Branchedchain amino acids

The branched-chain amino acids continue to attract much attention as regards oxidation, molecular roles and dynamics.

Oxidation

The catabolism of branched-chain amino acids (BCAA) is initiated by a reversible aminotransferase reaction (Chapter 4) leading to the formation of branched-chain keto acids (BCKA). These intermediates may then undergo irreversible oxidative decarboxylation to yield acyl-CoA compounds, with further catabolism occurring via reactions analogous to those in oxidation of fatty acids. Harper et al. (1984) suggested that enhanced BCKA

© CAB international 2003. Amino Acids in Animal Nutrition, 2nd edition (ed. J.P.F. D'Mello)

oxidation might account for the depletion of plasma isoleucine and valine concentrations in antagonisms induced by feeding excess leucine. Such a mechanism would also account for the increased requirements for valine and isoleucine in poultry fed excess leucine (Chapter 14).

Oxidation of BCKA may be influenced by dietary carnitine. Owen et al. (2001) conducted a trial to elucidate the biochemical basis of reduced lipid and enhanced protein accretion in pigs fed L-carnitine. They proposed that dietary carnitine might decrease BCKA activity and thus conserve tissue pools of BCAA. Their results, summarized in Table 26.1, supported the hypothesis in that carnitine reduces BCKA dehydrogenase activity. They also observed enhanced rates of palmi-tate oxidation, more rapid flux through pyruvate carboxylase and higher rates of incorporation of amino acids into proteins in isolated hepatocytes following dietary supplementation with carnitine. Owen et al. (2001) interpreted the results to signify that carnitine availability enabled greater use of fat for energy, and diverted carbon along synthetic pathways, at the same time channelling BCAA away from oxidation and towards protein synthesis. The role of carnitine in the amelioration of BCAA antagonisms in poultry (Chapters 7 and 14) is now worthy of investigation and might help to substantiate and increase the scope of the conclusions of Owen et al. (2001).

Molecular action

Reference has already been made to the work of Anthony et al. (2000a,b) suggesting that leucine may act as a signalling molecule in the stimulation of muscle protein synthesis by enhancing availability of specific eukaryotic initiation factors (Chapter 1). Their studies demonstrated that leucine is possibly unique among the BCAA in its ability to stimulate muscle protein synthesis.

The role of leucine as a nutritional signal has been reviewed in a recent symposium (Table 26.2). Hutson and Harris (2001) explained the rationale for the selection of leucine as the theme for this symposium. The justification is based on recent findings of a new non-protein role for amino acids. There is evidence that amino acids may act in signal transduction pathways activating in particular cells some of the same signalling cascades as the anabolic hormone insulin. Leucine is unique in that it can exert the same effects as complete amino acid mixtures. Anthony et al. (2001) reported that leucine stimulated protein synthesis in skeletal muscle by enhancing both the activity and synthesis of proteins involved in mRNA translation. This stimulation is thought to be mediated partly via the mammalian target of a rapamycin (mTOR) signalling pathway where both insulin and leucine act in concert to maximize protein synthesis. Dardevet et al. (2002) have shown that leucine supplementation stimulates mus-

Table 26.1. Effect of dietary L-carnitine on performance, carcass characteristics and branched-chain keto acid (BCKA) dehydrogenase activity in pigs3.

Added L-carnitine (mg kg'1)

Table 26.1. Effect of dietary L-carnitine on performance, carcass characteristics and branched-chain keto acid (BCKA) dehydrogenase activity in pigs3.

Added L-carnitine (mg kg'1)

0

50

125

Weight gain (g day 1)

890

910

880

Feed intake (g day 1)

2840

2930

2800

Backfat thickness (cm)

3.05

2.97

2.92

Lean (%)

50.0

50.9

52.1

BCKA dehydrogenase flux in liver

82.2

60.4

54.1

mitochondria (nmol mg protein 1 It1)

BCKA dehydrogenase flux in muscle

108.8

110.1

86,5

mitochondria (nmol mg protein 1 h_1)

aCompiIed from Owen et al. (2001).

mitochondria (nmol mg protein 1 h_1)

aCompiIed from Owen et al. (2001).

Table 26.2. Leucine as a nutritional signal: aspects reviewed in a recent symposium.

Topic

Reference

Regulation of branched-chain a-keto acid dehydrogenase kinase expression in rat liver

Function of leucine in excitatory neurotransmitter metabolism in the central nervous system

Molecular mechanisms in the brain involved in the anorexia of branched-chain amino acid deficiency

Signalling pathways involved in translational control of protein synthesis in skeletal muscle by leucine

Role of leucine in the regulation of mTORa by amino acids: revelations from structure-activity studies

Harris et al. (2001) Hutson et al. (2001) Gietzen and Magrum (2001) Anthony et al. (2001) Lynch (2001)

aMammalian target of rapamycin.

cle protein synthesis in old rats. They attributed this effect to enhanced efficiency of protein translation. The overall implications of these findings for high-performance farm animals have yet to be explored.

Leucine flux

The dynamics of leucine metabolism are inextricably involved with that of isoleucine and valine impacting on dietary requirements for the three amino acids (Chapter 14). In these interactions leucine consistently emerges as a dominant antagonist, with particular effects on valine metabolism and utilization (Chapter 14). Nevertheless, under certain conditions, reciprocity may be demonstrated in these interactions. It is thus always advisable to examine BCAA dynamics as a whole rather than on an individual amino acid basis. Despite strengthening evidence of complex interactions among the BCAA, studies continue to be conducted on the component amino acids in isolation. For example, the differences in placental transport characteristics between normal and retarded pig fetuses have been reported for leucine (Table 26.3). It would be instructive to examine whether these characteristics also apply to isoleucine and valine. These results, nevertheless, support the notion that, in comparison with normal-sized siblings, retarded fetuses have lower circulating concentrations of many essential amino acids emanating from reduced placental transport of amino acids. There is mounting evidence of a direct relationship between placental amino acid transport and fetal growth. The results in Table 26.3 may reflect a general pattern for all amino acids. On the other hand, there may be leucine-specific effects. The role of leucine as a signalling molecule in the regulation of gene expression is gaining momentum. Indeed, the

Table 26.3. Leucine transport characteristics of placentae supplying normal and retarded pig fetuses at three stages of gestation3.

Stage of gestation

Type of placenta

45 days

65 days

100 days

To normal fetus To retarded fetus

Na+ independent

Na+ independent at reduced capacity relative to normal

Na+ independent

Na+ independent at equivalent rates to normal

Na+ independent and Na+ dependent at approximately equal capacity Na+ independent only

aBased on review by Ashworth et al. (2001).

aBased on review by Ashworth et al. (2001).

putative existence of a leucine-recognition molecule has been proposed (Jefferson and Kimball, 2001). Furthermore, recent studies show that other amino acids may exert specific effects during fetal development (see below).

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