Gpm

chnh2 I

cooh

Glutaminase

Fig. 6.16 The reactions that synthesise (glutamine synthetase) and break down (glutaminase) glutamine. (Note that, for simplicity, ionisation states are not shown correctly: e.g. NH3 would be in the form of NH4+ at physiological pH.)

in blood in blood

Fig. 6.17 Major amino acids interconversions in muscle. (Adipose tissue and brain may be similar.) J, alanine aminotransferase (also called gluta mate-pyruvate transaminase); 2, leucine, valine or other aminotransferase; 3, glutamine synthetase; 4, glutamate dehydrogenase; 5, branched-chain 2-oxoacid dehydrogenase and further catabolism; 6, muscle protein synthesis; 7 muscle protein breakdown (proteolysis). For simplicity, ionisation states are not shown (e.g. NH3 would be in the form of NH4+ at physiological pH).

Fig. 6.17 Major amino acids interconversions in muscle. (Adipose tissue and brain may be similar.) J, alanine aminotransferase (also called gluta mate-pyruvate transaminase); 2, leucine, valine or other aminotransferase; 3, glutamine synthetase; 4, glutamate dehydrogenase; 5, branched-chain 2-oxoacid dehydrogenase and further catabolism; 6, muscle protein synthesis; 7 muscle protein breakdown (proteolysis). For simplicity, ionisation states are not shown (e.g. NH3 would be in the form of NH4+ at physiological pH).

6.3.2.3 Alanine and glutamine

These amino acids have a special place in a discussion of energy metabolism, as they provide links between amino acid and carbohydrate metabolism.

As discussed above, alanine and glutamine predominate amongst the amino acids leaving muscle. This is also true of other 'peripheral tissues', including adipose tissue and brain. Since glutamine carries two nitrogen atoms (in its amino group and its amide group), it is usually a larger transporter of nitrogen than is alanine. The preponderance of alanine and glutamine is much greater than would be expected if the amino acids leaving muscle simply reflected the composition of proteins being degraded (Fig. 6.15). Therefore, they must be synthesised in the tissues. We will consider their formation a little more deeply. The amino groups for alanine and glutamine, and the amide group of glutamine, may arise from the amino groups of other amino acids as discussed above. What, then, is the origin of their 'carbon skeletons' (i.e. the corresponding 2-oxoacids)?

For alanine, the corresponding 2-oxoacid is pyruvate, the end-product of glycolysis. Treatments which increase glycolysis (for instance, in isolated muscle preparations, addition of extra insulin or glucose) usually also increase alanine release. It is possible in principle that the carbon skeletons of some amino acids may form pyruvate, but the evidence that these routes contribute much to the carbon skeleton of alanine leaving muscle is not strong, and it is most likely that most of the carbon skeleton of the excess alanine leaving peripheral tissues (i.e. in excess of that produced by protein breakdown) arises from glycolysis.

For glutamine, the 2-oxoacid is 2-oxoglutarate, an intermediate in the tricarboxylic acid cycle. It is rather more possible that the carbon skeletons of other amino acids may contribute to glutamine than to alanine, since any amino acid whose breakdown leads to acetyl-CoA may do so. However, an intermediate of the tricarboxylic acid cycle cannot be 'tapped off' indefinitely without some topping up of cycle intermediates - or, since it is a cycle, it will stop. It may be that pairs of amino acids contribute to this process: for instance, catabolism of leucine leads to acetyl-CoA, and catabolism of valine leads to succinyl-CoA, another intermediate in the tricarboxylic acid cycle. Thus, these two amino acids together may replace the 2-oxoglutarate used in glutamine formation.

Alanine is taken up avidly by the liver, particularly under conditions of active gluconeogenesis, when its uptake is stimulated by glucagon. Within the liver, which has very active transaminases, alanine readily passes its amino group to 2-oxoglutarate, leaving its carbon skeleton as pyruvate, a substrate for gluconeogenesis.

Glutamine is not as good a substrate for hepatic uptake, but is removed particularly by the kidney and by the intestinal mucosal cells. In the kidney, the action of glutaminase (Fig. 6.16) removes the amide group (forming ammonia) and leaves glutamate; glutamate can be converted to 2-oxoglutarate by the action of glutamine dehydrogenase, again forming ammonia. It is generally believed that this ammonia is a route for urinary excretion of protons (H+ ions), especially in conditions of excessive acidity in the body. This point is controversial, however, and will not be further discussed here. In the intestinal cells, glutamine is an important metabolic fuel (Section 4.7.2). The pathway of metabolism leads to production of alanine, which leaves in the portal vein and thus reaches the liver, again as a substrate for conversion to pyruvate and hence glucose. Glutamine is also an important fuel for other rapidly dividing cells, as discussed in Section 4.7.2.

The major pathways of amino acid flow between tissues discussed in the last two sections are outlined in Fig. 6.18.

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