| METABOLISM OF THE CARBON SKELETONS OF AMINO ACIDS
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Metabolism of amino acids interfaces with carbohydrate and lipid metabolism
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| When one examines the metabolism of the carbon skeletons of the 20 common amino acids, there is an obvious interface with carbohydrate and lipid metabolism. Virtually all the carbons can be converted into intermediates in the glycolytic pathway, the TCA cycle, or lipid metabolism. The first step in this process is the transfer of the α-amino group by transamination to α-ketoglutarate or oxaloacetate, providing glutamate and aspartate, the sources for the nitrogen atoms of the urea cycle (Fig. 18.3). The exception to this is lysine, which does not undergo transamination. Although the details of pathways for the various amino acids vary, the general rule is that there is loss of the amino group, followed by either direct metabolism in a central pathway (glycolysis, the TCA cycle, or ketone body metabolism), or one or more intermediate conversions to yield a metabolite in one of the central pathways. Examples of amino acids that follow the former scheme include alanine, glutamate, and aspartate, which yield pyruvate, α-ketoglutarate and oxaloacetate, respectively, upon removal of their amino group. The branched-chain amino acids, leucine, valine, and isoleucine, and the aromatic amino acids, tyrosine, tryptophan, and phenylalanine are examples of the latter, more complex scheme.
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| Amino acids may be either glucogenic or ketogenic
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| HOMOCYSTINURIA (Incidence 1 in 340 000) |
| A tall 23-year-old male with wide-span and long 'spidery' fingers and lens dislocation, thought to result from Marfan's syndrome, was admitted with a deep vein thrombosis, following a transatlantic flight. The resident questioned the diagnosis of Marfan's and requested plasma amino acid measurements. These showed elevated methionine and homocysteine dimers, which are diagnostic of homocystinuria. |
| Comment. The features of Marfan's syndrome and homocystinuria are similar. In Marfan's syndrome, regular echocardiography is appropriate to assess aortic valve and thoracic aortic size to identify risk of rupture. In homocystinuria, there is, in addition, an increased risk of thrombotic events in the arterial or venous system. This can be reduced by a combination of anti-platelet agents (aspirin and dipyridamole) and reduction in plasma homocysteine levels. |
| The metabolism of methionine is complex involving recycling and desulfuration pathways. Catabolism proceeds by demethylation to homocysteine, which is converted to an intermediate cystathionine by the enzyme cystathionine β-synthase, then to cysteine. Fortunately, approximately half the cases of cystathionine β-synthase deficiency improve on treatment with pharmacological doses of pyridoxine (the enzyme co-factor). In other cases, a combination of protein restriction, amino acid supplementation (excluding methionine) or betaine, which acts as an alternate methyl donor to convert homocysteine into methionine - reduce the homocysteine levels. |
| Depending on the point at which the carbons from an amino acid enter central metabolism, that amino acid may be considered to be either glucogenic or ketogenic (i.e. possessing the ability to increase the concentrations of either glucose or ketone bodies, respectively, when fed to an animal). Those
amino acids that feed carbons into the TCA cycle at the level of α-ketoglutarate, succinyl-CoA, fumarate, or oxaloacetate, and those that produce pyruvate can all give rise to the net synthesis of glucose via gluconeogenesis and are hence designated glucogenic. Those amino acids that feed carbons into central metabolism at the level of acetyl-CoA or acetoacetyl-CoA are considered ketogenic. Because of the nature of the TCA cycle, no net flow of carbons can occur between acetate or its equivalent to glucose via gluconeogenesis (see Chapter 12).
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Several amino acids, primarily those with more complex or aromatic structures, can yield both glucogenic and ketogenic fragments (Fig. 18.9). Only the amino acids, leucine and lysine, are regarded as being exclusively ketogenic and, because of its complex metabolism and lack of ability to undergo transamination, some authors do not consider lysine to be exclusively ketogenic. These classifications may be summarized as follows:
- glucogenic amino acids (yield pyruvate, or a TCA cycle intermediate): aspartic acid, glutamic acid, asparagine, glutamine, histidine, proline, arginine, glycine, alanine, serine, cysteine, methionine, valine;
- ketogenic amino acids (yield acetoacetate or acetyl-CoA): leucine, lysine;
- both glucogenic and ketogenic amino acids (yield pyruvate, or a TCA cycle intermediate, in addition to acetoacetate or acetyl-CoA): phenylalanine, tyrosine, tryptophan, isoleucine, threonine.
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| Figure 18.9 Amino acid metabolism and central metabolic pathways. This figure summarizes the interactions between amino acid metabolism and central metabolic pathways. The amino acids marked with an asterisk are ketogenic only. PEP: phosphoenolpyruvate. |
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