Skip to main content

Functional amino acids in nutrition and health

Abstract

The recent years have witnessed growing interest in biochemistry, physiology and nutrition of amino acids (AA) in growth, health and disease of humans and other animals. This results from the discoveries of AA in cell signaling involving protein kinases, G protein-coupled receptors, and gaseous molecules (i.e., NO, CO and H2S). In addition, nutritional studies have shown that dietary supplementation with several AA (e.g., arginine, glutamine, glutamate, leucine, and proline) modulates gene expression, enhances growth of the small intestine and skeletal muscle, or reduces excessive body fat. These seminal findings led to the new concept of functional AA, which are defined as those AA that participate in and regulate key metabolic pathways to improve health, survival, growth, development, lactation, and reproduction of the organisms. Functional AA hold great promise in prevention and treatment of metabolic diseases (e.g., obesity, diabetes, and cardiovascular disorders), intrauterine growth restriction, infertility, intestinal and neurological dysfunction, and infectious disease (including viral infections).

Introduction

Amino acids (AA) are building blocks for tissue proteins and essential substrates for the synthesis of many low-molecular-weight substances (e.g., NO, polyamines, glutathione, creatine, carnitine, carnosine, thyroid hormones, serotonin, melanin, melatonin, and heme) with enormous physiological importance (Blachier et al. 2011; Kim et al. 2012; Kong et al. 2012; Wu 2009). Based on the growth or nitrogen balance of animals, AA have been traditionally classified as nutritionally “essential” or “nonessential” (see Wu 2009 for review). AA whose carbon skeletons are not synthesized de novo by animal cells must be provided in diets to sustain life and, therefore, are nutritionally essential (Table 1). Accordingly, cysteine and tyrosine, whose carbon skeletons are not synthesized de novo in animals, should be classified as nutritionally essential AA (Wu 2013). In contrast, AA that are synthesized de novo in animals have been previously thought to be dispensable in diets and, therefore, considered nutritionally “nonessential”. However, nitrogen balance is not a sensitive indicator of optimal dietary AA requirements (Wu 2013). For example, adult men consuming an arginine-free diet can maintain a nitrogen balance for 9 days, but both the number and vitality of their sperm cells are decreased by 90 % (see Wu et al. 2009 for review). In addition, a lack of arginine from the maternal diet impairs embryonic/fetal survival and growth despite the absence of a negative nitrogen balance in the gestating swine (Wu et al. 2010). Indeed, there has been no compelling evidence for sufficient synthesis of nutritionally “nonessential” AA in humans and other animals (Li et al. 2009; Wu 2010).

Table 1 Classification of AA in animal and human nutrition

Dietary requirements of AA depend on species, developmental stage, physiological status, the microbiota in the lumen of the small intestine, environmental factors, and pathological states (Dai et al. 2011, 2012a, b; Wu et al. 2013). Thus, some of the AA that are synthesized by animals have been classified as conditionally essential because rates of their utilization are greater than rates of their synthesis under certain conditions (e.g., early weaning, lactation, pregnancy, burns, injury, infection, heat stress, and cold stress) (Wu 2009). Examples include glutamine, arginine, proline, glycine and taurine for preterm human infants and weanling neonates (Table 1). Note that currently the major criterion for classification of conditionally essential AA is growth or N balance.

