The AtlasAmino acidsNonpolar, aliphatic
ProlinePro · P
The only amino acid whose side chain closes back onto its own nitrogen: a ring that bends protein chains, the residue collagen is built around once vitamin C has helped hydroxylate it, and a bond the cell turns to flip switches.
Molecule · Pro · 8 heavy atoms
Proline
C5H9NO2115.13 g/mol
The only amino acid whose side chain closes back onto its own nitrogen: a ring that bends protein chains, the residue collagen is built around once vitamin C has helped hydroxylate it, and a bond the cell turns to flip switches.
Built fromthe charted ones open their own entry
- Codes
- Pro · P
- Formula
- C5H9NO2
- Molar mass
- 115.13 g/mol
- Systematic name
- (2S)-pyrrolidine-2-carboxylic acid
- Side chain
- Three carbons bonded back to the α-amino nitrogen, closing a pyrrolidine ring; the amino group becomes a secondary amine.
- Class
- Nonpolar, aliphatic
- In the diet
- Conditionally essential
- Carbon skeleton
- Glucogenic
- pKa
- α-COOH 1.99 · α-NH3+ 10.96
- Isoelectric point
- pH 6.48
- Hydropathy
- -1.6 (Kyte–Doolittle)
- Codons
CCUCCCCCACCG- Main transporters
- SLC36A2 (PAT2), SLC6A20 (IMINO)
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 whose side chain bonds back to its own amino nitrogen, closing a five-membered ring. The body makes it from glutamate, and from arginine by way of ornithine 1.
Why it matters
Collagen, the most abundant protein in animals, is built around proline and the hydroxyproline made from it 2. Making hydroxyproline takes vitamin C, and when vitamin C runs out collagen fails: that is scurvy 3. Elsewhere, proline’s ring is what turns, kinks and ends protein structure 4,5.
Where it runs short
High ammonia that protein relieves, with signs that too little ornithine and proline are being made, marks P5CS deficiency, a block in the first step of making proline from glutamate 6.
Where it turns
Raised proline means a blocked exit: hyperprolinaemia type I (PRODH) or type II (ALDH4A1) 7. The 22q11 deletion leaves one copy of PRODH, and in one study the people with it who had the highest proline had lower IQ 8.
How high proline ran did not predict which psychiatric problems appeared, in a review of 35 studies 7.
The molecule
Proline is the only one of the standard amino acids whose side chain is bonded to its own backbone nitrogen. The ring fixes one of the two backbone angles that other residues rotate freely, and it leaves the nitrogen without a hydrogen to give to a hydrogen bond. So proline turns chains, kinks them and ends helices, and the bond before it, almost always trans for other residues, can be cis 4.
On the experimental helix scale, alanine is the most favourable residue and glycine the least favourable of the rest, about 1 kcal/mol behind; only proline is worse 5.
In collagen, three left-handed chains of the polyproline II type wind into a right-handed triple helix. Its stability rests to a large degree on stereoelectronic effects and preorganisation, much of it in the proline and hydroxyproline rings 2.
StereochemistryL-Proline is (S). The hydroxyproline in collagen is made from proline already in the chain, by 4-hydroxylation 9.
Move across the chart to read the charge at any pH.
Computed from its pKa values (α-carboxyl 1.99, α-amino 10.96) 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
Cells make proline from glutamate. P5C synthetase, a single enzyme with two activities encoded by ALDH18A1, turns glutamate into glutamate-5-semialdehyde, which closes on itself into pyrroline-5-carboxylate (P5C); P5C reductase, PYCR1 and its relatives, reduces that to proline 6,10,11.
The same P5C links proline to ornithine, and so to arginine and the urea cycle; ornithine aminotransferase sits at that junction 1,12.
On a per-gram basis, proline and hydroxyproline together are most abundant in collagen and milk protein, and the requirement for proline in whole-body protein synthesis is the highest of any amino acid. Most mammals can make it, but in newborns synthesis falls short of need 1.
Conditionally essentialMade from glutamate and arginine, but the need is the highest of any amino acid for protein synthesis, and in newborns synthesis falls short; in young pigs, the model for infant nutrition, adding proline to the diet improved growth dose by dose 1.
How much
No set intake. The body makes it, though in newborns not as fast as it is needed 1.
Where it is in food
- Collagen-rich foods (skin, gelatin, connective tissue) and milk protein are the richest sources of proline plus hydroxyproline 1.
