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Amino Acids: Beyond the Building Blocks!
Pierre-André GERAERT and Yves MERCIER
ADISSEO France SAS, 10 Place du Général de Gaulle, 92160 ANTONY, FRANCE
Introduction:
Modern broilers are marketed either at an earlier age than previous strains or much older as
heavy broilers competing with the turkey meat products. They exhibit higher breast meat potential
as well as a rather different feed intake regulation than previous birds. It thus appears crucial to
refine not only their energy needs but also their amino acid requirements. Such refinements are not
only crucial for growing poultry and swine with the rapid evolution of genotypes but also for
reproducing animals (male pigs, layers, breeders, sows) with their increased productivity.
However, it will not be the aim of the present review.
The objective of the nutritionists has long been to optimize growth and tissue accretion by
increasing nutrient density such as amino acids. The question remains about the potential benefits
of amino acids beyond the protein synthesis for muscle or reproductive organ developments. The
first step concerns the potential impact of dietary amino acids on feed intake and its regulation.
Amino acids will be absorbed at the intestinal level but might also have effects on the physiology
of the intestine : from the absorptive mechanisms to the interactions with the gut microflora.
Amino acids will then be metabolically active to enter into the protein synthesis but might also
have effect on immune function from gut to whole body. Finally, amino acids might also impact
the muscle composition and the meat quality and moreover final product stability and conservation.
Amino acids and feed intake
Lots of studies have demonstrated that mild deficiencies of protein, lysine, threonine in pigs
(Ferguson and Gous, 1997), methionine in layers (Picard et al., 1997) lead to small increase in
intake and animals adapt very quickly (days in layers) to such limited content variations. However,
deficiencies in essential amino acids, particularly tryptophan for pigs (Henry et al., 1992) and
methionine for broilers and layers strongly affect feed intake.
Excess dietary protein is often monitored through the plasma branched chain amino acid
levels such as Leucine which are not metabolised in the liver. High levels of plasma Leu have been
demonstrated to activate intracellular receptor (mTOR) which will lead to a depressed food intake
and enhanced energy expenditure (Black et al., 2009).
Palatability or umami taste is mainly related to protein-, peptide- or amino acid derived
chemicals. Pigs seem to be responsive to most D-AA and a few L-AA (Ala, Ser, Thr, Gln, Asn,
OH-Pro) and glycine known to be sweet to humans (Roura and Tedo, 2009).
Tryptophan has largely been demonstrated to be involved in the regulation of feed intake
and behaviour particularly in piglets (Le Floc’h et al., 2007). Indeed, Primot and Melchior (2008)
reviewed a large serie of trials demonstrating using various levels of Trp:Lys ratio (16 to 25) in
piglets weighing from 7 to 30 kg an increase in feed intake from 1.3 up to 16.9%. The variability of
the response is not linked to weight or age of the piglets but to the environment experienced by the
animals. Le Floc’h et al. (2007) have indeed illustrated the effect of sanitary status on the intake of
the piglets. Moreover, Jansman et al. (2000) have also shown the effect of dietary crude protein on
Trp response : decreasing the CP content of the diet increased the feed intake and weight gain
response to higher Trp levels of the diet in pres-starter and starter piglets.
The effect of tryptophan on appetite regulation might be mediated through the control of the
central production of the neuromediator : serotonin. Trp being the precursor of serotonin, it has
been demonstrated that a decrease in brain tryptophan leads to a decrease in the production of
serotonin (Henry et al., 1996 ; Sève et al., 1999 ; Pastuszewsaka et al., 2007). Inadequate feed
intake is also frequently mentioned as a limiting factor in lactating sows. The early phase of
lactation is associated with a high plasma Trp:BCAA ratio. However, reduction of this ratio
through addition of BCAA in the diet did not increase feed intake but rather decreased it (Trottier
and Easter, 1995).
Additionally, Trp might have more drastic impact on bird behaviour. Indeed, Corzo et al.
(2005) have demonstrated an increased nervousness in broiler fed Trp-deficient diets.
