Skip to main content

Advertisement

SpringerLink
Log in

Hydroxyproline in animal metabolism, nutrition, and cell signaling

  • Review Article
  • Published:
Amino Acids Aims and scope Submit manuscript

Abstract

trans-4-Hydroxy-l-proline is highly abundant in collagen (accounting for about one-third of body proteins in humans and other animals). This imino acid (loosely called amino acid) and its minor analogue trans-3-hydroxy-l-proline in their ratio of approximately 100:1 are formed from the post-translational hydroxylation of proteins (primarily collagen and, to a much lesser extent, non-collagen proteins). Besides their structural and physiological significance in the connective tissue, both trans-4-hydroxy-l-proline and trans-3-hydroxy-l-proline can scavenge reactive oxygen species and have both structural and physiological significance in animals. The formation of trans-4-hydroxy-l-proline residues in protein kinases B and DYRK1A, eukaryotic elongation factor 2 activity, and hypoxia-inducible transcription factor plays an important role in regulating their phosphorylation and catalytic activation as well as cell signaling in animal cells. These biochemical events contribute to the modulation of cell metabolism, growth, development, responses to nutritional and physiological changes (e.g., dietary protein intake and hypoxia), and survival. Milk, meat, skin hydrolysates, and blood, as well as whole-body collagen degradation provide a large amount of trans-4-hydroxy-l-proline. In animals, most (nearly 90%) of the collagen-derived trans-4-hydroxy-l-proline is catabolized to glycine via the trans-4-hydroxy-l-proline oxidase pathway, and trans-3-hydroxy-l-proline is degraded via the trans-3-hydroxy-l-proline dehydratase pathway to ornithine and glutamate, thereby conserving dietary and endogenously synthesized proline and arginine. Supplementing trans-4-hydroxy-l-proline or its small peptides to plant-based diets can alleviate oxidative stress, while increasing collagen synthesis and accretion in the body. New knowledge of hydroxyproline biochemistry and nutrition aids in improving the growth, health and well-being of humans and other animals.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Reproduced from Wu et al. (2011) with permission

Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Abbreviations

AA:

Amino acid

Akt:

Protein kinase B

BW:

Body weight

DYRK1A:

Dual-specificity tyrosine-phosphorylation-regulated kinases 1A

DYRK1B:

Dual-specificity tyrosine-phosphorylation-regulated kinases 1B

eEF2:

Eukaryotic elongation factor 2

HIF:

Hypoxia-inducible factor

3-Hyp:

3-Hydroxyproline

4-Hyp:

4-Hydroxyproline

MTOR:

Mechanistic target of rapamycin

PHD1:

Prolyl hydroxylase-1

PHD2:

Prolyl hydroxylase-2

PHD3:

Prolyl hydroxylase-3

ROS:

Reactive oxygen species

References

  • Adams E, Frank L (1980) Metabolism of proline and the hydroxyprolines. Annu Rev Biochem 49:1005–1061

    Article  CAS  PubMed  Google Scholar 

  • Aksnes A, Mundheim H, Toppe J, Albrektsen S (2008) The effect of dietary hydroxyproline supplementation on salmon (Salmo salar L.) fed high plant protein diets. Aquaculture 275:242–249

    Article  CAS  Google Scholar 

  • Albaugh VL, Mukherjee K, Barbul A (2017) Proline precursors and collagen synthesis: biochemical challenges of nutrient supplementation and wound healing. J Nutr 147:2011–2017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ao J, Li B (2012) Amino acid composition and antioxidant activities of hydrolysates and peptide fractions from porcine collagen. Food Sci Technol Int 18:425–434

    Article  CAS  PubMed  Google Scholar 

  • Balasuriya N, Davey NE, Johnson JL, Liu H, Biggar KK, Cantley LC, Li SS, O’Donoghue P (2020) Phosphorylation-dependent substrate selectivity of protein kinase B (AKT1). J Biol Chem 295:8120–8134

