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: hyperprolinemia 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 favorable residue and glycine the least favorable 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 preorganization, much of it in the proline and hydroxyproline rings 2.
Proline is also hard for a ribosome to thread, which is a structural fact with its own machinery. Proteomic screening in Streptococcus pyogenes found 30 previously uncharacterized RNA-binding proteins, one of them the widely conserved YebC, which transiently contacts 23S rRNA near the peptidyl-transferase center. Without it, ribosome profiling shows increased pausing at proline-rich motifs, and work in two bacteria and an in vitro system makes YebC a translation factor needed for the efficient synthesis of proline-rich proteins 9. The residue that kinks a finished chain slows the machine that makes it, and cells keep dedicated factors to get past that.
StereochemistryL-Proline is (S). The hydroxyproline in collagen is made from proline already in the chain, by 4-hydroxylation 10.
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 6,11,12.
The same P5C links proline to ornithine, and so to arginine and the urea cycle; ornithine aminotransferase sits at that junction 1,13.
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-liter fermenter 12.
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 10.
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 10. A drug that blocks them, daprodustat, raised hemoglobin in kidney disease as well as an injected erythropoiesis stimulant did 14. Which proline matters has since been revised. PHD2 hydroxylates one or both conserved prolines in HIFα's oxygen-dependent degradation domain, and the C-terminal event was taken to be the predominant and sufficient one, leaving the N-terminal proline's significance unclear. Examining seven disease-associated PHD2 mutations that cause erythrocytosis by time-resolved NMR, all seven had a structural or catalytic defect — and one, P317R, hydroxylated the C-terminal proline about as well as the wild-type enzyme while being uniquely unable to hydroxylate the N-terminal one 15. A human mutation that causes disease by failing at the step thought to be dispensable is an argument that it is not. The drug built on this chemistry has meanwhile been moved down the guidelines 16.
Saliva carries proline-rich proteins that bind and precipitate tannins from plant food, probably a first line of defense against them, and proline plays an important part in the binding 17. In animals, eating tannins induces more of these proteins, and species whose diets carry tannins tend to make more 18.
Proline also marks places where signals act. Pin1 turns the bond before a proline only after the neighboring serine or threonine has been phosphorylated, so a kinase’s mark becomes a change of shape 19.
Free proline has a second job that is not about structure at all. Proline metabolism is increased during hepatocellular carcinoma metastasis, with higher proline and higher proline-metabolism enzymes in metastatic patients and mice, and high proline promoting metastasis. The mechanism is direct binding: L-proline binds glutamyl-prolyl-tRNA synthetase 1, selectively enhancing translation of PIK3CA, AKT3 and ITGB1. Bersiporocin, an EPRS1 inhibitor that prevents proline from binding, abolished the enhanced translation and suppressed metastasis in patient-derived orthotopic xenografts 20. An amino acid acting as a ligand that retunes which messages a cell reads is a different kind of role from the one the rest of this page describes.
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 10. 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, signaling, the cell cycle and apoptosis 19.
How it is made, moved and broken down
Breakdown runs the other way through different enzymes: proline dehydrogenase (PRODH, also called proline oxidase) oxidizes proline to P5C, and P5C dehydrogenase (ALDH4A1) turns P5C into glutamate 7,8.
P5C can trap vitamin B6. A well-nourished child with hyperprolinemia type II and fits was found to be B6-deficient, most likely because P5C had inactivated the vitamin 21.
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 22.
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 23.
There is a route out of hydroxyproline this page did not carry, and it ends in kidney stones. Hydroxyproline dehydrogenase — HYPDH, encoded by PRODH2, which is why a second proline dehydrogenase exists at all — takes the first step in the liver's production of glyoxylate and then oxalate from hydroxyproline. In mice lacking GRHPR, a model of primary hyperoxaluria type 2 whose median survival is 15 weeks, an oral small-molecule HYPDH inhibitor, N-propargylglycine, cut hyperoxaluria and weight loss within three weeks and, over 24 weeks, restored weight and survival to that of wild-type controls while preventing stones, tubule injury and loss of kidney function 24. How much oxalate a hydroxyproline load becomes depends on the liver doing the conversion: a high-fat diet raised urinary oxalate about 20% in mice and RAISED the glyoxylate-detoxifying enzymes, while a Western diet producing steatohepatitis lowered those enzymes and raised oxalate 47% — and only the Western-diet mice excreted significantly more oxalate after a hydroxyproline challenge 25. Both are mouse studies, and both are the reason to be interested in what a daily spoonful of gelatin meets on arrival.