Some of the nutritionally “nonessential” AA (e.g., arginine, glutamine, glutamate, glycine, and proline for adults) play important roles in regulating gene expression (Kim et al. 2011a, b; Wu et al. 2011a, b) and micro-RNA levels (Liu et al. 2012), cell signaling (Bazer et al. 2012; Jewell et al. 2013), blood flow (Tan et al. 2012), nutrient transport and metabolism in animal cells (Suryawan et al. 2012; Wang et al. 2013), development of brown adipose tissue (Wu et al. 2012), intestinal microbial growth and metabolism (Dai et al. 2012a, b), anti-oxidative responses (Hou et al. 2012a, b), as well as innate and cell-mediated immune responses (Ren et al. 2011, 2013). Of particular interest, AA participate in and modulate cell signaling through: (1) several well-conserved protein kinases (including mammalian target of rapamycin, AMP-activated protein kinase, cGMP-dependent kinase, cAMP-dependent kinase, and mitogen-activated protein kinase), (2) G protein-coupled receptors, and (3) gaseous molecules, including NO, CO, and H2S (Wu 2013). In addition, glutamate, glutamine, and aspartate [abundant AA in food proteins of plant and animal origin (Li et al. 2011a)] are major metabolic fuels for mammalian enterocytes (Burrin and Stoll 2009; Rezaei et al. 2013a, b). Emerging evidence shows a crucial role for glutamate in chemical sensing in the gastrointestinal tract (San Gabriel and Uneyama 2012) and possibly in other tissues (Gallinetti et al. 2013). Furthermore, these AA, along with glycine, tryptophan, tyrosine and d-amino acids (e.g., d-alanine, d-aspartate, and d-serine), regulate neurological development and function (Fernstrom 2012; Friedman and Levin 2012; Hou et al. 2012a, b; Wang et al. 2013). Moreover, leucine activates the mammalian target of rapamycin to stimulate protein synthesis and inhibit intracellular proteolysis (Dillon 2012; Li et al. 2011b), whereas methionine is the major donor of the methyl group to affect DNA and protein methylation in cells (Wang et al. 2012). Notably, nutritional studies have shown that dietary supplementation with several AA (e.g., arginine, glutamine, glutamate, leucine, and proline) modulates gene expression and enhances growth of the small intestine and skeletal muscle (Geng et al. 2011; Jobgen et al. 2009; Wang et al. 2008; Wu et al. 2011a, b; Yao et al. 2008; Yin et al. 2010). The diverse and crucial roles of AA in metabolism, physiology, and immunity against infectious diseases (including viral infections) are truly remarkable (Table 2).

Table 2 Roles of functional AA in nutrition and health

Based on the foregoing lines of compelling evidence from animal and human studies, Wu (2010) proposed the new concept of functional AA, which are defined as those AA that participate in and regulate key metabolic pathways to improve health, survival, growth, development, lactation, and reproduction of the organisms. Metabolic pathways include: (1) intracellular protein turnover (synthesis and degradation) and associated events (Bertrand et al. 2012; Kong et al. 2012; Wauson et al. 2013; Xi et al. 2011, 2012; Yao et al. 2012), (2) AA synthesis and catabolism (Brosnan and Brosnan 2012; Lei et al. 2012a, b), (3) generation of small peptides, nitrogenous metabolites, and sulfur-containing substances [e.g., H2S (Mimoun et al. 2012)], (4) urea cycle and uric acid synthesis (Wu 2013), (5) lipid and glucose metabolism (Dai et al. 2013; Go et al. 2012; Satterfield et al. 2011, 2012), (6) one-carbon unit metabolism (Wang et al. 2012), and (7) cellular redox signaling (Hou et al. 2012a). Functional AA can be nutritionally “essential”, “nonessential”, or conditionally essential AA (Table 1). It is noteworthy that the concept of functional AA takes into consideration, the animal’s metabolic needs for dietary AA beyond serving as the building blocks for proteins, large peptides, and small peptides. These new advances in AA nutrition are highlighted in the pages of this special issue of “Amino Acids” to further stimulate development of the field. Functional AA hold great promise in prevention and treatment of metabolic diseases (e.g., obesity, diabetes, and cardiovascular disorders), lactation failure, fetal and postnatal growth restriction, male and female infertility, organ (e.g., intestinal, neurological and renal) dysfunction, and infectious disease (including viral infections).

References

  1. Bazer FW, Song GH, Kim JY et al (2012) Mechanistic mammalian target of rapamycin (MTOR) cell signaling: effects of select nutrients and secreted phosphoprotein 1 on development of mammalian conceptuses. Mol Cell Endocrinol 354:22–33

    PubMed  Article  CAS  Google Scholar 

  2. Bertrand J, Goichon A, Déchelotte P et al (2012) Regulation of intestinal protein metabolism by amino acids. Amino Acids (in this issue). doi:10.1007/s00726-012-1325-8

    PubMed  Google Scholar 

  3. Blachier F, Davila AM, Benamouzig R, Tome D (2011) Channelling of arginine in NO and polyamine pathways in colonocytes and consequences. Front Biosci 16:1331–1343

    Google Scholar 

  4. Brosnan JT, Brosnan ME (2012) Glutamate: a truly functional amino acid. Amino Acids (in this issue). doi:10.1007/s00726-012-1280-4