Amino acids and intestinal physiology
The gastrointestinal tract, while representing only 4-6 % of body mass, accounts for 2550% of whole body protein turnover. The extraction of essential dietary amino acids by the gut
might represent 20-70%. Burrin and coll showed that 60-90% of threonine intake was extracted on
first pass by the portal-drained viscera. One of the primary fates of these extracted amino acids is
synthesis of intestinal proteins which are mainly secreted into the lumen as mucus which protect
the gut from pathogens and antinutritional factors. Mucins are glycosylated proteins secreted along
the intestinal epithelium and involved in the diffusion and absorption of the nutrients along the
digestive tract. Mucins are particularly rich in threonine, proline and serine with Thr representing
as much as 28-40% of the total amino acids of mucins. Thr is thus important for gut function. De
novo synthesis of mucosal and mucin proteins appeared to be highly sensitive to luminal threonine
concentration which demonstrates the importance of dietary Thr supply to gut protein metabolism
(Nichols and Bertolo, 2008).
All environmental factors impacting the gut integrity might thus impact the need for Thr.
Intestinal inflammation (ileitis in pigs) by increasing the mobilisation of endogenous protein
appears to reinforce the demand for Thr. Moreover, using different environmental conditions such
as a clean and a dirty litter, it has been demonstrated that Cobb birds in the dirty conditions
responded better to the Thr supplementation than birds in the clean environment (Kidd and Corzo,
2006). However, a mild coccidial challenge which might slightly affect the intestinal mucosa did
not require further threonine supplementation (Kidd et al., 2003).
Competition for essential nutrients such as amino acids between native microflora and
pathogens may also be a limiting factor in gut colonization by pathogenic microorganisms. Amino
acids such as Ser, Thr, Asp and Arg have been suggested to inhibit invading microorganisms
(Ushijima and Seto, 1991).
Amino acids and immunity
A deficiency of dietary protein or amino acids has long been demonstrated to impair
immune function and increase the sensitivity of animals to infectious challenges or stressful
conditions. Recently, more fundamental research have been undertaken to better understand the
relationships between amino acid and immune function. Amino acids might indeed regulate
activation of T-lymphocytes, B-lymphocytes, natural killer cells and macrophages, improve
cellular redox status, lymphocyte proliferation, as well as the production of antibodies and
cytokines. Dietary supplementation with amino acids beyond their requirements for growth
deposition might thus be useful depending on environmental conditions particularly with the
evolution to reduce use of medication in all animal productions worldwide.
Methionine (Met) is the most important limiting amino acids in broiler diets based on cornsoybean meal. Thus requirements in Met and Total Sulphur AA have been largely addressed
including immunity in addition to growth. Dietary supplementation with methionine or cysteine
has indeed been proven beneficial for the immune system in chickens infected with Newcastle
virus through T-cell proliferation, IgG secretion, leucocyte migration and antibody titre (Tsiagbe et
al., 1987). However, using a purified diet, Met need appeared higher for growth than for humoral
immunity (Bhargava et al., 1971). Supplementary Met, but not choline, optimized the response to
phyto-hemagglutinin as well as total antibody response to SRBC a T-dependent antigen (Tsiagbe et
al., 1987). The Met level to optimize leukocyte migration inhibition assay was also higher than the
level to improve growth in broiler chicks (review Kidd, 2004). Moreover, cysteine has been found
to be 70 to 84% as effective as Met for humoral and cellular immunity.
Taurine, which is generated also from sulphur amino acids metabolism, is known as a
strong antioxidant and is the most abundant free amino acid in lymphocytes reducing the
production of proinflammatory cytokines and prostaglandin E2 (review by Li et al., 2007).
Lysine, one the key AA for protein synthesis and muscle deposition has also been
demonstrated to be involved in the synthesis of cytokines, proliferation of lymphocytes and thus in
the optimum functioning of immune system in response to infection (Konashi et al., 2000). An
inadequate supply of Lys would reduce antibody response and cell-mediated immunity in chickens
(Chen et al., 2003).
The role of Arginine in immune function has recently been reviewed by Kidd (2004).