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Baskal S, Bollenbach A, Mels C, Kruger R, Tsikas D (2021a) Development, validation of a GC–MS method for the simultaneous measurement of amino acids, their PTM metabolites and AGEs in human urine, and application to the bi-ethnic ASOS study with special emphasis to lysine. Amino Acids. https://doi.org/10.1007/s00726-021-03031-6

    Article  PubMed  PubMed Central  Google Scholar 

  • Baskal S, Büttner P, Werner S, Besler C, Lurz P, Thiele H, Tsikas D (2021b) Profile of urinary amino acids and their post-translational modifications (PTM) including advanced glycation end-products (AGEs) of lysine, arginine and cysteine in lean and obese ZSF1 rats. Amino Acids. https://doi.org/10.1007/s00726-021-03042-3

    Article  PubMed  PubMed Central  Google Scholar 

  • Bienkowski RS (1984) A criterion to determine whether cis-4-hydroxyproline is produced in animal tissues. Arch Biochem Biophys 229:455–458

    Article  CAS  PubMed  Google Scholar 

  • Buck TB, Hall AL, Sinha CC, Bunce OR, Thorgeirsson UP (2000) cis-Hydroxyproline stimulates the growth of rat mammary carcinoma cells. Vivo 14:7–11

    CAS  Google Scholar 

  • Chamond N, Goytia M, Coatnoan N, Barale JC, Cosson A, Degrave WM, Minoprio P (2005) Trypanosoma cruzi proline racemases are involved in parasite differentiation and infectivity. Mol Microbiol 58:46–60

    Article  CAS  PubMed  Google Scholar 

  • Chen S, White CE, diCenzo GC, Zhang Y, Stogios PJ, Savchenko A, Finan TM (2016) l-Hydroxyproline and d-proline catabolism in Sinorhizobium meliloti. J Bacteriol 198:1171–1181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chotphruethipong L, Binlateh T, Hutamekalin P, Sukketsiri W, Aluko RE, Benjakul S (2021) In vitro antioxidant and wound-healing activities of hydrolyzed collagen from defatted Asian sea bass skin as influenced by different enzyme types and hydrolysis processes. RSC Adv 11:18144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Clifton IJ, Hsueh L-C, Baldwin JE, Harlos K, Schofield CJ (2001) Structure of proline 3-hydroxylase: evolution of the family of 2-oxoglutarate dependent oxygenases. Eur J Biochem 268:6625–6636

    Article  CAS  PubMed  Google Scholar 

  • Cooper SK, Pandhare J, Donald SP, Phang JM (2008) A novel function for hydroxyproline oxidase in apoptosis through generation of reactive oxygen species. J Biol Chem 283:10485–10492

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dai ZL, Wu G, Zhu WY (2011) Amino acid metabolism in intestinal bacteria: links between gut ecology and host health. Front Biosci 16:1768–1786

    Article  CAS  Google Scholar 

  • Davis TA, Nguyen HV, Garciaa-Bravo R, Fiorotto ML, Jackson EM, Lewis DS, Lee DR, Reeds PJ (1994) Amino acid composition of human milk is not unique. J Nutr 124:1126–1132

    Article  CAS  PubMed  Google Scholar 

  • Devlin TM (2006) Textbook of Biochemistry with clinical correlations. Wiley-Liss Press, Hoboken

    Google Scholar 

  • Dillon EL, Wu G (2021) Cortisol enhances ctrulline synthesis from proline in enterocytes of suckling piglets. Amino Acids. https://doi.org/10.1007/s00726-021-03039-y

    Article  PubMed  Google Scholar 

  • Donald SP, Sun XY, Hu CA, Yu J, Mei JM, Valle D, Phang JM (2001) Proline oxidase, encoded by p53-induced gene-6, catalyzes the generation of proline-dependent reactive oxygen species. Cancer Res 61:1810–1815

    CAS  PubMed  Google Scholar 

  • Durante W (2020) Amino acids in circulatory function and health. Adv Exp Med Biol 1265:39–56

    Article  CAS  PubMed  Google Scholar 

  • Dziewiatkowski DD, Hascall VC, Riolo RL (1972) Epimerization of trans-4-hydroxy-l-proline to cis-4-hydroxy-d-proline during acid hydrolysis of collagen. Anal Biochem 49:550–558