    PubMed  Google Scholar 

  5. Burrin DG, Stoll B (2009) Metabolic fate and function of dietary glutamate in the gut. Am J Clin Nutr 90:850S–856S

    Google Scholar 

  6. 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 

  7. Dai ZL, Li XL, Xi PB et al (2012a) Regulatory role for l-arginine in the utilization of amino acids by pig small-intestinal bacteria. Amino Acids 43:233–244

    PubMed  Article  CAS  Google Scholar 

  8. Dai ZL, Li XL, Xi PB et al (2012b) l-Glutamine regulates amino acid utilization by intestinal bacteria. Amino Acids (in this issue). doi:10.1007/s00726-012-1264-4

    Google Scholar 

  9. Dai ZL, Wu ZL, Yang Y et al (2013) Nitric oxide and energy metabolism in mammals. Biofactors. doi:10.1002/biof.1099

    PubMed  Google Scholar 

  10. Dillon EL (2012) Nutritionally essential amino acids and metabolic signaling in aging. Amino Acids (in this issue). doi:10.1007/s00726-012-1438-0

  11. Fernstrom JD (2012) Large neutral amino acids: dietary effects on brain neurochemistry and function. Amino Acids (in this issue). doi:10.1007/s00726-012-1330-y

    PubMed  Google Scholar 

  12. Friedman M, Levin CE (2012) Nutritional and medicinal aspects of d-amino acids. Amino Acids 42:1553–1582

    PubMed  Article  CAS  Google Scholar 

  13. Gallinetti J, Harputlugil E, Mitchell JR (2013) Amino acid sensing in dietary-restriction-mediated longevity: roles of signal-transducing kinases GCN2 and TOR. Biochem J 449:1–10

    PubMed  Article  CAS  Google Scholar 

  14. Geng MM, Li TJ, Kong XF et al (2011) Reduced expression of intestinal N-acetylglutamate synthase in suckling piglets: a novel molecular mechanism for arginine as a nutritionally essential amino acid for neonates. Amino Acids 40:1513–1522

    PubMed  Article  CAS  Google Scholar 

  15. Go GW, Wu G, Silvey DT et al (2012) Lipid metabolism in pigs fed supplemental conjugated linoleic acid and/or dietary arginine. Amino Acids 43:1713-1726

    Google Scholar 

  16. Hou YQ, Wang L, Zhang W et al (2012a) Protective effects of N-acetylcysteine on intestinal functions of piglets challenged with lipopolysaccharide. Amino Acids 43:1233–1242

    PubMed  Article  CAS  Google Scholar 

  17. Hou YQ, Wang L, Yi D et al (2012b) N-Acetylcysteine reduces inflammation in the small intestine by regulating redox, EGF and TLR4 signaling. Amino Acids (in this issue). doi:10.1007/s00726-012-1295-x

    Google Scholar 

  18. Jewell JL, Russell RC, Guan KL (2013) Amino acid signalling upstream of mTOR. Nat Rev Mol Cell Biol 14:133–139

    PubMed  Article  CAS  Google Scholar 

  19. Jobgen W, Fu WJ, Gao H et al (2009) High fat feeding and dietary l-arginine supplementation differentially regulate gene expression in rat white adipose tissue. Amino Acids 37:187–198

    PubMed  Article  CAS  Google Scholar 

  20. Kim JY, Burghardt RC, Wu G et al (2011a) Select nutrients in the ovine uterine lumen: VII. Effects of arginine, leucine, glutamine, and glucose on trophectodem cell signaling, proliferation, and migration. Biol Reprod 84:62–69

    PubMed  Article  CAS  Google Scholar 

  21. Kim JY, Burghardt RC, Wu G et al (2011b) Select nutrients in the ovine uterine lumen: IX. Differential effects of arginine, leucine, glutamine and glucose on interferon tau, orinithine decarboxylase and nitric oxide synthase in the ovine conceptus. Biol Reprod 84:1139–1147

    PubMed  Article  CAS  Google Scholar 

  22. Kim JY, Song GW, Wu G, Bazer FW (2012) Functional roles of fructose. Proc Natl Acad Sci USA 109:E1619–E1628

    PubMed  Article  CAS  Google Scholar 

  23. Kong XF, Tan BE, Yin YL et al (2012) l-Arginine stimulates the mTOR signaling pathway and protein synthesis in porcine trophectoderm cells. J Nutr Biochem 23:1178–1183