In the bottle · fermentedMade by microbes, usually along the same route cells use, from glutamate in three enzyme steps and one ring closure; one strain engineered to make it from arginine instead reached 38.4 g/L in a 5-litre fermenter 11.
What the body does with it
Collagen is the most abundant protein in animals 2. Its hydroxyproline is never eaten into it: collagen prolyl 4-hydroxylases in the endoplasmic reticulum make it from prolines already in the chain, working as tetramers in which protein disulfide isomerase is the β subunit 9.
The chemistry has a second use. Related prolyl 4-hydroxylases in the cytoplasm regulate HIF-α, the transcription factor that runs the response to low oxygen 9. A drug that blocks them, daprodustat, raised haemoglobin in kidney disease as well as an injected erythropoiesis stimulant did 13.
Saliva carries proline-rich proteins that bind and precipitate tannins from plant food, probably a first line of defence against them, and proline plays an important part in the binding 14. In animals, eating tannins induces more of these proteins, and species whose diets carry tannins tend to make more 15.
Proline also marks places where signals act. Pin1 turns the bond before a proline only after the neighbouring serine or threonine has been phosphorylated, so a kinase’s mark becomes a change of shape 16.
In three sentences each
A ring that bends chains
Tied to its own nitrogen, proline has no backbone N–H for a hydrogen bond and less freedom to rotate. A 1991 survey of every proline in the Protein Data Bank set out its unique role in local conformation, including the cis bond that can precede it 4. On the helix scale it is set apart below even glycine 5.
Hydroxylated after the chain is made
Collagen prolyl 4-hydroxylases in the endoplasmic reticulum add a hydroxyl to prolines already in the chain, and related enzymes in the cytoplasm hydroxylate HIF-α, the switch for the low-oxygen response 9. Without vitamin C, prolyl and lysyl hydroxylases lose activity and collagen fails 3.
A bond that is turned
The bond before a proline can sit cis or trans, and enzymes turn it. Pin1 does so only once the serine or threonine before a proline is phosphorylated, which makes it a switch on folding, signalling, the cell cycle and apoptosis 16.
How it is made, moved and broken down
Breakdown runs the other way through different enzymes: proline dehydrogenase (PRODH, also called proline oxidase) oxidises proline to P5C, and P5C dehydrogenase (ALDH4A1) turns P5C into glutamate 7,8.
P5C can trap vitamin B6. A well-nourished child with hyperprolinaemia type II and fits was found to be B6-deficient, most likely because P5C had inactivated the vitamin 17.
Proline from collagen is recycled. Prolidase, encoded by PEPD, plays a major role in breaking down proline-rich proteins, splitting the small peptides that end in proline so the proline can be used again 18.
Eaten collagen is mostly digested, but some hydroxyproline survives in peptides. After gelatin hydrolysate, peptide hydroxyproline in blood peaked at 1 to 2 hours, and Pro-Hyp was the main collagen peptide 19.
Carbon skeleton · glucogenicBroken down to glutamate by proline dehydrogenase and P5C dehydrogenase, the two steps that fail in hyperprolinaemia types I and II 7,8.
- Glutamate
- P5C synthetaseALDH18A1 · ATP, NADPH
- Glutamate-5-semialdehyde
- Closes on itself
- Pyrroline-5-carboxylate (P5C)
- P5C reductasePYCR1, PYCR2 · NAD(P)H
- Proline
- Proline
- Proline dehydrogenasePRODH · FAD
- P5C
- P5C dehydrogenaseALDH4A1 · NAD⁺
- Glutamate
- Arginine
- ArginaseARG1, ARG2 · Mn²⁺
- Ornithine + urea
- Ornithine aminotransferaseOAT · vitamin B6
- P5C
- P5C reductasePYCR1, PYCR2 · NAD(P)H
- Proline
- Proline in procollagen
- Collagen prolyl 4-hydroxylaseP4HA1, P4HA2, P4HB · Fe²⁺, O₂, 2-oxoglutarate, vitamin C
- 4-Hydroxyproline in collagen
- Collagen breakdown
- Small peptides ending in proline
- ProlidasePEPD · Mn²⁺
- Free proline, reused
Where it matters most
When it goes wrong
Too little
Scurvy
A failure of proline hydroxylation, not of proline: without vitamin C, prolyl and lysyl hydroxylases lose activity, and bleeding gums, bruising, poor wound healing and leg pain follow 3. Among US children in hospital it rose from 8.2 to 26.7 per 100,000 between 2016 and 2020, and 64% had autism 21. In adults it hides behind restrictive diets, homelessness and isolation, and is mistaken for autoimmune and bleeding disorders 22.