Conversely to mammals, chickens cannot synthesize Arg de novo and are dependent from its
dietary supply. Arg impact on immune response in chickens involves NO (nitric oxide) production
of macrophages, antitumor properties, increased lymphoid organ weights, increased percentage of
CD8+ cells and an enhanced heterophil to lymphocyte ratio in response to a viral infection (review
Kidd, 2004). The immunomodulatory action of Arg is mainly mediated through cellular immune
responses rather than humoral ones (Jahanian, 2009). Using a range of CP and Arg contents,
Jahanian demonstrated that the Arg requirements of starting chicks for optimal immune functions
was largely higher than for maximum growth or feed efficiency.
Threonine is also a major component of plasma γ-globulin in animals. Dietary Thr intake
also influences components of the immune system (review Li et al., 2007) : increasing serum IgG
levels in sows, jejunal mucosal concentrations of IgA and IgG in E. coli challenged young pigs.
While Thr often appears as the third limiting amino acids, there is no clear report of a special need
of Thr for immunity in poultry (Kidd, 2004).
Branched-chain AA (Val, Ile, Leu) have also been demonstrated important for the immune
organ development whereas it appears difficult to dissociate the specific effect of each BCAA
(Kidd, 2004).
Finally, glutamine regulates the synthesis of glutathione involved in oxidative stress
defence and is required for the production of purine and pyrimidine nucleotides required for
proliferation of lymphocytes (review Li et al., 2007).
Table 1: Roles of amino acids in immune responses (from Kidd, 2004; Li et al., 2007; Niewold, 2008)
AA
Products
Alanine
Alanine
Arginine
Cysteine
Glutamate
Glutamine
Glycine
Histidine
Leucine
Lysine
Methionine
Phenylalanine
Proline
Serine
Threonine
Tryptophan
Tyrosine
Arg, Met
Arg, Met, Gly
Arg, Pro, Gln
Cys, Glu, Gly
Gln, Asp, Gly
Gln, Glu, Pro
Gln, Trp
Lys, Met, Ser
Ile, Leu, Val
Major Functions
Stimulation of lymphocyte proliferation, enhancement of
antibody production
NO
Signaling molecule; killing of pathogens; regulation of cell
metabolism and cytokine production; immunity
Taurine
Antioxidant
GABA
Neurotransmitter; inhibition of T-cells and inflammation
Glutamine
Upregulation of immune cell metabolism and function
Glu, Asp
Neurotransmitters; cell metabolism
Serine
Ceramide and phosphatidylserine formation
Histamine
Allergic reaction; vasodilator; gastric acid & central
acetylcholine secretion
HMB
Inhibition inflammation, enhancement specific immunity (1)
Lysine
Regulation of NO synthesis; antiviral activity; ketogenesis;
collagen crosslinks (lysine or hydroxylysine)
Homocysteine Oxidant; inhibitor of NO synthesis
Choline
Synthesis of betaine, acetylcholine and phosphatidylcholine
Cysteine
Glutathione synthesis, production of H2S
Tyrosine
Synthesis of bioactive substances regulating neuronal
function and cell metabolism
H2O2
Killing pathogens; intestinal integrity; a signalling
molecule; immunity
P5C
Cell proliferation; ornithine formation; gene expression;
Glycine
Antioxidant; neurotransmitter; immunomodulator
Threonine
Synthesis of mucin protein intestinal integrity; immunity
Serotonin
Neurotransmitter; inhibition of inflammation
Melatonin
Bio-rhythms; free radical scavenger; antioxidant
ANS
Inhibiting production of proinflammatory cytokines; enhancing
immunity
Dopamine
Neurotransmitter; control of behaviour, immune response
EPN, NEPN Neurotransmitters; glycogen and energy metabolism
Melanin
Free radical scavenger; inhibition of inflammation
Polyamines
Gene expression; DNA and protein synthesis; antioxidants; cell
function, proliferation and differentiation
Creatine
Energy metabolism (muscle, nerve); antioxidant; antiviral
Ornithine
Glutamate, glutamine and polyamine synthesis
Glutathione
Free radical scavenger; antioxidant; formation of
leukotrienes; immunity
Nucleic acids Genetic information; gene expression; cell cycle
and function
Citrulline
Free radical scavenger; arginine synthesis
NAD(P)
Coenzymes for oxidoreductases
Carnitine
Oxidation of LCFA, storage of energy as acetylcarnitine;
glucocorticoid-like function in immunity (2)
Glutamine
Upregulation of immune cell metabolism and function
1. Buyse et al 2008, 2. Buyse et al 2007
ANS: anthranilic acid, EPN: epinephrine, GABA: gamma-amino-butyrate, HMB: beta-hydroxy-betamethylbutyrate, LCFA: log-chain fatty acids, NEPN: norepinephrine, P5C: pyrroline-5-carboxylate
Amino acids and protein metabolism signaling
Accretion of muscle mass is dependent upon faster rates of protein synthesis than degradation.