The synthesis enzyme has become a drug target too, far from the disease that named it. PYCR1 — known to this page only through cutis laxa — is reported upregulated in hepatocellular, lung, breast, bladder and gastric cancer, where it promotes proliferation, migration and therapy resistance and tracks advanced stage and poor prognosis, and PYCR1-driven proline metabolism has been linked to pulmonary, myocardial and cutaneous fibrosis. Small-molecule inhibitors have shown potential preclinically, and the review says plainly that clinical translation is yet to be validated 26.
Carbon skeleton · glucogenicBroken down to glutamate by proline dehydrogenase and P5C dehydrogenase, the two steps that fail in hyperprolinemia 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
- Skin, tendon, bone
- Collagen, built around proline and hydroxyproline 2.
- Salivary glands
- Proline-rich proteins that bind dietary tannins 17.
- Kidney
- Reabsorbs proline, hydroxyproline and glycine through SLC36A2 and SLC6A20 27.
- Milk
- With collagen, the richest source of proline plus hydroxyproline 1.
- Liver
- Converts hydroxyproline to glyoxylate and then oxalate through HYPDH/PRODH2, at a rate that depends on how fatty the liver is 24,25.
- Heart
- In diabetic HFpEF mice and patients, circulating proline is raised, and giving proline worsened fibrosis and drove ferroptosis in cardiac fibroblasts 28.
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 29. In adults it hides behind restrictive diets, homelessness and isolation, and is mistaken for autoimmune and bleeding disorders 30. A 2026 systematic review pools what that looks like: across 25 studies and 147 patients with confirmed scurvy in high-income countries between 2012 and 2025, patients presented with a mean of 2.29 affected organ systems (95% CI 1.62 to 2.96), musculoskeletal involvement was the commonest domain and neurological manifestations were significantly less common (OR 0.42, 95% CI 0.28 to 0.62), with cases clustering in children with neurodevelopmental disorders, restrictive diets, medical complexity and psychosocial vulnerability — and with the authors noting that concomitant micronutrient deficiencies cannot be excluded 31.
How it is foundA question about diet first 3; then plasma vitamin C.
Inherited
Hyperprolinemia 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 hyperprolinemia, 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
Hyperprolinemia 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 7,21.
How it is foundPlasma amino acids; vitamin B6 status 21.
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 11.
How it is foundGenetic testing 11.
Inherited
Prolidase deficiency
PEPD · autosomal recessive
Collagen turnover is impaired 32. Intellectual disability, recurrent infections, a large spleen, skin ulcers, autoimmunity and low blood counts 22; it can look like lupus 33. In one 18-year-old, a regimen that included oral L-proline, manganese and vitamin C healed the ulcers over six months 32. The eye belongs on that list. The first detailed multimodal imaging of corneal involvement, in a 21-year-old man homozygous for a PEPD frameshift, found bilateral asymmetric corneal disease: diffuse opacification, epithelial and subepithelial fibrosis, anterior stromal haze, limbal neovascularization, bilaterally reduced corneal sensitivity, a fragmented subbasal nerve plexus, fine stromal deposits consistent with imidodipeptide accumulation and significantly reduced keratocyte density, with vision counting fingers at one meter in the worse eye. The authors attribute it to impaired collagen homeostasis plus chronic immune-mediated inflammation, and recommend systematic ophthalmologic surveillance for everyone with the diagnosis 34.
How it is foundUrine peptides; PEPD sequencing 22.
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 27. SLC6A20 has since become something stranger: a transporter that neurologists want to switch OFF. An antisense oligonucleotide against mouse Slc6a20a normalized autism-related phenotypes in Shank2- and Shank3-mutant male mice with model-dependent rescue, and restored NMDA receptor function and synaptic phospho-proteomic profiles in prefrontal cortex; an ASO against human SLC6A20 rescued suppressed NMDA receptor function in cortical organoids carrying SHANK2 or SHANK3 mutations. The authors present the work as showing both the potential and the limitations of the approach 35. The gene that loses proline in urine when it fails is being deliberately silenced in brain, for a different disease.
How it is foundUrine amino acids; first found on newborn screening 27.
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 13.
How it is foundPlasma amino acids and ammonia 13.
