin ulcers.

Gyrate atrophy of the retina is an inherited eye disease in which proline was tried as a treatment.

Forms of proline: absorption and effects

Proline reaches people in four main ways. It comes bound in food protein, as free L-proline in capsules or powder, as collagen peptides or gelatin, and as related compounds. Unlike minerals, there is no list of forms with known absorption rates.

We found no human study comparing free L-proline with proline from food protein, and none comparing free proline with collagen peptides. The only oral free-proline study we found used 2 to 10 g a day in four patients with an eye disease.

The honest bottom line: for proline itself, the form is not the question, because no trial shows that extra proline helps healthy people. Nearly all the useful human work is on collagen peptides, which deliver proline together with glycine and hydroxyproline. The single trials in the benefits section above used collagen at 5 to 15 g a day.

The studies below compare products or show what reaches the blood. We found no trial that compared collagen with the same amount of free proline. Nor did we find a trial that tested free proline for skin, joints or wound healing.

Form	What it is	What studies show	Source
Free L-proline (capsules, powder)	The single amino acid, not bound in protein	The only oral proline study we found gave 2 to 10 g a day (usually 3 g) to four patients with gyrate atrophy for up to 5 years, according to the National Academies; a review reports 488 mg per kg a day with no deleterious side effects. We found no trial in healthy people, none for skin, joints or wound healing, and none comparing it with food or collagen. A 2017 review describes biochemical barriers that limit amino acid supplements for wound healing.	1, 2, 3, 11
Collagen peptides (hydrolyzed collagen)	Collagen broken into short peptides; a mix rich in glycine, proline and hydroxyproline	The single trials above used 5 to 15 g a day. After a dose, Pro-Hyp is the main peptide in blood. Peak levels rose with dose in four volunteers. Enzymatic hydrolysis raised the absorption rate and bioavailability of glycine, proline and hydroxyproline in ten men, and a hydrolysate with more Pro-Hyp and Hyp-Gly improved facial skin more than one with less.	5, 6, 7, 8
Gelatin or collagen with added vitamin C	Collagen-derived protein taken with vitamin C before exercise	15 g of vitamin C-enriched gelatin an hour before exercise doubled a blood marker of collagen synthesis in eight men. In another eight, 15 g of vitamin C-enriched hydrolyzed collagen restored the marker and 30 g raised it further. Neither study had a collagen arm without vitamin C, so the two effects cannot be separated.	9, 10
Proline in food protein	Bound in protein; richest per gram in collagen and milk proteins	Provides a mean of 5.2 g a day in US survey data. We found no study comparing absorption of food-bound and free proline.	1, 4
Hydroxyproline	Proline with a hydroxyl group, made after proline is built into collagen	Not an amino acid used to build protein; it forms inside collagen when an enzyme modifies proline. Inherited high hydroxyproline (hyperhydroxyprolinemia) is believed to be benign. We found no trial of hydroxyproline supplements for health.	1, 12, 13
Proline betaine	A proline derivative found in citrus fruit	Used as a urinary marker of citrus intake: in the validation data it identified citrus consumers with 86.3% sensitivity and 90.6% specificity. It is not sold as a supplement for health, and we found no trial.	14

Here are the studies that compare products or show what reaches the blood, five in all.

Is proline safe? Supplements, dose and interactions

Proline from food is not a concern for most people. The National Academies set no tolerable upper intake level (the most you can take each day without likely harm) for proline. They found minimal data on adverse effects in animals or humans, and the data were not available for a dose-response assessment.

The only long-term human study they found gave 2 to 10 g a day (most often 3 g) to four patients with gyrate atrophy. It lasted up to 5 years. No overt adverse effects were reported, though it was unclear which effects were studied.

A 2008 review reports 488 mg per kg a day in that disease with no deleterious side effects. It says that, without controlled trials, a safe upper limit cannot be estimated.

The 2012 EFSA protein opinion did not set an upper level for protein either, and we found no EFSA upper level for proline.

• Collagen products. Trials gave 5 to 15 g a day for 12 weeks to 12 months. In a meta-analysis of knee osteoarthritis trials, side effects did not clearly differ from placebo (1.66 times the odds). But the evidence was very low quality. The Cochrane pressure ulcer review calls the evidence on side effects of collagen supplements very uncertain.
• Inherited metabolic disorders. People with hyperprolinemia type I or II, a P5C synthetase deficiency or prolidase deficiency handle proline differently. They should check with their metabolic team before taking any proline or collagen supplement. We found no trial of supplements in these disorders. Studies in hyperprolinemia found psychiatric problems but no link between the proline level and the specific picture.
• Observational signals. In a Tehran cohort, the top third of proline intake had higher odds of new high blood pressure (1.45 times the odds). In a study of three cohorts, high proline intake was the dietary factor most linked to depression, and mice given proline showed worse depression-like behavior. These are associations. They do not show that proline in food or pills causes either condition.
• Drug interactions. We found no reported interaction between proline or collagen supplements and medicines.
• Who should ask a doctor. Anyone who is pregnant or breastfeeding, has kidney or liver disease, or has an inherited metabolic disorder. We found no trial of proline supplements in pregnancy or in kidney or liver disease.