When an animal is deprived of dietary protein, loss of body weight and negative nitrogen balance
ensue. Likewise, re-feeding accelerates protein synthesis and results in resumption of positive
nitrogen balance. Amino acids and anabolic hormones both interact to maximally enhance rates of
protein synthesis during re-feeding through an acceleration of the messenger mRNA translation
initiation. Suryawan et al. (2009) determine the role of insulin and amino acids on protein synthesis
in different tissues. The conclusion of the authors was that both insulin and amino acids increased
the fractional rate of protein synthesis in longissimus dorsi, gastrocnemius, masseter, and
diaphragma muscles in neonate piglets. Moreover, insulin, but not amino acids, stimulate skin
protein synthesis. Conversely, amino acids but not insulin stimulate protein synthesis in liver,
pancreas, spleen and lung. The stimulation of protein synthesis by amino acids is attributed to
stimulation of mRNA translation initiation. Studies conducted over the last ten years have
indicated that amino acids act as mediators of metabolic pathways in the same manner as certain
hormones (e.g. insulin) (Grizard et al., 1995 ; Lobley, 1998). One of the most frequently explored
signaling pathways is the mammalian target of rapamycin (mTOR) pathway. mTOR integrates
signals from amino acids and hormones, e.g. insulin/insulin-like growth factors (Prod’homme et al.
2004). Amino acid and insulin /IGF signalling pathways present similarities or at least common
kinase such as mTOR and P70S6K but are mediated by independent signals. Leucine (Anthony et
al. 2001 ; Kimball et al. 2006) is well described through mTOR activation resulting in S6K1
phosphorylation which lead to initiate mRNA translation and protein synthesis.
More recently, methionine has been shown to act as mRNA translation activator through S6K1
phosphorylation but without increasing eIF2α phosphorylation (Metayer-Coustard et al., 2010).
The ability of methionine in S6K1 phosphorylation in QM7 myoblasts appears also carried by the
methionine precursor keto-methylthio-butanoic acid (KMB). However, D-methionine or DLHMTBA appeared non effective to stimulate kinase activation in this cellular model.
Moreover, methionine is also involved in gene expression through epigenetic gene
regulation and DNA methylation (Waterland, 2006). The term epigenetic, literally meaning “above
genetic”, describes mechanisms that are layered on top of the DNA sequence information. The
DNA Cytosine methylation rate influences the affinity of the methylation-sensitive DNA binding
protein which plays an important role in tissue-specific gene expression. The DNA methylation
process occurs when S-Adenosyl methionine is demethylated into S-Adenosyl homocysteine. The
DNA-methylation level is thought to be responsible of various diseases (Egger et al., 2004 ; Jiang
et al., 2004). For instance, increasing dietary methionine level in broilers above the requirement
(0.37% ; 0.42% ; 0.47%) results in significant improvement of broiler breast muscle development
(from 19.9 % to 20.6%)(Corzo et al. 2009). Moreover, this increased methionine supply results in
increasing breast muscle genes expression depending on the methionine dose from 0.37 to 0.42 %
3 289 genes were differentially expressed and from 0.37 to 0.47%, 3 635 genes were differentially
expressed.