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 hemoglobin and for major cardiovascular events; the manufacturer funded the trial 14. The class has since been placed behind the injections. The 2026 KDIGO anemia guideline — the first substantial update in more than a decade — recommends erythropoiesis-stimulating agents as the preferred first-line therapy, and the European Renal Best Practice commentary gives the reason as persisting concerns about cardiovascular safety and methodological limitations of the available trials, while noting that European and US regulators have not approved the same drugs 16. The whole-class numbers behind that read as a split decision. Across 46 randomized trials and 32,305 patients, roxadustat produced the largest hemoglobin rise in both non-dialysis and dialysis disease (1.21 and 1.78 g/dL) — and ranked LAST on safety, while erythropoiesis-stimulating agents had the lowest composite adverse-event risk in non-dialysis disease (OR 0.85, 95% CI 0.74 to 0.98) 36. Against that, 36 trials and 27,680 participants show the class does something patients feel: fewer red cell transfusions of any kind (RR 0.74) and fewer rescue transfusions (RR 0.70), without significantly raising major cardiovascular events, all-cause mortality or serious adverse events — though the iron-sparing claim did not reach significance (RR 0.66, 95% CI 0.38 to 1.14) and there is a hyperkalemia signal in non-dialysis patients 37. Biggest hemoglobin gain is not the same as best drug, and a guideline demotion is not the same as a drug that does nothing.
How it is measured
Plasma proline is part of the standard amino acid panel 38. A high value points to hyperprolinemia, 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 39.
One proposed way of choosing who should get a prolyl hydroxylase inhibitor has been tested and failed. In a post hoc analysis of the drug's own two phase 3 trials, baseline hepcidin — available for 3,807 non-dialysis and 2,881 dialysis patients — had a non-linear relationship with major adverse cardiovascular events in non-dialysis chronic kidney disease (the second quartile lowest, the fourth highest; p for non-linearity 0.032) and no relationship at all in dialysis patients. Changes in hepcidin over time were not independently associated with risk, and baseline hepcidin did not modify daprodustat's treatment effect in either trial, which the authors read as limited usefulness for guiding treatment choice 40.
- Plasma prolinePart of the plasma amino acid panel 38.Raised in hyperprolinemia 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 39.They may add to bone density in predicting fracture, and the change on treatment accounts for much of a drug’s fracture benefit 39.The standard itself asked for stronger evidence before they guide individual decisions 39.
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 41; of 23 trials, the high-quality ones and those not funded by industry found no effect 42. A 2026 meta-analysis puts a number on the part that survives pooling: across 19 randomized trials and 1,341 participants, peptides improved hydration and brightness, with a pooled wrinkle effect of MD 0.27 (p = 0.04) that subgroup analysis attributed largely to oral polypeptides (MD 1.5, p = 0.01), while elasticity and density were inconsistent and tolerability was good 43. A 2026 dermatology review reaches the same place from the other direction: benefits are most consistent for low-molecular-weight hydroxyproline-rich peptides, and peptide characteristics matter more than which animal the collagen came from — but short durations, heterogeneous designs, multi-ingredient formulations and industry funding reduce confidence in both the size and the consistency of the effects, and independently funded long-term trials with standardized outcomes are still needed 44.
- Oral L-proline in prolidase deficiency, used within wider treatment, with case-level evidence only 32.
- Collagen peptides for bone and muscle, which is the second front of the marketing. A 2025 meta-analysis reports higher bone mineral density at the femoral neck and spine, improved bone turnover markers (SMD 0.40 to 0.58) and improved muscle performance (SMD 0.60, 95% CI 0.05 to 1.15), with more effect alongside vitamin D and calcium 45. Two things to note before quoting it: the heterogeneity across the bone density results is 80.1%, and the abstract never states how many trials were pooled.
- Collagen peptides for weight and metabolic health, where the only pooled evidence is in animals. Nineteen trials in 339 rodents on high-fat or high-calorie diets gave large reductions in body mass (SMD −1.87), food intake, glucose measures, adipose content, LDL and triacylglycerol, with higher HDL and adiponectin — at a moderate-to-high risk of bias and VERY LOW certainty for every single parameter, and with the authors stating that the effects in humans remain largely unexplored 46. The powders are already sold for this.
Sold asthe claim on the label, against the evidence
- “Collagen goes to your skin.” Collagen is digested; what reaches the blood intact is small peptides, mainly Pro-Hyp 23, and the high-quality and independent trials found no benefit to skin 42. When the trials are pooled, the surviving wrinkle effect is MD 0.27 43, and the review that most favors the supplements says the confidence in that magnitude is reduced by industry funding among other things 44.
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 signaling 47.
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.