    Article  CAS  PubMed  Google Scholar 

  • Fitzgerald J, Lamandé SR, Bateman JF (1999) Proteasomal degradation of unassembled mutant type I collagen pro-a1(I) chains. J Biol Chem 274:27392–27398

    Article  CAS  PubMed  Google Scholar 

  • Floyd RA, Nagy I (1984) Formation of long-lived hydroxyl free radical adducts of proline and hydroxyproline in a Fenton reaction. Biochim Biophys Acta 790:94–97

    Article  CAS  PubMed  Google Scholar 

  • Gallop PM, Blumenfeld OO, Seifter S (1972) Structure and metabolism of connective 801 tissue proteins. Annu Rev Biochem 41:617–672

    Article  CAS  PubMed  Google Scholar 

  • Gilbreath KR, Bazer FW, Satterfield MC, Wu G (2021) Amino acid nutrition and reproductive performance in ruminants. Adv Exp Med Biol 1285:43–61

    Article  PubMed  Google Scholar 

  • Gorres KL, Raines RT (2010) Prolyl 4-hydroxylase. Crit Rev Biochem Mol Biol 45:106–124

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goto M, Muramatsu H, Mihara H, Kurihara T, Esaki N, Omi R, Miyahara I, Hirotsu K (2005) Crystal structures of Δ1-piperideine-2-carboxylate/Δ1-pyrroline-2-carboxylate reductase belonging to a new family of NAD(P)H-dependent oxidoreductases: conformational change, substrate recognition, and stereochemistry of the reaction. J Biol Chem 280:40875–40884

    Article  CAS  PubMed  Google Scholar 

  • Goytia M, Chamond N, Cosson A, Coatnoan N, Hermant D, Berneman A, Minoprio P (2007) Molecular and structural discrimination of Proline Racemase and Hydroxyproline-2-epimerase from nosocomial and bacterial pathogens. PLoS ONE 2(9):e885

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Guo J, Chakraborty AA, Liu P, Gan W, Zheng X, Inuzuka H, Wang B, Zhang J, Zhang L, Yuan M, Novak J, Cheng JQ, Toker A, Signoretti S, Zhang Q, Asara JM, Kaelin WG Jr, Wei W (2016) pVHL suppresses kinase activity of Akt in a proline-hydroxylation–dependent manner. Science 353:929–932

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hamanaka RB, Mutlu GM (2021) The role of metabolic reprogramming and de novo amino acid synthesis in collagen protein production by myofibroblasts: implications for organ fibrosis and cancer. Amino Acids. https://doi.org/10.1007/s00726-021-02996-8

    Article  PubMed  Google Scholar 

  • Hara R, Kino K (2009) Characterization of novel 2-oxoglutarate dependent dioxygenases converting l-proline to cis-4-hydroxy-l-proline. Biochem Biophys Res Commun 379:882–886

    Article  CAS  PubMed  Google Scholar 

  • Hausmann E (1967) Cofactor requirements for the enzymatic hydroxylation of lysine in a polypeptide precursor of collagen. Biochim Biophys Acta 133:591–593

    Article  CAS  PubMed  Google Scholar 

  • He WL, Li P, Wu G (2021) Amino acid nutrition and metabolism in chickens. Adv Exp Med Biol 1285:109–131

    Article  PubMed  Google Scholar 

  • Hirota K (2021) HIF-α prolyl hydroxylase inhibitors and their implications for biomedicine: a comprehensive review. Biomedicines 9:468

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hou YQ, He WL, Hu SD, Wu G (2019) Composition of polyamines and amino acids in plant-source foods for human consumption. Amino Acids 51:1153–1165

    Article  CAS  PubMed  Google Scholar 

  • Hu SD, Nawaratna G, Long BD, Bazer FW, Johnson GA, Brosnan JT, Wu G (2017) The hydroxyproline–glycine pathway for glycine synthesis in neonatal pigs. J Anim Sci 95(Suppl 4):45