Interestingly, amino acid which were considered as only building blocks for protein
synthesis for years, are now more and more known to be involved directly or indirectly in the
regulation of the protein synthesis.
Amino Acids and Meat Quality
It has long been reported that the AA supply can modify muscle growth but not AA
composition of the muscles. However, a recent report from Conde-Aguilera et al. (2010) showed
that a deficient supply of Met and/or Cys in piglets affected the AA composition of body proteins.
Among all tissues, the longissimus dorsi muscle responded most to the Met and Cys deficiency,
with important reductions in weight, protein and Met content of the muscle but increased lipid.
Meat quality also depends on rearing conditions that can be modulated by amino acid
supply. Berri et al. (2008) showed the effect of high and low rearing density that significantly
altered the drip loss of the meat during storage. In this study drip loss was significantly increased
from 1.01 to 1.18% respectively with bird density changing from 13 to 26 birds per m². Moreover,
the increased of dietary lysine from 0.83 to 1.13% in finishing diet, allowed to decrease drip loss
from 1.01 to 0.82% and from 1.18 to 0.91% respectively in low and high density groups. This
effect was correlated with a higher ultimate pH value obtained with the high dietary lysine
compared to low dietary supply.
More surprisingly, the methionine source supply appears also a good leverage to improve
meat quality. Supplying diet with additional methionine using DL-methionine, DLhydroxyanalogue or both sources (50% DL-Methionine + 50% DL-hydroxyanalogue) lead to
obtain significant effect on meat transformation ability. Indeed, the mixed dietary methionine
sources treatment allowed a significant increase of Napole (ham transformation efficiency) yield
compared to other treatments (DL-met and DL-HMTBA) : 84.5 vs 82.8% (Berri et al. 2009).
Free Glu contributes to meat taste including ‘delicious’, ‘umami’ and ‘brothy’ tastes, and is
one important taste-active component of meat. It was suggested that among chicken, pork, and
beef, the meat including the most free Glu was chicken, followed by pork, and beef (Kato et al.,
1989). Free glutamate (Glu) content in chicken meat was decreased by 10 or 35 days of restricted
feeding (Fujimura et al., 1997, 2001). Chickens given ad libitum or restricted feeding exhibited
different meat tastes, using sensory evaluation assays (Fujimura et al., 2001). Therefore, it became
obvious that feed was one important factor of meat taste. Moreover, positive interactions between
Glu, inosine monophosphate (IMP), and potassium have been reported on taste-active components
of meat. However, Glu largely contributed to meat taste (Fujimura et al., 1996). Hence, it is
conceivable that increasing free Glu content in muscles would improve meat quality. It was clear
that free Glu content in chicken meat could be regulated by dietary CP and BCAA. Dietary high
CP level increased the free Glu of meat. And a decrease in dietary Leu induced an increase in free
Glu content and improved meat taste. These observations provide new insights for an effective
method to improve meat taste.
Amino acids as anti-oxidants
Cellular antioxidant mechanisms are more often attributed to vitamins (e.g. Vitamin E and Vitamin
C) than to amino acids. However, sulphur amino acids play a major role in antioxidant systems of
the cell through various systems.
Methionine sulfoxide reductase A and B (MSR-A and MSR-B) is an enzymatic system which turns
back into methionine, methionine sulfoxide (Figure 1). Methionine are considered as the one main
target of free radicals in protein and by the action of MSR A or B system reverse to methionine, it
can be considered as a free radical scavenging system (Stadman et al., 2005).
(CH2)2
CH3
SH
Met-SO
SOH SH
Met
CysA CysB
CysA CysB
II
MsrA or MsrB
MsrA or MsrB
S
CH3
Methionine
III
COOH
CH
ROS
Msr B
NH2
SH
S
Methionine-S-Sulfoxide
COOH
NH2
(CH2)2
CH
ROS
CH
O
COOH
MsrA
NH2
(CH2)2
S
S
S
II
O
CH3
CysA CysB
MsrA or MsrB
Methionine-R-Sulfoxide
Figure 1 : General Methionine oxydo-reduction cycle and different steps in Msrs reduction
mechanism. I) CysA radical attack the methionine sulfoxide and is converted into sulfonic acid
intermediate. II) The CysB radical attack the sulfenic acid to form a disulfide bond. III) the
disulfide bond is then reduced back to cyst radical by thioredoxin (TrX) a selenocysteine reductase.