How it is foundA question about diet first 3; then plasma vitamin C.
Inherited
Hyperprolinaemia type I
PRODH · autosomal recessive
Proline dehydrogenase activity is reduced; in eight children the disorder came with intellectual disability, epilepsy and in some psychiatric features, and residual activity of 30% or less produced it 8. Across 35 studies of hyperprolinaemia, developmental delay, intellectual disability, autism and psychosis were common 7.
How it is foundPlasma amino acids; PRODH sequencing 8.
Inherited
22q11.2 deletion syndrome
PRODH, COMT
The deletion removes one copy each of PRODH and COMT. Among 92 adolescents and adults, plasma proline correlated inversely with IQ, and those with high proline who carried the low-activity Met allele of COMT had 2.8 times the odds of psychosis 8.
How it is foundPlasma proline 8.
Inherited
Hyperprolinaemia type II
ALDH4A1 · autosomal recessive
Fits in childhood, usually set off by infection. P5C accumulates and can inactivate vitamin B6, which may be part of why the fits happen 7,17.
How it is foundPlasma amino acids; vitamin B6 status 17.
Inherited
P5CS deficiency
ALDH18A1 · autosomal recessive or dominant
The first enzyme of proline synthesis. Variants cause either a cutis laxa syndrome, with high ammonia that protein relieves, intellectual disability, short stature, cataracts and loose joints, or the spastic paraplegia SPG9; each comes in recessive and dominant forms 6.
How it is foundPlasma amino acids and ammonia; ALDH18A1 sequencing 6.
Inherited
PYCR1 cutis laxa
PYCR1 · autosomal recessive
Lax, wrinkled skin with a prematurely aged look, osteopenia and intellectual disability. The enzyme sits in mitochondria, and patients’ fibroblasts had abnormal mitochondria and died more readily under oxidative stress 10.
How it is foundGenetic testing 10.
Inherited
Prolidase deficiency
PEPD · autosomal recessive
Collagen turnover is impaired 23. Intellectual disability, recurrent infections, a large spleen, skin ulcers, autoimmunity and low blood counts 18; it can look like lupus 24. In one 18-year-old, a regimen that included oral L-proline, manganese and vitamin C healed the ulcers over six months 23.
How it is foundUrine peptides; PEPD sequencing 18.
Inherited
Iminoglycinuria
SLC36A2, SLC6A20 · semidominant
Proline, hydroxyproline and glycine are lost in the urine. Two non-working copies of SLC36A2 give iminoglycinuria and one gives hyperglycinuria alone; weaker SLC36A2 variants produce it together with variants in SLC6A20 20.
How it is foundUrine amino acids; first found on newborn screening 20.
Inherited
Ornithine aminotransferase deficiency
OAT · autosomal recessive
Usually a childhood retinal degeneration, gyrate atrophy, with high ornithine. In a few infants it first appears as high ammonia with low ornithine, citrulline and arginine, like a urea cycle disorder; in one such infant citrulline treated it 12.
How it is foundPlasma amino acids and ammonia 12.
Drug
HIF prolyl hydroxylase inhibitors
Daprodustat blocks the prolyl hydroxylases that regulate HIF. In 3,872 people with chronic kidney disease not on dialysis, taken by mouth, it was noninferior to darbepoetin alfa injections for haemoglobin and for major cardiovascular events; the manufacturer funded the trial 13.
How it is measured
Plasma proline is part of the standard amino acid panel 25. A high value points to hyperprolinaemia, inherited or from the 22q11 deletion 7,8.
Collagen turnover in bone is tracked not with proline but with fragments of type I collagen: serum PINP for formation and serum CTX for resorption, the two reference markers 26.
- Plasma prolinePart of the plasma amino acid panel 25.Raised in hyperprolinaemia types I and II 7. In type I, PRODH activity of 30% or less produced the disorder 8.The level did not predict the psychiatric picture 7.
- PINP and CTXFragments of type I collagen, released as it is made (PINP) and broken down (CTX): the reference bone turnover markers 26.They may add to bone density in predicting fracture, and the change on treatment accounts for much of a drug’s fracture benefit 26.The standard itself asked for stronger evidence before they guide individual decisions 26.
