The metabolism of amino acids

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An adult has a requirement for a dietary intake of protein because there is continual oxidation of amino acids as a source of metabolic fuel and for gluconeogenesis in the fasting state. In the fed state, amino acids in excess of immediate requirements for protein synthesis are oxidized. Overall, for an adult in nitrogen balance, the total amount of amino acids being metabolized will be equal to the total intake of amino acids in dietary proteins.

Amino acids are also required for the synthesis of a variety of metabolic products, including:

  • purines and pyrimidines for nucleic acid synthesis;
  • haem, synthesized from glycine;
  • the catecholamine neurotransmitters, dopamine, noradrenaline and adrenaline, synthesized from tyrosine;
  • the thyroid hormones thyroxine and tri-iodothyronine, synthesized from tyrosine (section;
  • melanin, the pigment of skin and hair, synthesized from tyrosine;
  • the nicotinamide ring of the coenzymes NAD and NADP, synthesized from tryptophan (section 11.8.2);
  • the neurotransmitter serotonin (5-hydroxytryptamine), synthesized from tryptophan.
  • The neurotransmitter histamine, synthesized from histidine;
  • the neurotransmitter GABA (y-aminobutyrate) synthesized from glutamate (see Figure 5.19);
  • carnitine (section 5.5.1), synthesized from lysine and methionine;
  • creatine (section, synthesized from arginine, glycine and methionine;
  • the phospholipid bases ethanolamine and choline (section, synthesized from serine and methionine. Acetyl choline functions as a neurotransmitter;
  • taurine, synthesized from cysteine.

In general, the amounts of amino acids required for synthesis of these products are small compared with the requirement for maintenance of nitrogen balance and protein turnover.


The initial step in the metabolism of amino acids is the removal of the amino group (—NH2), leaving the carbon skeleton of the amino acid. Chemically, these carbon skeletons are ketoacids (more correctly, they are oxo-acids). A ketoacid has a —C = O group in place of the HC—NH2 group of an amino acid; the metabolism of ketoacids is discussed in section 9.3.2. Deamination

Some amino acids can be directly oxidized to their corresponding ketoacids, releasing ammonia: the process of deamination (Figure 9.7). There is a general amino acid oxidase which catalyses this reaction, but it has a low activity.

There is an active D-amino acid oxidase in the kidneys, which acts to deaminate, and hence detoxify, the small amounts of D-amino acids that arise from bacterial proteins. The ketoacids resulting from the action of D-amino acid oxidase on D-amino acids can undergo transamination (section to yield the L-isomers. This means that, at least to a limited extent, D-amino acids can be isomerized and used for protein synthesis. Although there is evidence from experimental animals that D-isomers of (some of) the essential amino acids can be used to maintain nitrogen balance, there is little information on utilization of D-amino acids in human beings.

Four amino acids are deaminated by specific enzymes:

Glyoxylic Acid Metabolism
Figure 9.7 Deamination of amino acids.
  • Glycine is deaminated to its ketoacid, glyoxylic acid, and ammonium ions by glycine oxidase.
  • Glutamate is deaminated to ketoglutarate and ammonium ions by glutamate dehydrogenase.
  • Serine is deaminated and dehydrated to pyruvate by serine deaminase (sometimes called serine dehydratase).
  • Threonine is deaminated and dehydrated to oxobutyrate by threonine deaminase. Transamination

Most amino acids are not deaminated, but undergo the process of transamination. The amino group of the amino acid is transferred onto the enzyme, leaving the ketoacid. In the second half of the reaction, the enzyme transfers the amino group onto an acceptor, which is a different ketoacid, so forming the amino acid corresponding to that ketoacid. The acceptor for the amino group at the active site of the enzyme is pyridoxal phosphate, the metabolically active coenzyme derived from vitamin B6 (section 11.9.2), forming pyridoxamine phosphate as an intermediate in the reaction. The reaction of transamination is shown in Figure 9.8, and the ketoacids corresponding to the amino acids in Table 9.9.

Transamination is a reversible reaction, so that if the ketoacid can be synthesized in the body, so can the amino acid. The essential amino acids (section 9.1.3) are those for which the only source of the ketoacid is the amino acid itself. Three of the ketoacids listed in Table 9.9 are common metabolic intermediates; they are the precursors of the three amino acids that can be considered to be completely dispensable, in that there is no requirement for them in the diet (section 9.1.3):

  • pyruvate — the ketoacid of alanine;
  • a-ketoglutarate — the ketoacid of glutamate;
  • oxaloacetate — the ketoacid of aspartate.

The reversibility of transamination has been exploited in the treatment of patients in renal failure. The traditional treatment was to provide them with a very low-protein diet, so as to minimize the total amount of urea that has to be excreted (section However, they still have to be provided with the essential amino acids. If they are provided with the essential ketoacids, they can synthesize the corresponding essential amino acids by transamination, so reducing yet further their nitrogen burden. The only amino acid for which this is not possible is lysine — the ketoacid corresponding to lysine undergoes rapid non-enzymic condensation to pipecolic acid, which cannot be metabolized further.