Interestingly protein linked-methionine oxidation level is though to be involved in regulation of
immune response by modulating the activity of calcinerin (Cn) that lead to ineffective activation of
IκBα kinase complex in T lymphocytes. Thus reduced level of IκBα kinase may cause lower level
of phosphorilated level of IκBα, resulting in a compromised degradation of IκBα and an enhanced
inhibition of NFκB (Agbas & Moskovitz, 2009).
Moreover, cysteine appears as a powerful detoxifying amino acid because of it importance in
glutathione synthesis and as taurine precursor (Figure 2).
Glutathione which is a tripeptide L-Glutamyl-L-cysteinyl-Glycine appears as one of the powerful
hydrosoluble antioxidant in the cell. Due to it composition it appears obvious that Cys is the
limiting step of glutathione synthesis in the cell and that adequate sulphur amino acid supply is
needed to ensure antioxidant function of the cell.
Figure 2: Sulfur amino acids: their role in the control of oxidative status (from Metayer et al.,
2007)
As for the system methionine and Msr-A / Msr-B glutathione appears “linked” to a seleno-enzyme
glutathione peroxydase to be effective as antioxidant agent against lipid peroxide and hydrogen
peroxide.
As Cysteine appears like a “conditional” limiting amino acid depending on the stress level or
inflammatory step, methionine sources seems to give differential results on oxidative status. In
different pro-oxidant conditions (e.g. protein level and heat stress) DL-HMTBA, which is more
easily transformed into Cysteine and Taurine than DL-Methionine (Martin-Venegas et al., 2006),
appears more effective to sustain antioxidant status of the cell, mainly by maintaining higher
GSH/GSSG ratio (Swennen et al., 2010; Willemsen et al., 2010) (Figure 3). Interestingly, the effect
of DL-hydroxy-methionine on antioxidant status was also demonstrated on breast meat lipid
peroxidation during storage (Berri et al., 2009).
Tryptophan catabolism generates serotonin, melatonin and anthranilic acid (Li et al., 2007).
The latter is produced through the indoleamine 2,3-dioxygenase pathway during inflammation or
stimulation by lipoprotein polysaccharide or cytokines. Anthranilic acid has recently been found to
inhibit proinflammatory cytokines. Under inflammation, plasma Trp decreases suggesting a critical
role of Trp in the functioning of macrophages and lymphocytes. Anthranilic acid also appears an
efficient free radical scavenger of hydroxyl radical (Christen et al., 1990).
Reduced GSH/Total GSH
85
a
DLM
HMTBA
a
Reduced GSH/Total GSH (%)
*
80
b
b
75
70
65
60
Control
Heat stress
Figure 3: Liver reduced Glutathione/Total Glutathione ratio depending on methionine climatic
conditions and methionine sources. Temperature effect (<0.0001); Methionine source effect
(P=0.0057); Temp x Met. Sources (p=0.175) (Adapted form Willemsen et al. 2010)
Conclusion
Amino acids have largely demonstrated effects beyond their roles of building blocks of the
protein accretion : from a better gut functioning to an enhanced immune system. More research is
necessary to determine the optimal requirements of amino acids to improve not only muscle
development but also meat quality and stability.
Dietary supplementation beyond the quantity required for optimal growth and feed
efficiency has often been demonstrated to improve homogeneity or reduce flock variability which
has important economic impact at the slaughter plant level (Schutte et al., 1997 ; Leclercq et al.
1998 ; Corzo et al. 2004).
Finally, a promising area of research concerns the early feeding of chicks or even in ovo to
stimulate development of the potential benefits for later growth and health of the animals.
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