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

2-aminoadipic acid pipecolic acid

2-oxoadipic acid glutaryl CoA

glutaconyl CoA

crotonyl CoA

3-hydroxybutyryl CoA

acetoacetyl CoA

acetyl CoA Figure 6 Metabolism of lysine.

Methionine and cysteine The conversion of methionine to cysteine via the so-called transsulfura-tion pathway has already been mentioned (Figure 5). This pathway appears to act mainly as a biosyn-thetic pathway for the synthesis of cysteine. There is an alternative pathway for methionine catabolism that involves transamination to methyl thio-a-oxo-butyrate and then to methyl thiopropionate.

Cysteine can be transaminated to thiopyruvate, which then undergoes desulfuration to pyruvate and hydrogen sulfide (Figure 5). Cysteine can also be oxidized to cysteine sulfinic acid, which can then be decarboxylated to hypotaurine, and this is then oxidized to taurine. High concentrations of taurine are found within most cells of the body, although its role is far from clear. In the liver the main fate of taurine is the production of taurocholic acid, which acts as an emulsifier in the bile. Another key role for cysteine is in the synthesis of the tripeptide glu-tathione, which is an important intracellular antioxidant.

Leucine, isoleucine, and valine The branched-chain amino acids are unusual in that the first step in their metabolism occurs in muscle rather than liver. This step is transamination, producing a-oxoisocaproic acid, a-oxo-^-methyl valeric acid, and a-oxoisova-leric acid. These ketoacids are then transported to the liver for decarboxylation and dehydrogenation. Subsequent catabolism yields acetyl CoA and acetoacetate in the case of leucine, acetyl CoA and propionyl CoA from isoleucine, and succinyl CoA from valine (Figure 7).

Histidine The first step in histidine metabolism is deamination to urocanic acid. Subsequent metabolism of this compound can follow several different pathways, but the major pathway is the one that involves formiminoglutamic acid (FIGLU), which is demethylated by a terahydrofolic acid-dependent leucine

a-oxoisocaproate

isovaleryl CoA

,3-methyl valeryl CoA

,3-methyl crotonyl CoA

^-methyl glutaconyl CoA

^-methyl glutaconyl CoA

^-hydroxy-^-methyl glutaryl CoA acetyl CoA acetoacetate isoleucine

a-oxo-^-methyl valerate

a-methylbutyryl CoA

tiglyl CoA

a-methyl-^-hydroxybutyryl CoA

a -methylacetoacetyl CoA

propionyl CoA acetyl CoA

valine

a-oxoisovalerate

isobutyryl CoA

methacrylyl CoA

^-hydroxyisobutyryl CoA

^-hydroxyisobutyrate

methylmalonic semialdehyde

methylmalonyl CoA

succinyl CoA

Figure 7 Metabolism of the branched-chain amino acids.

reaction to glutamic acid (Figure 4). This forms the basis of the FIGLU test for folate status. Another physiologically important pathway of histidine metabolism is decarboxylation to histamine, for which vitamin B6 is a cofactor.

Phenylalanine and tyrosine Since mammalian enzymes cannot break open the benzene ring of phenylalanine, the only important pathway for cat-abolism of this amino acid is through hydroxylation to tyrosine. If the phenylalanine hydroxylase enzyme is lacking, as in phenylketonuria, a high concentration of phenylalanine accumulates and it is converted to phenylpyruvate, phenyllactate, and phenylacetate, which are toxic.

Tyrosine is transaminated to p-hydroxyphenylpyr-uvate, which is then decarboxylated to homogentisic acid. This is subsequently metabolized to acetoacetic acid and fumaric acid (Figure 8). Small amounts of tyrosine are hydroxylated to 3,4-dihydroxyphenyla-lanine (DOPA), which is then decarboxylated to the catecholamines dopamine, noradrenaline, and adrenaline. DOPA can also be converted to the pigment melanin. In the thyroid gland, protein-bound tyrosine is iodinated to the thyroid hormones tri-iodothyronine and thyroxine.

Tryptophan Tryptophan is oxidized by the hormone-sensitive enzyme tryptophan oxygenase to N-formyl kynurenine, which then follows a series of steps to yield amino-carboxymuconic semialdehyde. Most of this undergoes enzymic decarboxylation, leading ultimately to acetyl CoA. However, a small proportion undergoes nonenzymic cyclization to quinolic acid, which leads to the formation of NAD. This is why excess dietary tryptophan can meet the requirement for the vitamin niacin (Figure 9).

One of the steps in the catabolism of tryptophan is catalyzed by the vitamin B6-dependent enzyme kynureninase. If vitamin B6 status is inadequate phenylalanine

p-hydroxyphenylpyruvic acid dopamine

homogentisic acid noradrenaline i e maleyl acetoacetic acid adrenaline acetoacetic acid fumaric acid

Figure 8 Metabolism of phenylalanine and tyrosine.

tryptophan

A/-formyl kynurenine

kynurenine

3-hydroxykynurenine

3-hydroxyanthranilic acid

amino carboxymuconic _

semialdehyde

2-aminomuconic semialdehyde

2-aminomuconic acid u a -oxoadipic acid

acetyl CoA Figure 9 Metabolism of tryptophan and a large dose of tryptophan is administered, much of the tryptophan will be metabolized by an alternative pathway to kynurenic and xanthurenic acids, which will be excreted in the urine. This is the basis of the tryptophan load test for vitamin B6 status.

A small amount of tryptophan undergoes hydro-xylation to 5-hydroxytryptophan, which is then decarboxylated to the physiologically active amine 5-hydroxytryptamine (serotonin).

Alanine Alanine is metabolized by transamination to pyruvate.

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