Blocking the enzyme that puts a hydroxyl on a proline is now a doping method, policed to picograms. Because HIF-activating agents turn on transcription of the erythropoietin gene and so raise an athlete's red cells, they are prohibited in sport, and a 2026 method detects and confirms eleven of them — daprodustat among them — in equine plasma and urine, with limits of detection of 10 to 50 pg/mL in plasma, validated on samples from a horse dosed orally 48. A kidney drug and a banned substance are the same molecule read by different institutions.
There is a current clinical use of free L-proline, and it looks nothing like a supplement. Semen from 30 men with asthenozoospermia was frozen with or without L-proline in the medium: at 2 mM, post-thaw progressive motility, viability and chromatin integrity were all higher than in unsupplemented medium, with lower malondialdehyde and nitric oxide and higher total antioxidant capacity, while 4 mM was LESS effective than 2 mM 49. Millimolar concentrations, in a dish, for a few minutes, with a dose that stops helping if you raise it.
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
49 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 stabilizes 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
Hyperprolinemia type I; proline, IQ and COMT in 22q11.
- 9Ignatov D, Shanmuganathan V, Ahmed-Begrich R, et al. RNA-binding protein YebC enhances translation of proline-rich amino acid stretches in bacteria.doi:10.1038/s41467-025-60687-4 · PMID 40624002
Ribosome profiling showing where the ribosome stalls, and the conserved factor that stops it.
- 10Myllyharju 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.
- 11Reversade 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.
- 12Long 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.
- 13Kaczmarczyk 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.
- 14Singh 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.
- 15Taber CC, He W, Gasmi-Seabrook GMC, et al. Erythrocytosis-inducing PHD2 mutations implicate biological role for N-terminal prolyl-hydroxylation in HIF1α oxygen-dependent degradation domain.doi:10.7554/eLife.107121 · PMID 41114716
Seven human disease mutations, time-resolved NMR, and one mutant that separates the two prolines.
- 16Del Vecchio L, Cases A, Eisenga MF, et al. KDIGO 2026 clinical practice guideline for anemia in chronic kidney disease (CKD): a commentary from the European Renal Best Practice (ERBP).doi:10.1093/ndt/gfag014 · PMID 41604211
The first substantial KDIGO anemia update in more than a decade, read by European nephrologists. The reason given for the demotion is stated in one clause.
- 17Bennick A. Interaction of plant polyphenols with salivary proteins.doi:10.1177/154411130201300208 · PMID 12097360
Proline-rich proteins and tannins.
- 18Shimada T. Salivary proteins as a defense against dietary tannins.doi:10.1007/s10886-006-9077-0 · PMID 16770710
Tannin-binding salivary proteins across species.
- 19Fagiani 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 isomerization.
- 20Zhang H, Gu L, Su X, et al. Dysregulated proline metabolism exacerbates hepatocellular carcinoma metastasis via EPRS1-mediated mRNA translation.doi:10.34133/cancomm.0028 · PMID 42147354
Free proline binding a synthetase and changing which messages get translated, with an inhibitor built on that binding site.
- 21Walker 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.
- 22Spodenkiewicz 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.
- 23Iwai 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.
- 24Hady M, Tadeo A, Stoyanova D, et al. N-propargylglycine restores survival by preventing calcium oxalate stone formation, tubular injury, and kidney dysfunction in a lethal mouse model of primary hyperoxaluria type 2.doi:10.1016/j.kint.2026.02.024 · PMID 41866121
An oral inhibitor of the second proline dehydrogenase, and a survival curve returned to wild type. Mice.
- 25Li X, Cunneely OP, Foote JB, et al. Endogenous oxalate synthesis in mouse models of metabolic dysfunction-associated steatotic liver disease.doi:10.1152/ajprenal.00308.2025 · PMID 42021709
How much oxalate a hydroxyproline load becomes depends on the state of the liver. Mice.
- 26Guo P, Wu C, Wang T, et al. The key enzyme PYCR1 in proline metabolism: a dual driver of cancer progression and fibrotic remodeling.doi:10.1080/14756366.2025.2545620 · PMID 40891362
The cutis laxa enzyme as a drug target, with the review stating plainly that nothing has been validated in humans.
- 27Bröer 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.
- 28Huang K, Lu J, Yu Y, et al. Ferroptotic vulnerability drives cardiac fibrosis and diastolic dysfunction in diabetic HFpEF via a gut-associated proline-PPARγ axis.doi:10.1016/j.freeradbiomed.2026.07.020 · PMID 42442433
The one current paper where giving proline makes the animal worse, with a matching human association.
