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Ketogenesis Lipogenesis Gluconeogenesis

Fig. 4.6 Outline of amino acid metabolism in the liver. The intracellular effects of glucagon are relatively long-term, particularly increased expression of the enzymes for transamination and of the urea cycle. TCA cycle, tricarboxylic acid cycle.

and that of aspartic acid is oxaloacetate. The last two are intermediates of the tricarboxylic acid cycle. Each of these may lead to glucose synthesis by the pathway of gluconeogenesis (Box 4.2). Alternatively, the 2-oxoacid may undergo further metabolic transformations leading to a compound which can enter one of the catabolic pathways (acetyl-CoA for many amino acids, which can then be oxidised in the tricarboxylic acid cycle).

An important function of the liver is to synthesise urea, a relatively non-toxic compound, which is then excreted by the kidneys. Urea is the form in which we, as humans, excrete most of the amino nitrogen that is 'left over' after amino acid oxidation, although we also excrete some nitrogen in the form of ammonia, especially during starvation (see Section 8.3.2.4). The enzymes of the urea cycle are found at low levels also in the brain and adipose tissue, but the liver is the only organ contributing significant amounts of urea to the circulation.

We need to understand how amino acid nitrogen feeds into the urea cycle. This is illustrated in Fig. 4.7. The two nitrogen atoms of urea arise from ammonia and from the amino group of aspartate. Aspartate can arise, like any amino acid, from protein breakdown or from the diet, but is also readily formed by transamination of oxaloacetate (an intermediate of the tricarboxylic acid cycle), and hence many amino acids can feed their amino nitrogen in through this route. Ammonia arises essentially from two reactions: the catabolism of glutamine by glutaminase and the oxidative deamination of glutamate by glutamate dehydrogenase. The former will be covered again in Chapter 6 (Fig. 6.16). The latter is illustrated in Fig. 4.8. By linking transamination of

Mitochondrial membrane

H2N-COO-® (carbamoyl phosphate)

Ornithine

Citrulline ATP

Arginine

Arginine succinate r

Glutamate

Alanine Pyruvate

Malate K

Fig. 4.7 Outline of the supply of nitrogen atoms to the urea cycle. The donors, ammonia and aspartate, are encircled, as is the end-product, urea. The source of ammonia is discussed in the text.

Amino acid + 2-Oxoglutarate -► Glutamate + 2-Oxoacid

Transamination

L-Glutamate + NAD(P)+ + H2O-► 2-Oxoglutarate + NAD(P)H + NH4+ + H+

Glutamate dehydrogenase

Amino acid + NAD(P)+ + H2O-► 2-Oxoacid + NAD(P)H + NH4+ + H+

Net: oxidative deamination of amino acid

Fig. 4.8 Importance of glutamate dehydrogenase. The reaction catalysed by glutamate dehydrogenase, when coupled with transamination of any amino acid, leads to production of the corresponding 2-oxoacid and ammonia. (Please note that, for simplicity, ionisation states are not always shown as they would be at physiological pH; ammonium ion shown here (NH4+) may be considered the same as ammonia shown in Fig. 4.7.)

any amino acid with the reaction catalysed by glutamate dehydrogenase, there is effectively an oxidative deamination of the amino acid with the production of ammonia that can enter the urea cycle.

Catabolism of amino acids by the liver is mainly regulated on a short-term basis by substrate supply. Substrate supply depends in the fed state on the arrival of dietary amino acids, and in the starved state on the net rate of body protein breakdown. The latter is itself under hormonal control (discussed later, Section 6.3.3). On a longer-term basis amino acid catabolism is regulated by the hormones glucagon and cortisol and again by the supply of amino acids. These hormones stimulate the synthesis of enzymes of amino acid catabolism and urea synthesis. Glucagon has a short-term effect by activating amino acid transporters, particularly that for alanine, to increase amino acid uptake. In addition, there is long-term control by the amount of dietary protein (Section 2.4.2.4); when the dietary protein content is low, the hepatic enzymes of amino acid catabolism are repressed; when dietary protein is more than adequate, their expression is stimulated. Thus, the liver regulates the body's overall store of amino acids.

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