Amino Acid Catabolism

Many amino acids can be converted to other useful molecules within the cell, and the same pathways may also lead to oxidation of the amino acid. It is therefore convenient to consider these metabolic fates together.

Glycine, serine, and threonine The interconversion of glycine and serine has already been mentioned (Figure 3), and this can act as a mechanism for disposal of either amino acid. In quantitative terms, however, the main tendency is for both to be converted to the common intermediate methylene tetrahydrofolate, which acts as a methyl donor in many important biosynthetic reactions, including the conversion of dUMP to dTMP for DNA synthesis.

An alternative pathway for serine catabolism is deamination to pyruvate. However, the Km of this enzyme is relatively high, so the pathway would only operate at high serine concentrations (Figure 3).

Another pathway of glycine catabolism is by condensation with acetyl CoA to form amino-acetone. This is then transaminated and dehydr-ogenated to yield carbon dioxide and pyruvate. Amino-acetone is also formed by the NAD-linked dehydrogenation of threonine, followed by the spontaneous decarboxylation of the unstable intermediate 2-amino-3-oxo-butyrate, and this appears to be the main pathway of catabolism of threonine in mammals (Figure 3).

Glycine is also an important precursor for several larger molecules. Purines are synthesized by a pathway that begins with the condensation of glycine and phosphoribosylamine. Porphyrins, including hem, are synthesized from glycine and succinyl CoA via ¿-aminolevulinic acid. Creatine synthesis involves the addition of the guanidino nitrogen from arginine to glycine. Glycine is also used to conjugate many foreign compounds, allowing them to be excreted in the urine. Glycine also conjugates with cholic acid to form the major bile acid glycocholic acid.

Glutamic acid, glutamine, proline, and arginine

Glutamic acid can be transaminated to 2-oxogluta-rate, which can enter the TCA cycle. The amino group would be tranferred to aspartate, which would then enter the urea cycle. Alternatively, glutamate can be deaminated by glutamate dehydro-genase, with the resulting ammonium entering the urea cycle as carbamoyl phosphate. Decarboxylation of glutamate yields 7-aminobutyric acid, an important inhibitory neurotransmitter.

Glutamine is deaminated to glutamic acid in the kidney; this process is central to the maintenance of acid-base balance and the control of urine pH. Glu-tamine also acts as a nitrogen donor in the synthesis of purines and pyrimidines.

Proline is metabolized by oxidation to glutamic acid, although the enzymes involved are not the same as those that are responsible for the synthesis of proline from glutamic acid (Figure 2).

Arginine is an intermediate of the urea cycle and is metabolized by hydrolysis to ornithine. Ornithine can transfer its ¿-amino group to 2-oxoglutarate, forming glutamic-7-semialdehyde, which can then be metabolized to glutamate (Figure 2). Ornithine can also be decarboxylated to putrescine, which in turn can be converted to other polyamines such as spermidine and spermine.

Arginine can also be oxidized to nitric oxide and citrulline. Nitric oxide appears to be an important cellular signaling molecule that has been implicated in numerous functions, including relaxation of the vascular endothelium and cell killing by macrophages. In the vascular endothelium, nitric oxide is made by two different nitric oxide synthase iso-zymes, one of which is inducible and the other acts constitutitively.

Aspartic acid and asparagine Aspartic acid can be transaminated to oxaloacetic acid, a TCA cycle intermediate. Alternatively, when aspartic acid feeds its amino group directly into the urea cycle, the resulting keto acid is fumarate, another TCA cycle intermediate. Aspartic acid is also the starting point for pyrimidine synthesis. Asparagine is metabolized by deamidation to aspartic acid.

Lysine In mammals, lysine is catabolized by condensing with 2-oxoglutarate to form saccharopine, which is then converted to a-aminoadipic acid and glutamate. The a-aminoadipic acid is ultimately converted to acetyl CoA. In the brain, some lysine is metabolized via a different pathway to pipecolic acid (Figure 6). Lysine is also the precursor for the synthesis of carnitine, which carries long-chain fatty acids into the mitochondrion for oxidation. In mammals this process starts with three successive methy-lations of a lysine residue in a protein. The trimethyl lysine is then released by proteolysis before undergoing further reactions to form carnitine.

-2-oxoglutarate

Iysine r2

saccharopine

|v—glutamate 2-aminoadipic semialdehyde

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