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2-oxoglutarate

Glutamate

Fig. 6.2.1 A representative transamination reaction.

Some amino acids and their 2-oxoacid derivatives are listed below.

Amino acid 2-Oxoacid

Relevance to energy metabolism

Alanine Pyruvate

Glutamate 2-Oxoglutarate

Aspartate Oxaloacetate

Leucine 2-Oxo-3-methylvalerate

Isoleucine 2-Oxo-4-methylvalerate

Valine 2-Oxo-3-methylbutyrate

End-product of glycolysis Intermediate in tricarboxylic acid cycle

Intermediate in tricarboxylic acid cycle

May be oxidised in muscle May be oxidised in muscle May be oxidised in muscle acid from which an amino group has been removed is a 2-oxoacid (often called a keto-acid). Each amino acid has a 2-oxoacid partner. Some examples are alanine and pyruvate, aspartate and oxaloacetate, glutamate and 2-oxoglu-tarate (Box 6.2). The 2-oxoacids corresponding to the branched-chain amino acids are less well known, but important nonetheless: they are also listed in Box 6.2. Since the 2-oxoacid partners listed above have obvious roles in other metabolic systems (e.g. pyruvate in glucose metabolism, oxaloacetate and 2-oxoglutarate as intermediates of the tricarboxylic acid cycle), it is clear that transamination serves both as a link between amino acid and other aspects of metabolism, and as a route for oxidation of amino acids.

6.3.2 Some particular aspects of amino acid metabolism

6.3.2.1 Essential and non-essential amino acids, and other metabolically distinct groups of amino acids

The classification of amino acids into essential and non-essential was originally based upon the need for them to be supplied in the diet: the non-essential were regarded as those which could be synthesised within the body. A group of conditionally essential amino acids was also distinguished. In recent years tracer methodology has led to an improved understanding of the essential nature of amino acids: see Table 6.2.

The twenty different amino acids that normally form proteins occur in reasonably constant proportions in a range of proteins. In some metabolic studies, obvious differences from these proportions are seen and these observations have led to some of our knowledge of amino acid metabolism in individual tissues.

For instance, after eating a meal containing protein, amino acids appear in the portal vein. We presume that these largely reflect the composition of the meal. However, those leaving the liver in the hepatic vein after a meal show quite different proportions. In particular, they are enriched in the three branched-

Table 6.2 Essential and non-essential amino acids.

Essential

Non-essential

Arginine (C)

Alanine

Isoleucine

Aspartic acid

Leucine

As paragine

Valine

Cysteine (C)

Histidine (C)

Glutamic acid

Lysine

Glutamine

Methionine

Glycine (C)

Threonine

Proline (C)

Phenylalanine

Serine (C)

Tryptophan

Tyrosine (C)

Essential amino acids are those which must be supplied in the diet (since they cannot be synthesised within the human body).

Non-essential amino acids can be synthesised directly by transamination of a 'carbon skeleton' which is a readily available metabolic intermediate (e.g. pyruvate, forming alanine). The conditionally essential amino acids may in principle be synthesised from the essential amino acids: in nutritional terms, they may be needed in the diet under some circumstances. For instance, histidine cannot be synthesised sufficiently rapidly if none is provided in the diet, and arginine is needed by young children. Tyrosine and cysteine can both be synthesised, but from other essential amino acids (phenylalanine and methionine respectively). Thus, they become essential if other amino acids are lacking. The classification of amino acids into essential and non-essential is always controversial. For further discussion see Further Reading.

Essential amino acids are those which must be supplied in the diet (since they cannot be synthesised within the human body).

Non-essential amino acids can be synthesised directly by transamination of a 'carbon skeleton' which is a readily available metabolic intermediate (e.g. pyruvate, forming alanine). The conditionally essential amino acids may in principle be synthesised from the essential amino acids: in nutritional terms, they may be needed in the diet under some circumstances. For instance, histidine cannot be synthesised sufficiently rapidly if none is provided in the diet, and arginine is needed by young children. Tyrosine and cysteine can both be synthesised, but from other essential amino acids (phenylalanine and methionine respectively). Thus, they become essential if other amino acids are lacking. The classification of amino acids into essential and non-essential is always controversial. For further discussion see Further Reading.

chain amino acids, valine, leucine and isoleucine. These three essential amino acids constitute about 20% of dietary protein, but represent about 70% of the amino acids leaving the liver after a meal. The implication is that other amino acids have been preferentially retained in the liver. The branched-chain amino acids are instead preferentially removed by muscle after a meal. Since muscle removes these amino acids preferentially, it cannot require them simply for protein synthesis, or they would not be matched in proportion by other amino acids. In fact, skeletal muscle has the ability to oxidise the branched-chain amino acids.