How to get more proline

• Best food. One cup of soybeans gives 1.68 g of proline, a chicken drumstick 1.03 g and 4 oz of ground beef 0.99 g. Per 100 g, spelt leads with 1.63 g, then hemp seeds (1.6 g) and barley (1.48 g).
• Eat enough protein from varied foods. Average intake is 5.2 g a day in US data. Collagen and milk proteins are the richest sources per gram.
• Skip single proline pills. No trial shows a benefit of proline pills for healthy people. If you try collagen, the trials used 5 to 15 g a day, with mixed results, and the benefit is not credited to proline.

History of proline

Proline was found at the turn of the 20th century. Reference works credit Richard Willstätter with making it in 1900 while working on N-methylproline. They credit Emil Fischer with isolating it from casein, the milk protein, in 1901.

A history of proteins says Fischer’s laboratory first isolated proline, along with valine, in 1901. The name comes from pyrrolidine, the ring in its structure.

Hydroxyproline was also first found by Fischer, in the breakdown products of casein and of gelatin, according to a 1914 textbook of physiological chemistry. The textbook adds that Leuchs and Brewster later worked out its structure.

A century later the same chemistry turned up in cell biology. Prolyl hydroxylases were found to be how cells sense oxygen, by marking the HIF protein. In 2019 William Kaelin, Peter Ratcliffe and Gregg Semenza shared the Nobel Prize in Physiology or Medicine. It was for discovering how cells sense and adapt to oxygen.

As a nutrient, proline has had a quieter life. The one report of proline pills as a treatment that we found is from 1985, in gyrate atrophy. The collagen trials of recent years test a mixture, not proline.

Frequently asked questions about proline

Is proline an essential amino acid?

No. Proline is not one of the nine essential amino acids, because the body makes it from glutamate and ornithine. The WHO and the US National Academies put it in the conditionally indispensable group. That means the body may not make enough in some situations, such as premature birth or severe illness. EFSA lists it as dispensable and also names it among those that can become limiting. Healthy adults who eat enough protein get enough, and average intake in US survey data is 5.2 g a day.

What does proline do in the body?

Proline builds proteins, and it is most important in collagen, the main protein of connective tissue. Its ring shape helps form the collagen helix. An enzyme that needs vitamin C then adds a hydroxyl group to many of the prolines to make hydroxyproline. The same type of enzyme lets cells sense oxygen. Proline is broken down back to glutamic acid.

How much proline do you need per day?

There is no official amount. The WHO and the National Academies set requirements for the nine indispensable amino acids only. Neither the FDA nor the EU has a daily value for proline. In US survey data the mean intake was 5.2 g a day, with a highest median of 7.2 g in men aged 19 to 30. The one long-term study of proline pills used 2 to 10 g a day in four patients with an eye disease.

Which foods are highest in proline?

Soybeans lead our USDA ranking per serving, with 1.68 g per cup. A chicken drumstick (1.03 g), ground beef (0.99 g in 4 oz) and shrimp (0.89 g in 3 oz) follow. Per 100 g, spelt leads with 1.63 g, then hemp seeds (1.6 g) and barley (1.48 g). Per 100 kcal, shrimp (0.88 g), cod (0.77 g) and tuna (0.76 g) lead. Collagen and milk proteins are the richest per gram, according to a 2011 review.

Do proline or collagen supplements help skin and joints?

Not proline by itself: we found no trial of proline pills for skin or joints. Collagen peptides do better. Meta-analyses of 19 and 26 trials found better skin hydration than placebo. A meta-analysis of four trials found less knee osteoarthritis pain, but the trials are small and at high risk of bias. A 167-person trial of 10 g a day found no effect on knee pain. Collagen is a mixture of amino acids, so the result is not credited to proline.

Does vitamin C help your body use proline?

Vitamin C acts after proline is already built into collagen. According to reviews, it is a cofactor for the enzyme that turns proline inside collagen into hydroxyproline. In guinea pigs with scurvy, adding vitamin C reversed defective proline hydroxylation. Two small trials gave vitamin C-enriched gelatin or collagen and raised a marker of collagen synthesis, but neither had a collagen arm without vitamin C.

Is proline safe to take as a supplement?

Proline from food is safe for most people, and the National Academies set no upper limit because data are lacking. Four patients took 2 to 10 g a day for up to 5 years with no overt adverse effects reported. But nobody has tested it in healthy people. People with inherited proline disorders should ask a doctor first. High proline intake has been linked to high blood pressure and depression in observational studies, which does not show cause.

What is the difference between proline and hydroxyproline?

Hydroxyproline is proline with a hydroxyl group added. It is not used to build proteins directly. An enzyme makes it inside collagen after proline is already in the chain, and this step needs vitamin C and oxygen. It stabilizes the collagen helix. Hydroxyproline-containing peptides such as Pro-Hyp appear in blood after you eat collagen or gelatin.