    PubMed  Article  CAS  Google Scholar 

  24. Lei J, Feng DY, Zhang YL et al (2012a) Nutritional and regulatory role of branched-chain amino acids in lactation. Front Biosci 17:2725–2739

    Article  Google Scholar 

  25. Lei J, Feng DY, Zhang YL et al (2012b) Hormonal regulation of leucine catabolism in mammary epithelial cells. Amino Acids (in this issue). doi:10.1007/s00726-012-1332-9

    Google Scholar 

  26. Li P, Mai KS, Trushenski J, Wu G (2009) New developments in fish amino acid nutrition: towards functional and environmentally oriented aquafeeds. Amino Acids 37:43–53

    PubMed  Article  Google Scholar 

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

    PubMed  Article  CAS  Google Scholar 

  28. Li FN, Yin YL, Tan BE et al (2011b) Leucine nutrition in animals and humans: mTOR signaling and beyond. Amino Acids 41:1185–1193

    PubMed  Article  CAS  Google Scholar 

  29. Liu XD, Wu X, Yin YL et al (2012) Effects of dietary l-arginine or N-carbamylglutamate supplementation during late gestation of sows on the miR-15b/16, miR-221/222, VEGFA and eNOS expression in umbilical vein. Amino Acids 42:2111–2119

    PubMed  Article  CAS  Google Scholar 

  30. Mimoun S, Andriamihaja M, Chaumontet C et al (2012) Detoxification of H2S by differentiated colonic epithelial cells: implication of the sulfide oxidizing unit and of the cell respiratory capacity. Antioxid Redox Signal 17:1–10

    PubMed  Article  CAS  Google Scholar 

  31. Ren WK, Luo W, Wu MM et al (2011) Dietary l-glutamine supplementation improves pregnancy outcome in mice infected with type-2 porcine circovirus. Amino Acids (in this issue). doi:10.1007/s00726-011-1134-5

    Google Scholar 

  32. Ren WK, Zou LX, Ruan Z et al (2013) Dietary l-proline supplementation confers immuno-stimulatory effects on inactivated Pasteurella multocida vaccine immunized mice. Amino Acids (in this issue). doi:10.1007/s00726-013-1490-4

  33. Rezaei R, Wang WW, Wu ZL et al (2013a) Biochemical and physiological bases for utilization of dietary amino acids by young pigs. J Anim Sci Biotech 4:7. doi:10.1186/2049-1891-4-7

    Article  CAS  Google Scholar 

  34. Rezaei R, Knabe DA, Tekwe CD et al (2013b) Dietary supplementation with monosodium glutamate is safe and improves growth performance in postweaning pigs. Amino Acids 44:911–923

    PubMed  Article  CAS  Google Scholar 

  35. San Gabriel A, Uneyama H (2012) Amino acid sensing in the gastrointestinal tract. Amino Acids (in this issue). doi:10.1007/s00726-012-1371-2

    PubMed  Google Scholar 

  36. Satterfield MC, Dunlap KA, Keisler DH et al (2011) Arginine nutrition and fetal brown adipose tissue development in nutrient-restricted sheep. Amino Acids (in this issue). doi:10.1007/s00726-011-1168-8

    Google Scholar 

  37. Satterfield MC, Dunlap KA, Keisler DH et al (2012) Arginine nutrition and fetal brown adipose tissue development in diet-induced obese sheep. Amino Acids 43:1593–1603

    Article  Google Scholar 

  38. Suryawan A, Nguyen HV, Almonaci RD, Davis TA (2012) Abundance of amino acid transporters involved in mTORC1 activation in skeletal muscle of neonatal pigs is developmentally regulated. Amino Acids (in this issue). doi:10.1007/s00726-012-1326-7

    PubMed  Google Scholar 

  39. Tan BE, Li XG, Wu G et al (2012) Dynamic changes in blood flow and oxygen consumption in the portal-drained viscera of growing pigs receiving acute administration of l-arginine. Amino Acids 43:2481–2489

    PubMed  Article  CAS  Google Scholar 

  40. Wang JJ, Chen LX, Li P et al (2008) Gene expression is altered in piglet small intestine by weaning and dietary glutamine supplementation. J Nutr 138:1025–1032