Another departure from the proportions in protein is in the pattern of amino acids leaving muscle and other non-hepatic tissues after an overnight fast; there is always a large preponderance of alanine and glutamine (Fig. 6.15), much more than their occurrence in muscle protein would suggest. Similarly, it is possible to measure the uptake of amino acids across the liver and intestine, and glutamine and alanine are found to contribute the majority of amino acids taken up (Fig. 6.15). These observations show us that individual amino acids

Fig. 6.15 The typical pattern of amino acid metabolism in different tissues. The diagram shows the difference in concentration between arterial blood and (1) the blood in a hepatic vein, carrying the venous blood from the liver; or (2) a femoral vein, which carries the venous blood mainly from the skeletal muscles of the leg. Thus, the solid bars represent the extent to which different amino acids are taken up across the small intestine and liver (the splanchnic bed), whilst the open bars show the release of amino acids from muscle into the bloodstream. These observations led to the idea that alanine (Ala) and glutamine (Gln) predominated in transferring both amino groups and carbon atoms from muscle proteolysis, to be taken up by the liver for urea synthesis and gluconeogenesis. The studies were carried out in normal subjects after an overnight fast. AIB: a-amino-isobutyric acid (a minor amino acid, not incorporated into protein). Based on Felig, P. (1975). With permission, from the Annual Review of Biochemistry 44: 933-955. ©1975 by Annual Reviews www.an nual reviews.org.

Fig. 6.15 The typical pattern of amino acid metabolism in different tissues. The diagram shows the difference in concentration between arterial blood and (1) the blood in a hepatic vein, carrying the venous blood from the liver; or (2) a femoral vein, which carries the venous blood mainly from the skeletal muscles of the leg. Thus, the solid bars represent the extent to which different amino acids are taken up across the small intestine and liver (the splanchnic bed), whilst the open bars show the release of amino acids from muscle into the bloodstream. These observations led to the idea that alanine (Ala) and glutamine (Gln) predominated in transferring both amino groups and carbon atoms from muscle proteolysis, to be taken up by the liver for urea synthesis and gluconeogenesis. The studies were carried out in normal subjects after an overnight fast. AIB: a-amino-isobutyric acid (a minor amino acid, not incorporated into protein). Based on Felig, P. (1975). With permission, from the Annual Review of Biochemistry 44: 933-955. ©1975 by Annual Reviews www.an nual reviews.org.

have specific pathways of metabolism in different tissues, some of which we shall discuss.

6.3.2.2 Branched-chain amino acids and muscle amino acid metabolism

The branched-chain amino acids (leucine, isoleucine and valine) are preferentially taken up by skeletal muscle after a meal. Their uptake is not directly stimulated by insulin and increases because the blood concentration rises. The size of the pool of branched-chain amino acids within muscle reflects the balance between a number of processes: inward transport from plasma and outward release into plasma, utilisation for protein synthesis, production from protein breakdown, and loss by transamination and degradation. There is no synthesis from other amino acids, since they are essential amino acids.

Muscle possesses a specific branched-chain 2-oxoacid dehydrogenase, which is a large complex related, and similar in many ways, to pyruvate de-hydrogenase (also a 2-oxoacid dehydrogenase). Thus, branched-chain amino acids in muscle may be transaminated and oxidised, providing a source of energy for the muscle. The amino group is transferred to a 2-oxoacid. It may then be 'passed around' between recipients, but usually the ultimate acceptor 2-oxoacid is either pyruvate (forming alanine) or 2-oxoglutarate (forming glutamate). In addition, amino groups may form ammonia (strictly, ammonium ions, NH4+) through the action of glutamate dehydrogenase (Fig. 4.8) which removes the amino group from glutamate as NH4+, producing 2-oxoglutarate again, which may again participate in transamination reactions. Glutamate and ammonia may also combine to form glutamine through the action of glutamine synthetase (Fig. 6.16). Thus, catabolism of branched chain and other amino acids leads predominantly to the release of glutamine and alanine (see Fig. 6.15). Alanine and glutamine are considered further in the next section. These interrelationships are shown in Fig. 6.17.

cooh conh2

cooh cooh Glutamine synthetase

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