    Article  Google Scholar 

  • Hu SD (2017) Endogenous synthesis of glycine from hydroxyproline in neonatal pigs. Ph.D. Dissertation, Texas A&M University, College Station, Texas

  • Ingber D, Folkman J (1988) Inhibition of angiogenesis through modulation of collagen metabolism. Lab Invest 59:44–51

    CAS  PubMed  Google Scholar 

  • Irreverre F, Morita K, Ishii S, Witkop B (1962) Occurrence of cis- and trans-3-hydroxy-l-proline in acid hydrolyzate of telomycin. Biochem Biophys Res Commun 9:69–71

    Article  CAS  PubMed  Google Scholar 

  • Ishikawa Y, Wirz J, Vranka JA, Nagata K, Bächinger HP (2009) Biochemical characterization of the prolyl 3-hydroxylase 1 cartilage-associated protein cyclophilin B complex. J Biol Chem 284:17641–17647

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Isobe K, Jung HJ, Yang CR, Claxton J, Sandoval P, Burg MB, Raghuram V, Knepper MA (2017) Systems-level identification of PKA-dependent signaling in epithelial cells. Proc Natl Acad Sci USA 114:E8875–E8884

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ji Y, Wu ZL, Dai ZL, Wang XL, Li J, Wang BG, Wu G (2017) Fetal and neonatal programming of postnatal growth and feed efficiency in swine. J Anim Sci Biotechnol 8:42

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Johnston RM, Chu LN, Liu M, Goldberg SL, Goswami A, Patel RN (2009) Hydroxylation of l-proline to cis-3-hydroxy-l-proline by recombinant Escherichia coli expressing a synthetic l-proline-3-hydroxylase gene. Enzyme Microb Technol 45:484–490

    Article  CAS  Google Scholar 

  • Kennaugh LM, Arthur PG, Hartmann PE (1997) The concentrations of creatine and creatine phosphate in sow colostrum and milk throughout lactation and weaning. Aust J Agric Res 48:1105–1110

    Article  CAS  Google Scholar 

  • Klein BY, Gal I, Segal D (1994) Marrow stromal cell commitment to mineralization under the effect of a prolyl hydroxylase inhibitor. J Cell Biochem 54:354–364

    Article  CAS  PubMed  Google Scholar 

  • Krane SM (2008) The importance of proline residues in the structure, stability and susceptibility to proteolytic degradation of colla-gens. Amino Acids 35:703–710

    Article  CAS  PubMed  Google Scholar 

  • Kusubata M, Koyama Y, Tometsuka C, Shigemura Y, Sato K (2015) Detection of endogenous and food-derived collagen dipeptide prolylhydroxyproline (Pro-Hyp) in allergic contact dermatitis-affected mouse ear. Biosci Biotechnol Biochem 79:1356–1361

    Article  CAS  PubMed  Google Scholar 

  • Lee SB, Young AK, Oh T, Shi P, D’Angelo F, Frangaj B, Koller A, Chen EI, Cardozo T, Iavarone A, Lasorella A (2020) Proline hydroxylation primes protein kinases for autophosphorylation and activation. Mol Cell 79:376–389

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lewko WM, Liotta LA, Wicha MS, Vonderhaar BK, Kidwell WR (1981) Sensitivity of N-nitrosomethylurea-induced rat mammary tumors to cis-hydroxyproline, an inhibitor of collagen production. Cancer Res 41:2855–2862

    CAS  PubMed  Google Scholar 

  • Li P, Wu G (2018) Roles of dietary glycine, proline and hydroxyproline in collagen synthesis and animal growth. Amino Acids 50:29–38

    Article  CAS  PubMed  Google Scholar 

  • Li P, Wu G (2020) Composition of amino acids and related nitrogenous nutrients in feedstuffs for animal diets. Amino Acids 52:523–542

    Article  CAS  PubMed  Google Scholar 

  • Li XL, Rezaei R, Li P, Wu G (2011) Composition of amino acids in feed ingredients for animal diets. Amino Acids 40:1159–1168