If the acceptor ketoacid in a transamination reaction is a-ketoglutarate, then glutamate is formed, and glutamate can readily be oxidized back to a-ketoglutarate, catalysed by glutamate dehydrogenase, with the release of ammonia. Similarly, if the acceptor ketoacid is glyoxylate, then the product is glycine, which can be oxidized


r-l— C— COO"

/ II

nh3+ \

/ °

substrate amino acid y

substrate keto-acid

amino donor ]

amino acceptor


r2— c— COO" 1



product keto-acid

product amino acid

Glycine Metabolism And Cns

pyridoxamine phosphate amino acceptor

Figure 9.8 Transamination of amino acids.

pyridoxamine phosphate amino acceptor

Figure 9.8 Transamination of amino acids.

back to glyoxylate and ammonia, catalysed by glycine oxidase. Thus, by means of a variety of transaminases, and using the reactions of glutamate dehydrogenase and glycine oxidase, all of the amino acids can, indirectly, be converted to their ketoacids and ammonia (Figure 9.9). Aspartate can also act as an intermediate in the indirect deamination of a variety of amino acids, as shown in Figure 9.12. The metabolism of ammonia

The deamination of amino acids (and a number of other reactions in the body) results in the formation of ammonium ions. Ammonium is highly toxic. The normal plasma concentration is less than 50 ^mol/L; an increase to 80—100 ^mol/L (far too little to have any detectable effect on plasma pH) results in disturbance of consciousness, and in patients whose blood ammonium rises above about 200 ^mol/L ammonia intoxication leads to coma and convulsions, and may be fatal.

Table 9.9 Transamination products of the amino acids

Amino acid






Aspartic acid




Glutamic acid



a-Ketoglutaramic acid










a-Keto-e-aminocaproate ^ pipecolic acid]


S-Methyl-ß-thiol 1 a-oxopropionate










a-Keto- ß -hydroxybutyrate







  • The ketoacid formed by transamination of lysine undergoes spontaneous cyclization.
  • The ketoacid formed by transamination of lysine undergoes spontaneous cyclization.

At any time, the total amount of ammonium to be transported around the body, and eventually excreted, is greatly in excess of the toxic level. What happens is that, as it is formed, ammonium is metabolized, mainly by the formation of glutamate from a-ketoglutarate, and then glutamine from glutamate, in a reaction catalysed by glutamine synthetase, as shown in Figure 9.10. Glutamine is transported in the bloodstream to the liver and kidneys.

It is the formation of glutamate from a-ketoglutarate that explains the neurotoxicity of ammonium; as ammonium concentrations in the nervous system rise, the reaction of glutamate dehydrogenase depletes the mitochondrial pool of a-ketoglutarate, resulting in impairment of the activity of the citric acid cycle (section 5.4.4), and so impairing energy-yielding metabolism.

In the kidneys, some glutamine is hydrolysed to glutamate (which remains in the body) and ammonium, which is excreted in the urine to neutralize excess acid excretion. The synthesis of urea

In the liver, ammonium arising from either the hydrolysis of glutamine or the reaction of adenosine deaminase (section is the substrate for synthesis of urea, the main nitrogenous excretion product. The cyclic pathway for urea synthesis is shown

Figure 9.9 Transdeamination of amino acids — transamination linked to oxidative deamination.
Alanine Deamination
Figure 9.10 The synthesis of glutamate andglutamine from ammonium, and hydrolysis of glutamine by glutaminase.

in Figure 9.11. The key compound is ornithine, which acts as a carrier on which the molecule of urea is built up. At the end of the reaction sequence, urea is released by the hydrolysis of arginine, yielding ornithine to begin the cycle again. Some urea is retained in the distal renal tubules, where it has an important role in maintaining an osmotic gradient for the resorption of water.

The total amount of urea synthesized each day is several-fold higher than the amount that is excreted. Urea diffuses readily from the bloodstream into the large intestine, where it is hydrolysed by bacterial urease to carbon dioxide and ammonium. Much of the ammonium is reabsorbed and used in the liver for the synthesis of glutamate and glutamine, and then a variety of other nitrogenous compounds. Studies with 15N urea show that a significant amount of label is found in essential amino acids. This may reflect intestinal bacterial synthesis of amino acids, or it may reflect the reversibility of the transamination of essential amino acids.

The urea synthesis cycle is also the pathway for the synthesis of the amino acid arginine. Ornithine is synthesized from glutamate, and then undergoes the reactions shown in Figure 9.11 to form arginine. Although the whole pathway of urea synthesis occurs only in the liver, the sequence of reactions leading to the formation of arginine also occurs in the kidneys, and the kidneys are the main source of arginine in the body.

