Acids Links to Energy Metabolism

Enzymes for the catabolism and synthesis of amino acids are present in every tissue, but their levels of expression and activities vary in some species to suit the metabolic needs or functions of the tissue. Catabolism involves deamination/deamidation reactions with the resulting carbon skeleton reaminated to form non-essential amino acids or the carbon skeleton can be channelled into the tricarboxylic acid cycle where it is either oxidized, channelled towards gluconeogenesis via pyruvate carboxylase, or from pyruvate converted into acetate for fatty acid synthesis (see Chapter 4). The excess nitrogen (amino groups) is ultimately transaminated to form alanine, aspartate, glutamine or glutamate for entry into the ornithine cycle for urea or arginine synthesis. Metabolism in ruminants is orchestrated to conserve glucose, and so it is no surprise that amino acid carbon contributes 12-35% to gluconeogenesis (see Annison and Bryden, 1999). In early lactation when glucose demands for lactose synthesis are high, and where glucose-precursor (propionate) supply is low, the channelling of amino acid carbon towards gluconeogenesis is probably vital. Fish species are unique in this respect because their diets are generally high in protein and fatty acids, but low in carbohydrates, particularly in carnivorous fish. Fish have adapted to use amino acids as the main substrates for gluconeogenesis and as the main oxidative fuel, especially in migratory fish, which may go for long periods without eating. Apart from dietary glucose and its immediate precursors (e.g. propionate in ruminants), all new glucose carbon derives from amino acid.

The intestines and the liver are the major sites of amino acid catabolic and synthesis (Fig. 5.1, see Wu, 1998). In all species examined to date, almost 100% of dietary glutamate, glutamine and aspartate are removed by the gastrointestinal tract (GIT) during absorptive metabolism, and further quantities are recycled from the blood supply to the GIT. Surprisingly, glucose contributes only 35% to oxidative metabolism of the GIT, with most of the remainder derived from amino acids (Reeds et al., 1998). In consequence, glutamate, glutamine and alanine must be synthesized almost entirely by the animal to support protein synthesis and other metabolic functions (e.g. synthesis of purines, pyrimidines and glutathione). The fluxes of alanine, glutamine and glutamate are considerable. To support these fluxes, plus other metabolic functions, requires equivalent synthesis of glutamate, which consumes 4 mol of ATP per mole of glutamate. Reeds et al. (1998) estimated that synthesis of glutamate could account for 10% of maintenance energy expenditures.

Most often, dietary shortfalls in proline, arginine, glutamine and alanine can be made up through intestinal synthesis. High arginase activity in the liver plus the lack of a full complement of enzymes in the liver and kidney to synthesize citrulline (from glutamine, glutamate and proline) means that the intestine is the major site of net arginine and citrulline synthesis. Wu et al. (1997) estimated in post-weaning pigs that 50% of the arginine requirement for protein deposition must derive from intestinal synthesis. Sucking pigs have a limited ability to synthesize arginine from glutamate and proline, however, and on this basis arginine may become limiting. The gastrointestinal tract of the ruminant, in particular the rumen tissues, is also capable of synthesizing arginine. However, very little arginine synthesized in the gut reaches the peripheral tissues due to the high activity of

LUMEN

GUT MUCOSA

BLOOD

Proteins i

Peptides

Mucins, etc

Mucins, etc

Fig. 5.1. A general schematic of amino acid metabolism by the gastrointestinal tract and regulation of peripheral tissue metabolism. Abbreviations: AA, amino acid; Arg, arginine; Asp, aspartate; BCAA, branched-chain amino acids; Cit, citrulline; EAA, essential AA; Gin, glutamine; Glu, glutamate; GSH, glutathione; NO, nitric oxide; NTP, nucleotides; Orn, ornithine; PA, polyamines; PD, protein degradation; Pro, proline; PS, protein synthesis; Thr, threonine; ??, mechanism not directly proven.

BCAA

BCAA

Fig. 5.1. A general schematic of amino acid metabolism by the gastrointestinal tract and regulation of peripheral tissue metabolism. Abbreviations: AA, amino acid; Arg, arginine; Asp, aspartate; BCAA, branched-chain amino acids; Cit, citrulline; EAA, essential AA; Gin, glutamine; Glu, glutamate; GSH, glutathione; NO, nitric oxide; NTP, nucleotides; Orn, ornithine; PA, polyamines; PD, protein degradation; Pro, proline; PS, protein synthesis; Thr, threonine; ??, mechanism not directly proven.

arginase in the hepatic urea cycle. The mammary gland is a site of extensive amino acid catabolism and biosynthesis (Bequette et a I., 1998). Arginine is extracted by the mammary gland in two- to threefold greater quantities than are required for milk protein synthesis.

Net contributions of arginine to nitric oxide and polyamine synthesis are negligible in most tissues, but no doubt important in the regulation of vasodilatation and for cell differentiation and proliferation. Arginase activity is abundant in the mammary gland, and so most of the extra arginine is probably degraded to ornithine and, via ornithine aminotransferase, converted into proline or glutamate. Proline and glutamate uptake by the mammary gland is always less than required for milk protein synthesis and so the conversion of arginine into proline and glutamate would appear to provide a mechanism to supply these.

Nutritionally significant quantities of essential amino acids are removed by the gastrointestinal tract during absorptive metabolism. In pigs, the net appearance of essential amino acid in the portal vein (i.e. the main blood supply to the liver) represents only 40-80% of dietary supply (Stoll et al, 1998). In ruminants, net appearance in the portal vein represents 55-77% of that disappearing from the small intestines (MacRae et al., 1997). Threonine removal by the intestines is the highest, and it is likely that most of the threonine removed is directed at mucin synthesis since oxidation of threonine by the pig gut appears to be negligible (Burrin et al., 2001). Lysine, leucine, and phenylalanine are oxidized to some extent by the pig gut (Stoll et al., 1999), which appears to be in contrast with observations in sheep where only leucine is oxidized to a significant extent (Yu et al., 2000; Lobley, 2001, personal communication). Studies in pigs indicate that oxidation of essential amino acids occurs only from the lumenal side of the intestines, representing 2-5% of that available for absorption (van Goudoever et al., 2000). Although 2-5% may seem insignificant, gut oxidation represents one-third of whole body oxidation, and thus gut metabolism has a major influence on whole body amino acid requirements (Burrin et al., 2001). Endogenous secretions and abraded mucosal cells also account for a significant proportion of essential amino acid losses by the gut. Recent advances in stable isotope labelling techniques have allowed estimation of endogenous losses in pigs, sheep and cattle. Based on tracer estimates, there is a close relationship between endogenous losses and dry matter intake with losses in pigs and sheep very similar when adjusted for intake differences (25-39 g protein kg 1 intake). Dietary factors, intestinal microbes and parasites will have a major impact on gastrointestinal metabolism, and, therefore, the nutritional requirement for amino acids.

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