    Article  CAS  PubMed  Google Scholar 

  • Li XY, Zheng SX, Wu G (2021a) Nutrition and functions of amino acids in fish. Adv Exp Med Biol 1285:133–168

    Article  PubMed  Google Scholar 

  • Li XY, Han T, Zheng SX, Wu G (2021b) Nutrition and functions of amino acids in aquatic crustaceans. Adv Exp Med Biol 1285:169–197

    Article  PubMed  Google Scholar 

  • Li P, He WL, Wu G (2021c) Composition of amino acids in foodstuffs for humans and animals. Adv Exp Med Biol 1332:189–210

    Article  PubMed  Google Scholar 

  • Liang X, Zhang L, Natarajan SK, Becker DF (2013) Proline mechanisms of stress survival. Antioxid Redox Signal 19:998–1011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu YZ, He G, Wang Q, Mai K, Xu W, Zhou H (2014) Hydroxyproline supplementation on the performances of high plant protein source based diets in turbot (Scophthalmus maximus L.). Aquaculture 433:476–480

    Article  CAS  Google Scholar 

  • Malhotra V, Erlmann P (2015) The pathway of collagen secretion. Annu Rev Cell Dev Biol 31:109–124

    Article  CAS  PubMed  Google Scholar 

  • Malhotra V, Erlmann P, Nogueira C (2015) Procollagen export from the endoplasmic reticulum. Biochem Soc Trans 43:104–107

    Article  CAS  PubMed  Google Scholar 

  • Meininger CJ, Marinos RS, Hatakeyama K, Martinez-Zaguilan R, Rojas JD, Kelly K, Wu G (2000) Impaired nitric oxide production in coronary endothelial cells of the spontaneously diabetic BB rat is due to tetrahydrobiopterin deficiency. Biochem J 349:353–356

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Meléndez-Hevia E, De Paz-Lugo P, Cornish-Bowden A, Cárdenas ML (2009) A weak link in metabolism: the metabolic capacity for glycine biosynthesis does not satisfy the need for collagen synthesis. J Biosci 34:853–872

    Article  PubMed  CAS  Google Scholar 

  • Milić S, Bogdanović Pristov J, Mutavdžić D, Savić A, Spasić M, Spasojević I (2015) The relationship of physicochemical properties to the antioxidative activity of free amino acids in Fenton system. Environ Sci Technol 49:4245–4254

    Article  PubMed  CAS  Google Scholar 

  • Moore CEJ, Mikolajek H, da Mota SR, Wang X, Kenney JW, Werner JM, Proud CG (2015) Elongation factor 2 kinase is regulated by proline hydroxylation and protects cells during hypoxia. Mol Cell Biol 35:1788–1804

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mori H, Shibasaki T, Yano K, Ozaki A (1997) Purification and cloning of a proline 3-hydroxylase, a novel enzyme which hydroxylates free l-proline to cis-3-hydroxy-l-proline. J Bacteriol 179:5677–5683

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mueller C, Emmrich J, Jaster R, Braun D, Liebe S, Sparmann G (2006) Cis-hydroxyproline-induced inhibition of pancreatic cancer cell growth is mediated by endoplasmic reticulum stress. World J Gastroenterol 12:1569–1576

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Myllyharju J, Koivunen P (2013) Hypoxia-inducible factor prolyl 4-hydroxylases: common and specific roles. Biol Chem 394:435–448

    Article  CAS  PubMed  Google Scholar 

  • Natarajan SK, Zhu W, Liang X, Zhang L, Demers AJ, Zimmerman MC, Simpson MA, Becker DF (2012) Proline dehydrogenase is essential for proline protection against hydrogen peroxide-induced cell death. Free Radic Biol Med 53:1181–1191

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nimni ME, De Guia E, Bavetta LA (1967) Synthesis and turnover of collagen precursors in rabbit skin. Biochem J 102:143–147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Offengenden M, Chakrabarti S, Wu J (2018) Chicken collagen hydrolysates differentially mediate anti-inflammatory activity and type I collagen synthesis on human dermal fibroblasts. Food Sci Hum Wellness 7:138–147