The precursor for ornithine synthesis is N-acetylglutamate, which is also an obligatory activator of carbamyl phosphate synthetase. This provides a regulatory mechanism — if N-acetylglutamate is not available for ornithine synthesis (and hence there would be impaired activity of the urea synthesis cycle), then ammonium is not incorporated into carbamyl phosphate. This can be a cause of hyperammonaemia in a variety of metabolic disturbances that lead to either a lack of acetyl CoA for N-acetyl glutamate synthesis or an accumulation of propionyl CoA, which is a poor substrate for, and hence an inhibitor of, N-acetylglutamate synthetase. Incorporation of nitrogen in biosynthesis

Amino acids are the only significant source of nitrogen for synthesis of nitrogenous compounds such as haem, purines and pyrimidines. Three amino acids are especially important as nitrogen donors:

  • Glycine is incorporated intact into purines, haem and other porphyrins, and creatine (section
  • Glutamine; the amide nitrogen is transferred in an ATP-dependent reaction, replacing an oxo-group in the acceptor with an amino group.
  • Aspartate undergoes an ATP- or GTP-dependent condensation reaction with an oxo-group, followed by cleavage to release fumarate.

As shown in Figure 9.12, reactions in which aspartate acts as a nitrogen donor in this way result in a net gain of ATP, as the fumarate is hydrated to malate, then oxidized to oxaloacetate, which is then available to undergo transamination to aspartate.

How Malate Converted Oxaloacetate
Figure 9.11 The synthesis of urea.
Urea Synthesis From Valine
Figure 9.12 The role of aspartate as a nitrogen donor in synthetic reactions, and of adenosine deaminase as a source of ammonium ions.

Adenosine deaminase converts adenosine monophosphate back to inosine monophosphate, liberating ammonia. This sequence of reactions thus provides a pathway for the deamination of a variety of amino acids, linked to transamination, similar to those shown in Figure 9.9 for transamination linked to glutamate dehydrogenase or glycine oxidase.

9.3.2 The metabolism of amino acid carbon skeletons

Acetyl CoA and acetoacetate arising from the carbon skeletons of amino acids may be used for fatty acid synthesis (section 5.6.1) or be oxidized as metabolic fuel, but cannot be utilized for the synthesis of glucose (gluconeogenesis; section 5.7). Amino acids that yield acetyl CoA or acetoacetate are termed ketogenic.

By contrast, those amino acids that yield intermediates that can be used for gluconeogenesis are termed glucogenic. As shown in Table 9.10, only two amino acids are purely ketogenic: leucine and lysine. Three others yield both glucogenic fragments and either acetyl CoA or acetoacetate: tryptophan, isoleucine and phenylalanine.

The principal substrate for gluconeogenesis is oxaloacetate, which undergoes the reaction catalysed by phosphoenolpyruvate carboxykinase to yield phos-phoenolpyruvate, as shown in Figure 5.31. The onward metabolism of phosphoenolpyruvate to glucose is essentially the reverse of glycolysis shown in Figure 5.10.

The points of entry of amino acid carbon skeletons into central metabolic pathways are shown in Figure 5.20. Those that give rise to ketoglutarate, succinyl CoA, fumarate or oxaloacetate can be regarded as directly increasing the tissue pool of citric acid cycle intermediates, and hence permitting the withdrawal of oxaloacetate for gluconeogenesis.

Those amino acids that give rise to pyruvate also increase the tissue pool of oxaloacetate, as pyruvate is carboxylated to oxaloacetate in the reaction catalysed by pyruvate carboxylase (section 5.7).

Gluconeogenesis is an important fate of amino acid carbon skeletons in the fasting state, when the metabolic imperative is to maintain a supply of glucose for the central nervous system and red blood cells. However, in the fed state the carbon skeletons of

Table 9.10 Metabolic fates of the carbon skeletons of amino acids

Glucogenic intermediates

Ketogenic intermediates




Glycine ^ serine








Acetyl CoA

Arginine ^ ornithine



Glutamine ^ glutamate



Proline ^ glutamate



Histidine ^ glutamate




Propionyl CoA



Propionyl CoA

Acetyl CoA


Succinyl CoA


Asparagine ^ aspartate




Oxaloacetate or fumarate


Phenylalanine ^ tyrosine





Acetoacetate and acetyl CoA


Acetyl CoA

amino acids in excess of requirements for protein synthesis will mainly be used for formation of acetyl CoA for fatty acid synthesis, and storage as adipose tissue triacylglycerol.

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    Which non standard amino acid form by carboxylation of glutamate?
    9 years ago
  • Cailyn
    How malate is converted to oxaloacetate?
    9 years ago
  • Duenna
    Which amino acid directly oxidized by deaminase?
    6 months ago

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