Food, supplements and the evidence
Establishedreplicated in people, for a named outcome
- The collagen failure of scurvy comes from missing vitamin C, not missing proline 3.
Uncertainsmall, short, mixed, surrogate or preclinical
- Collagen supplements for skin. Ten trials pooled found better hydration and elasticity, most often at 4 g a day 27; of 23 trials, the high-quality ones and those not funded by industry found no effect 28.
- Oral L-proline in prolidase deficiency, used within wider treatment, with case-level evidence only 23.
What is strange about it
Cyclosporin’s receptor is a proline-turning enzyme, cyclophilin, and tacrolimus binds another, FKBP. Neither drug suppresses immunity by stopping prolines turning: each drug–enzyme pair binds and blocks calcineurin, a phosphatase in T-cell signalling 29.
In P5CS deficiency, ammonia runs high and protein brings it down, a paradox that fits a shortage of ornithine, which this pathway also makes 6.
Scurvy is a disease of proline that has nothing to do with eating proline. It is the hydroxylating enzymes, starved of vitamin C, that fail 3.
Where it connects
In the Atlas
Topics on the map
On the map
A star in The rest of the amino acids, one of 6. The ring that kinks proteins. Collagen needs it hydroxylated, which takes vitamin C; scurvy is that step failing.
Sources
29 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.
- 1Wu G, Bazer FW, Burghardt RC, et al. Proline and hydroxyproline metabolism: implications for animal and human nutrition.doi:10.1007/s00726-010-0715-z · PMID 20697752
Synthesis, requirement, sources; neonatal shortfall.
- 2Shoulders MD, Raines RT. Collagen structure and stability.doi:10.1146/annurev.biochem.77.032207.120833 · PMID 19344236
The triple helix and what stabilises it.
- 3DeFrancesco CJ, Kell D, Owens S, et al. Scurvy as a cause of leg pain and limp in pediatric and adolescent patients.doi:10.1016/j.jposna.2024.100150 · PMID 40433577
Vitamin C, prolyl and lysyl hydroxylases, scurvy.
- 4MacArthur MW, Thornton JM. Influence of proline residues on protein conformation.doi:10.1016/0022-2836(91)90721-h · PMID 2010917
Every proline in the Protein Data Bank.
- 5Pace CN, Scholtz JM. A helix propensity scale based on experimental studies of peptides and proteins.doi:10.1016/s0006-3495(98)77529-0 · PMID 9649402
Helix propensity scale.
- 6Marco-Marín C, Escamilla-Honrubia JM, Llácer JL, et al. Δ1-Pyrroline-5-carboxylate synthetase deficiency: an emergent multifaceted urea cycle-related disorder.doi:10.1002/jimd.12220 · PMID 32017139
ALDH18A1: cutis laxa and SPG9.
- 7Namavar Y, Duineveld DJ, Both GIA, et al. Psychiatric phenotypes associated with hyperprolinemia: a systematic review.doi:10.1002/ajmg.b.32869 · PMID 34302426
35 studies; PRODH, ALDH4A1, 22q11.2.
- 8Raux G, Bumsel E, Hecketsweiler B, et al. Involvement of hyperprolinemia in cognitive and psychiatric features of the 22q11 deletion syndrome.doi:10.1093/hmg/ddl443 · PMID 17135275
Hyperprolinaemia type I; proline, IQ and COMT in 22q11.
- 9Myllyharju J. Prolyl 4-hydroxylases, the key enzymes of collagen biosynthesis.doi:10.1016/s0945-053x(03)00006-4 · PMID 12714038
Collagen and HIF prolyl 4-hydroxylases.
- 10Reversade B, Escande-Beillard N, Dimopoulou A, et al. Mutations in PYCR1 cause cutis laxa with progeroid features.doi:10.1038/ng.413 · PMID 19648921
PYCR1, mitochondria and cutis laxa.
- 11Long M, Xu M, Qiao Z, et al. Directed evolution of ornithine cyclodeaminase using an EvolvR-based growth-coupling strategy for efficient biosynthesis of L-proline.doi:10.1021/acssynbio.0c00198 · PMID 32551572
Microbial proline production.