    Article  Google Scholar 

  • Ogle JD, Arlinghaus RB, Logan MA (1961) Studies on peptides obtained from enzymic digests of collagen with evidence for the presence of an unidentified compound in this protein. Arch Biochem Biophys 94:85–93

    Article  CAS  PubMed  Google Scholar 

  • Phang JM (2019) Proline metabolism in cell regulation and cancer biology: recent advances and hypotheses. Antioxid Redox Signal 30:635–649

    Article  CAS  PubMed  Google Scholar 

  • Phang JM, Liu W (2012) Proline metabolism and cancer. Front Biosci 17:1835–1845

    Article  CAS  Google Scholar 

  • Phang JM, Hu CA, Valle A (2001) Disorders of proline and hydroxyproline metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular basis of inherited diseases, 8th edn. McGraw-Hill, New York, pp 1821–1838

    Google Scholar 

  • Postlethwaite AE, Kang AH (1976) Collagen-and collagen peptide-induced chemotaxis of human blood monocytes. J Exp Med 143:1299–1307

    Article  CAS  PubMed  Google Scholar 

  • Robins SP (2007) Biochemistry and functional signifcance of collagen cross-linking. Biochem Soc Trans 35:849–852

    Article  CAS  PubMed  Google Scholar 

  • Rong H, Zhang Y, Hao M, Lin F, Zou W, Zhang H, Yu C, Yu J, Shi Q, Aweya JJ, Wen X (2020) Effect of hydroxyproline supplementation on growth performance, body composition, amino acid profiles, blood-biochemistry and collagen synthesis of juvenile chu’s croaker (Nibea coibor). Aquac Res 51:1264–1275

    Article  CAS  Google Scholar 

  • Schmelzer CEH, Hedtke T, Heinz A (2020) Unique molecular networks: formation and role of elastin cross-links. IUBMB Life 72:842–854

    Article  CAS  PubMed  Google Scholar 

  • Semenza GL (2014) Oxygen sensing, hypoxia-inducible factors, and disease pathophysiology. Annu Rev Pathol 9:47–71

    Article  CAS  PubMed  Google Scholar 

  • Shibasaki T, Mori H, Chiba S, Ozaki A (1999) Microbial proline 4-hydroxylase screening and gene cloning. Appl Environ Microbiol 65:4028–4031

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Solano F (2020) Metabolism and functions of amino acids in the skin. Adv Exp Med Biol 1265:187–199

    Article  CAS  PubMed  Google Scholar 

  • Song F, He G, Wu G (2018) Catabolism of l-4-hydroxyproline in tissues of hybrid striped bass (Morone chrysops × M. Saxatilis). Aquaculture America Annual Meeting, Las Vegas (Feb. 19–22)

  • Strowitzki MJ, Cummins EP, Taylor CT (2019) Protein hydroxylation by hypoxia-inducible factor (HIF) hydroxylases: unique or ubiquitous? Cells 8:384

    Article  CAS  PubMed Central  Google Scholar 

  • Sturm D, Maletzki C, Braun D, Emmrich J (2010) cis-Hydroxyproline-mediated pancreatic carcinoma growth inhibition in mice. Int J Colorectal Dis 25:921–929

    Article  PubMed  Google Scholar 

  • Szpak P (2011) Fish bone chemistry and ultrastructure: implications for taphonomy and stable isotope analysis. J Archaeolog Sci 38:3358–3372

    Article  Google Scholar 

  • Tsikas D (2021) Post-translational modifications (PTM): analytical approaches, signaling, physiology and pathophysiology—part I. Amino Acids 53:485–487

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Uke E, Lee C, Grayhack JT (1983) The effect of cis hydroxyproline on ventral prostatic growth in rats. J Urol 129:171–174

    Article  CAS  PubMed  Google Scholar 

  • Verbruggen N, Hermans C (2008) Proline accumulation in plants: a review. Amino Acids 35:753–759

