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
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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
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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).