- 12Kaczmarczyk A, Baker M, Diddle J, et al. A neonate with ornithine aminotransferase deficiency; insights on the hyperammonemia-associated biochemical phenotype of gyrate atrophy.doi:10.1016/j.ymgmr.2022.100857 · PMID 35782604
OAT deficiency presenting in infancy.
- 13Singh AK, Carroll K, McMurray JJV, et al. Daprodustat for the treatment of anemia in patients not undergoing dialysis.doi:10.1056/NEJMoa2113380 · PMID 34739196
ASCEND-ND; manufacturer-funded.
- 14Bennick A. Interaction of plant polyphenols with salivary proteins.doi:10.1177/154411130201300208 · PMID 12097360
Proline-rich proteins and tannins.
- 15Shimada T. Salivary proteins as a defense against dietary tannins.doi:10.1007/s10886-006-9077-0 · PMID 16770710
Tannin-binding salivary proteins across species.
- 16Fagiani F, Govoni S, Racchi M, et al. The peptidyl-prolyl isomerase Pin1 in neuronal signaling: from neurodevelopment to neurodegeneration.doi:10.1007/s12035-020-02179-8 · PMID 33083964
Phosphorylation-dependent prolyl isomerisation.
- 17Walker V, Mills GA, Peters SA, et al. Fits, pyridoxine, and hyperprolinaemia type II.doi:10.1136/adc.82.3.236 · PMID 10685929
P5C and vitamin B6.
- 18Spodenkiewicz M, Spodenkiewicz M, Cleary M, et al. Clinical genetics of prolidase deficiency: an updated review.doi:10.3390/biology9050108 · PMID 32455636
All molecularly confirmed cases reviewed.
- 19Iwai K, Hasegawa T, Taguchi Y, et al. Identification of food-derived collagen peptides in human blood after oral ingestion of gelatin hydrolysates.doi:10.1021/jf050206p · PMID 16076145
Pro-Hyp in blood.
- 20Bröer S, Bailey CG, Kowalczuk S, et al. Iminoglycinuria and hyperglycinuria are discrete human phenotypes resulting from complex mutations in proline and glycine transporters.doi:10.1172/JCI36625 · PMID 19033659
SLC36A2, SLC6A20 and iminoglycinuria.
- 21Reikersdorfer KN, Singh A, Young JD, et al. The troubling rise of scurvy: a review and national analysis of incidence, associated risk factors, and clinical manifestations.doi:10.5435/JAAOSGlobal-D-24-00162 · PMID 39018570
US paediatric inpatient incidence, 2016–2020.
- 22Rivière E, Mathé A, Blaison F, et al. Scurvy, an enduring mimicker and diagnostic dilemma in adults: a review of the 280 relevant published cases in the twenty-first century.doi:10.1016/j.clnu.2026.106601 · PMID 41759242
280 adult cases, 2000–2025.
- 23Gupta V, Yadav V, Pandey VP, et al. Challenging diagnosis: prolidase deficiency presenting as nonhealing ulcers and pancytopenia complicated by gluten enteropathy—a case report.doi:10.1186/s13256-026-05949-5 · PMID 41957649
Treatment including oral L-proline.
- 24Baysal Bakır D, Asilsoy S, Uzuner N, et al. A rare cause of immune dysregulation, prolidase deficiency: a case report and review of the literature.doi:10.1007/s12026-024-09541-1 · PMID 39294430
Lupus-like presentation.
- 25Sharer 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
Methods for amino acid analysis.
- 26Vasikaran S, Cooper C, Eastell R, et al. International Osteoporosis Foundation and International Federation of Clinical Chemistry and Laboratory Medicine position on bone marker standards in osteoporosis.doi:10.1515/CCLM.2011.602 · PMID 21605012
PINP and CTX as reference markers.
- 27Danessa G, Notario D, Regina R. Effects of collagen-based supplements on skin’s hydration and elasticity: a systematic review and meta-analysis.doi:10.25259/IJDVL_1165_2023 · PMID 40826844
Ten trials, 646 participants.
- 28Myung SK, Park Y. Effects of collagen supplements on skin aging: a systematic review and meta-analysis of randomized controlled trials.doi:10.1016/j.amjmed.2025.04.034 · PMID 40324552
23 trials; by funding and quality.
- 29Liu J, Farmer JD, Lane WS, et al. Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes.doi:10.1016/0092-8674(91)90124-h · PMID 1715244
How the immunophilin drugs work.
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