    Article  CAS  PubMed  Google Scholar 

  • Visser WF, Verhoeven-Duif NM, de Koning TJ (2012) Identification of a human trans-3-hydroxy-l-proline dehydratase, the first characterized member of a novel family of proline racemase-like enzymes. J Biol Chem 287:21654–21662

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Voulgarelis M, Tsichlis PN (2016) Proline hydroxylation linked to Akt activation. Science 353:870–871

    Article  CAS  PubMed  Google Scholar 

  • Wang WW, Wu ZL, Dai ZL, Yang Y, Wang JJ, Wu G (2013) Glycine metabolism in animals and humans: implications for nutrition and health. Amino Acids 45:463–477

    Article  PubMed  CAS  Google Scholar 

  • Wang WW, Dai ZL, Wu ZL, Lin G, Jia SC, Hu SD, Dahanayaka S, Wu G (2014) Glycine is a nutritionally essential amino acid for maximal growth of milk-fed young pigs. Amino Acids 46:2037–2045

    Article  CAS  PubMed  Google Scholar 

  • Watanabe S, Tajima K, Fujii S, Fukumori F, Hara R, Fukuda R, Miyazaki M, Kino K, Watanabe Y (2016) Functional characterization of aconitase X as a cis-3-hydroxy-l-proline dehydratase. Sci Rep 6:38720

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Watanabe S, Fukumori F, Miyazaki M, Tagami S, Watanabe Y (2017) Characterization of a novel cis-3-hydroxy-l-proline dehydratase and a trans-3-hydroxy-l-proline dehydratase from bacteria. J Bacteriol 199:e00255-e317

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Watanabe S, Morimoto D, Fukumori F, Watanabe Y (2018) Characterization of cis-4-hydroxy-d-proline dehydrogenase from Sinorhizobium meliloti. Biosci Biotechnol Biochem 82:110–113

    Article  CAS  PubMed  Google Scholar 

  • Watanabe S, Tanimoto Y, Nishiwaki H, Watanabe Y (2015) Identification and characterization of bifunctional proline racemase/hydroxyproline epimerase from archaea: discrimination of substrates and molecular evolution. PLoS ONE 10(3):e0120349

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wei Z, Zhou H, Zhang Y, Zhang Q, Zhang W, Mai K (2018) Integrative analysis of transcriptomics and metabolomics profiling on flesh quality of large yellow croaker Larimichthys crocea fed a diet with hydroxyproline supplementation. Br J Nutr 119:359–367

    Article  CAS  PubMed  Google Scholar 

  • Weinberger B, Hanna N, Laskin JD, Heck DE, Gardner CR, Gerecke DR, Laskin DL (2005) Mechanisms mediating the biologic activity of synthetic proline, glycine, and hydroxyproline polypeptides in human neutrophils. Mediators Inflamm 2005:31–38

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Weis MA, Hudson DM, Kim L, Scott M, Wu J-J, Eyre DR (2010) Locationof 3-hydroxyproline residues in collagen types I, II, III, and V/XI implies a role in fibril supramolecular assembly. J Biol Chem 285:2580–2590

    Article  CAS  PubMed  Google Scholar 

  • Wu G (2018) Principles of Animal Nutrition. CRC Press, Boca Raton

    Google Scholar 

  • Wu G (2020) Important roles of dietary taurine, creatine, carnosine, anserine and 4-hydroxyproline in human nutrition and health. Amino Acids 52:329–360

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu G (2021) Amino acids: biochemistry and nutrition. CRC Press, Boca Raton

    Book  Google Scholar 

  • Wu G, Knabe DA (1994) Free and protein-bound amino acids in sow’s colostrum and milk. J Nutr 124:415–424

    Article  CAS  PubMed  Google Scholar 

  • Wu G, Morris SM Jr (1998) Arginine metabolism: nitric oxide and beyond. Biochem J 336:1–17

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu G, Ott TL, Knabe DA, Bazer FW (1999) Amino acid composition of the fetal pig. J Nutr 129:1031–1038

    Article  CAS  PubMed  Google Scholar 

  • Wu G, Flynn NE, Knabe DA (2000a) Enhanced intestinal synthesis of polyamines from proline in cortisol-treated piglets. Am J Physiol 279:E395–E402