    PubMed  CAS  Google Scholar 

  41. Wang JJ, Wu ZL, Li DF et al (2012) Nutrition, epigenetics, and metabolic syndrome. Antioxid Redox Signal 17:282–301

    PubMed  Article  CAS  Google Scholar 

  42. Wang WW, Wu ZL, Dai ZL et al (2013) Glycine metabolism in animals and humans: implications for nutrition and health. Amino Acids (in this issue). doi:10.1007/s00726-013-1493-1

    Google Scholar 

  43. Wauson EM, Zaganjor E, Cobb MH (2013) Amino acid regulation of autophagy through the GPCR TAS1R1–TAS1R3. Autophagy 9:418–419

    PubMed  Article  CAS  Google Scholar 

  44. Wu G (2009) Amino acids: metabolism, functions, and nutrition. Amino Acids 37:1–17

    PubMed  Article  Google Scholar 

  45. Wu G (2010) Functional amino acids in growth, reproduction and health. Adv Nutr 1:31–37

    PubMed  Article  CAS  Google Scholar 

  46. Wu G (2013) Amino acids: biochemistry and nutrition. CRC Press, Boca Raton, Florida

    Book  Google Scholar 

  47. Wu G, Bazer FW, Davis TA et al (2009) Arginine metabolism and nutrition in growth, health and disease. Amino Acids 37:153–168

    PubMed  Article  CAS  Google Scholar 

  48. Wu G, Bazer FW, Burghardt RC et al (2010) Impacts of amino acid nutrition on pregnancy outcome in pigs: mechanisms and implications for swine production. J Anim Sci 88:E195–E204

    PubMed  Article  CAS  Google Scholar 

  49. Wu G, Bazer FW, Johnson GA et al (2011a) Important roles for l-glutamine in swine nutrition and production. J Anim Sci 89:2017–2030

    PubMed  Article  CAS  Google Scholar 

  50. Wu G, Bazer FW, Burghardt RC et al (2011b) Proline and hydroxyproline metabolism: implications for animal and human nutrition. Amino Acids 40:1053–1063

    PubMed  Article  CAS  Google Scholar 

  51. Wu ZL, Satterfield MC, Bazer FW et al (2012) Regulation of brown adipose tissue development and white fat reduction by l-arginine. Curr Opin Clin Nutr Metab Care 15:529–538

    PubMed  Article  CAS  Google Scholar 

  52. Wu G, Wu ZL, Dai ZL et al (2013) Dietary requirements of “nutritionally nonessential amino acids” by animals and humans. Amino Acids 44:1107–1113

    PubMed  Article  CAS  Google Scholar 

  53. Xi PB, Jiang ZY, Zheng CT et al (2011) Regulation of protein metabolism by glutamine: implications for nutrition and health. Front Biosci 16:578–597

    Article  CAS  Google Scholar 

  54. Xi PB, Jiang ZY, Dai ZL et al (2012) Regulation of protein turnover by l-glutamine in porcine intestinal epithelial cells. J Nutr Biochem 23:1012–1017

    PubMed  Article  CAS  Google Scholar 

  55. Yao K, Yin YL, Chu WY et al (2008) Dietary arginine supplementation increases mTOR signaling activity in skeletal muscle of neonatal pigs. J Nutr 138:867–872

    PubMed  CAS  Google Scholar 

  56. Yao K, Yin YL, Li XL et al (2012) Alpha-ketoglutarate inhibits glutamine degradation and enhances protein synthesis in intestinal porcine epithelial cells. Amino Acids 42:2491–2500

    PubMed  Article  CAS  Google Scholar 

  57. Yin YL, Yao K, Liu ZJ et al (2010) Supplementing l-leucine to a low-protein diet increases tissue protein synthesis in weanling pigs. Amino Acids 39:1477–1486

    PubMed  Article  CAS  Google Scholar 

Download references

Acknowledgments

The author thanks Prof. Gert Lubec for his great support and guidance of editing this special issue for “Amino Acids”. Work in the author’s laboratory at Texas A&M University was supported by Grants from National Research Initiative Competitive Grants of the USDA National Institute of Food and Agriculture, American Heart Association, International Council of Amino Acid Science, International Glutamate Technical Committee, National Institute of Health, the National Natural Science Foundation of China, and Texas A&M AgriLife Research.

Conflict of interest

The author declares no conflict of interests.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Guoyao Wu.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Wu, G. Functional amino acids in nutrition and health. Amino Acids 45, 407–411 (2013). https://doi.org/10.1007/s00726-013-1500-6

Download citation