- 29Reikersdorfer 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 pediatric inpatient incidence, 2016–2020.
- 30Rivière 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.
- 31Cadeau-Comte N, Meléndez-Oliva E, Cuenca-Zaldívar JN, et al. Contemporary scurvy in vulnerable populations in high-income countries: a systematic review and multilevel meta-analysis.doi:10.3390/nu18142213 · PMID 42514284
25 studies, 147 patients, 2012 to 2025. The authors note other deficiencies travel with it.
- 32Gupta 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.
- 33Baysal 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.
- 34Consonni F, Forbice E, Semeraro F, et al. Corneal findings in a patient with prolidase deficiency: a multimodal imaging characterization.doi:10.1097/ICO.0000000000004255 · PMID 42551919
One 21-year-old man, imaged thoroughly, with a care recommendation that follows from it.
- 35Roh JD, Bae M, Oh Y, et al. Glycine-modulating Slc6a20a-ASO restores NMDA receptor function in SHANK2 and SHANK3-mutant mice and cortical organoids.doi:10.1038/s41467-026-73881-9 · PMID 42215483
The transporter behind iminoglycinuria, silenced on purpose in brain. The authors frame both the potential and the limitations.
- 36Niu Y, Wang T, Zhan Y, et al. Efficacy and safety of prolyl hydroxylase inhibitors for anemia in chronic kidney disease: a network meta-analysis.doi:10.1080/0886022X.2026.2616572 · PMID 41633330
46 trials, 32,305 patients, six drugs ranked separately for effect and for harm. The two rankings disagree.
- 37Huang J, Wang Y, Zhang H, Wang A, Zhang M, Cao Y. Effects of hypoxia-inducible factor prolyl hydroxylase inhibitors on transfusion and intravenous iron use in chronic kidney disease anemia: a systematic review and meta-analysis.doi:10.3389/fphar.2026.1916346 · PMID 42819330
The counterweight: 36 trials, 27,680 participants, and an outcome patients feel — fewer transfusions.
- 38Sharer 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.
- 39Vasikaran 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.
- 40Fujimoto Y, Matsue Y, Nakade T, et al. Hepcidin and cardiovascular events in CKD with and without dialysis.doi:10.1016/j.ekir.2026.106703 · PMID 42604012
A marker proposed for choosing the drug, tested inside the drug's own two pivotal trials.
- 41Danessa 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.
- 42Myung 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.
- 43Nukaly HY, Halawani IR, Irtaza HM, et al. Oral and topical peptides for skin aging: systematic review and meta-analysis of randomized controlled trials.doi:10.3389/fmed.2026.1618306 · PMID 41924746
19 trials, 1,341 participants, and a pooled number for wrinkles that is worth printing next to the advertising.
- 44Biełach-Bazyluk A, Jurga M, Flisiak I, et al. Dietary collagen supplementation as a strategy for skin health: a narrative review of clinical effects on skin, hair, nails, and wound healing.doi:10.3390/nu18132141 · PMID 42451143
Dermatologists naming the problems with their own evidence base, industry funding included.
- 45Sun C, Yang A, Teng F, et al. Efficacy of collagen peptide supplementation on bone and muscle health: a meta-analysis.doi:10.3389/fnut.2025.1646090 · PMID 41049371
Cited here with its own weaknesses attached: the abstract never states how many trials were pooled, and the bone density heterogeneity is 80%.
- 46Bischof K, Moitzi AM, König D. Regular collagen peptide administration exerts anti-obesity effects in high-caloric diet-fed rodents — a systematic review with meta-analysis of animal trials.doi:10.1038/s41366-025-01905-3 · PMID 41168365
339 rodents, large effects, very low certainty for every parameter, and the authors saying the human question is unexplored.
- 47Liu 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.
- 48Guan F, Adreance MA, Fay S, et al. Detection and confirmation of hypoxia-inducible factor activating agents in equine plasma and urine by liquid chromatography coupled to mass spectrometry.doi:10.1016/j.chroma.2026.467326 · PMID 42594630
Eleven prohibited substances, detected down to picograms per milliliter, in horses.
- 49Moradi M, Jahromi MG, Ghanbari E, et al. L-Proline supplementation preserves sperm function and chromatin integrity in asthenozoospermic patients during cryopreservation.doi:10.1186/s12610-025-00286-x · PMID 41083927
Semen from 30 men, in a dish. Nothing about this resembles swallowing a capsule.
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