    CAS  Google Scholar 

  • Wu G, Flynn NE, Knabe DA, Jaeger LA (2000b) A cortisol surge mediates the enhanced polyamine synthesis in porcine enterocytes during weaning. Am J Physiol 279:R554–R559

    CAS  Google Scholar 

  • Wu G, Bazer FW, Hu J, Johnson GA, Spencer TE (2005) Polyamine synthesis from proline in the developing porcine placenta. Biol Reprod 72:842–850

    Article  CAS  PubMed  Google Scholar 

  • Wu G, Bazer FW, Cudd TA, Jobgen WS, Kim SW, Lassala A, Li P, Matis JH, Meininger CJ, Spencer TE (2007) Pharmacokinetics and safety of arginine supplementation in animals. J Nutr 137:1673S-1680S

    Article  CAS  PubMed  Google Scholar 

  • Wu G, Bazer FW, Burghardt RC, Johnson GA, Kim SW, Knabe DA, Li P, Li XL, McKnight JR, Satterfield MC, Spencer TE (2011) Proline and hydroxyproline metabolism: implications for animal and human nutrition. Amino Acids 40:1053–1063

    Article  CAS  PubMed  Google Scholar 

  • Wu G, Bazer FW, Johnson GA, Hou YQ (2018) Arginine nutrition and metabolism in growing, gestating and lactating swine. J Anim Sci 96:5035–5051

    Article  PubMed  PubMed Central  Google Scholar 

  • Wu ZL, Hou YQ, Dai ZL, Hu CA, Wu G (2019) Metabolism, nutrition and redox signaling of hydroxyproline. Antioxid Redox Signal 30:674–682

    Article  CAS  PubMed  Google Scholar 

  • Xu S, Gu M, Wu K, Li G (2019) Unraveling the role of hydroxyproline in maintaining the thermal stability of the collagen triple helix structure using simulation. J Phys Chem B 123:7754–7763

    Article  CAS  PubMed  Google Scholar 

  • Yamauchi M, Shiiba M (2008) Lysine hydroxylation and cross-linking of collagen. Methods Mol Biol 446:95–108

    Article  CAS  PubMed  Google Scholar 

  • Yazaki M, Ito Y, Yamada M, Goulas S, Teramoto S, Nakaya M, Ohno S, Yamaguchi K (2017) Oral ingestion of collagen hydrolysate leads to the transportation of highly concentrated Gly-Pro-Hyp and its hydrolyzed form of Pro-Hyp into the bloodstream and skin. J Agric Food Chem 65:2315–2322

    Article  CAS  PubMed  Google Scholar 

  • Zhang Q, Hou YQ, Bazer FW, He WL, Posey EA, Wu G (2021a) Amino acids in swine nutrition and production. Adv Exp Med Biol 1285:81–107

    Article  PubMed  Google Scholar 

  • Zhang X, Liu D, Wang HD (2021b) Antioxidant activity in vitro of hydroxyproline peptides. Food Sci 42:55–60

    Google Scholar 

Download references

Acknowledgements

This work was supported by Agriculture and Food Research Initiative Competitive Grants no. 2014-67015-21770 from the USDA National Institute of Food and Agriculture, and Texas A&M AgriLife Research (H-8200).

Author information

Authors and Affiliations

  1. Department of Animal Science, Texas A&M University, College Station, TX, 77843, USA

    Shengdi Hu, Wenliang He & Guoyao Wu

Authors
  1. Shengdi Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wenliang He
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Guoyao Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Guoyao Wu.

Ethics declarations

Conflict of interest

The author declares no conflict of interest.

Ethical statement

This review article does not require either human consent or the approval of animal use.

Additional information

Handling editor: D. Tsikas.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hu, S., He, W. & Wu, G. Hydroxyproline in animal metabolism, nutrition, and cell signaling. Amino Acids 54, 513–528 (2022). https://doi.org/10.1007/s00726-021-03056-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00726-021-03056-x

Keywords

Search

Navigation