13. Amino acid metabolism; the fate of the carbon skeleton

Last updated on July 3, 2020 at 10:28

Learning objectives

  • What does it mean that an amino acid is ketogenic?
  • What does it mean that an amino acid is glucogenic?
  • Which amino acids are purely ketogenic?
  • Which amino acids are purely glucogenic?
  • Which amino acids are both ketogenic and glucogenic?
  • What is the function of biotin as a cofactor?
  • What is the function of THF as a cofactor?
  • What is the function of AdoMet as a cofactor?
  • Where are most amino acids metabolised?
  • Where are branched-chain amino acids metabolised?
  • What is the function of D-amino acid oxidase?

Ketogenic and glucogenic amino acids

Amino acids are either ketogenic, glucogenic, or both. This refers to which metabolic pathway their carbon skeletons can take. Ketogenic amino acids can be used as substrates for ketone body synthesis, while glucogenic amino acids can be used as substrates for gluconeogenesis.

Ketogenic amino acids are ketogenic because their carbon skeleton is metabolised into acetyl-CoA. Acetyl-CoA can not be used as a substrate for gluconeogenesis, which is why these amino acids are not glucogenic. Only two amino acids are purely ketogenic; leucine and lysine. Leucine is very common in proteins, so most proteins contain ketogenic amino acids.

The carbon skeleton of glucogenic amino acids are metabolised into pyruvate or any of the substrates of the TCA cycle, all of which can be used as substrates for gluconeogenesis. Nine amino acids are purely glucogenic. These are arginine, asparagine, aspartate, glutamate, glutamine, histidine, methionine, proline, and valine.

Nine amino acids are both glucogenic and ketogenic. The carbon skeleton of these amino acids can either go through two different pathways where one yields a glucogenic substrate and the other yields a ketogenic substrate, or their carbon skeleton is metabolised to both glucogenic and ketogenic substrates. These are alanine, cysteine, glycine, isoleucine, phenylalanine, serine, threonine, tryptophan, and tyrosine.

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Cofactors in one-carbon transfer reactions

Reactions where one-carbon groups are transferred are common, especially in the catabolism of the carbon skeleton of amino acids. There are three cofactors that are used in reactions related to this. They are biotin, tetrahydrofolate (THF), and adoMet. They all transfer chemical groups containing 1 carbon, but they transfer different groups.

Biotin transfers the most oxidized 1-carbon groups, the -COO group, which is basically CO2.

THF transfers the intermediately oxidized 1-carbon groups, including methylene (CH=CH), formyl, or methyl (CH3) groups.

AdoMet transfers the most reduced 1-carbon groups, the methyl groups. AdoMet is comprised of adenosine and methionine, hence the name. The methyl group which AdoMet transfers is 1000 times more reactive than the methyl group THF transfers.

AdoMet is synthesized and recycled in the methionine cycle. After donating a methyl group AdoMet will receive a new one in this cycle. The recycling of AdoMet requires methyl-THF, coenzyme B12, and the conversion of ATP to PPi + Pi. The latter step shows that three ATP equivalents are required to transfer the most reduced methyl groups.

Metabolism of the carbon skeleton of glucogenic amino acids

Amino acids which metabolise to pyruvate

Glycine, alanine, serine, and cysteine are metabolised into pyruvate.

Glycine cleavage enzyme converts THF to methylene-THF. This methylene, together with another molecule of glycine, yields serine. Serine is converted directly to pyruvate by serine dehydratase.

Alanine aminotransferase converts alanine and α-ketoglutarate to pyruvate and glutamate.

Amino acids which metabolise to succinyl-CoA

Methionine and valine are metabolised to succinyl-CoA.

Methionine is converted into homocysteine in three steps. Cystathionine β-synthase converts homocysteine and serine into cystathionine, which is converted into propionyl-CoA in 2 steps. Valine is converted into propionyl-CoA in 7 steps.

Propionyl-CoA is converted into methylmalonyl-CoA in 2 steps, which is then converted to succinyl-CoA by methylmalonyl-CoA mutase.

Amino acids which metabolise to α-ketoglutarate

Glutamine, arginine, histidine, and proline are metabolised to α-ketoglutarate.

Arginine is converted to ornithine by arginase. After a 2 more reactions ornithine is converted into glutamate. Glutamine is converted into glutamate by glutaminase. Histidine is converted into glutamate by a 4-step process. Proline is converted into glutamate in 2 steps.

Glutamate dehydrogenase converts glutamate into α-ketoglutarate.

Amino acids which metabolise to oxaloacetate

Aspartate and asparagine are metabolised to oxaloacetate.

Asparagine is converted into aspartate by asparaginase. Aspartate and α-ketoglutarate are converted into oxaloacetate and glutamate by aspartate aminotransferase.

Metabolism of the carbon skeleton of ketogenic amino acids

Lysine and leucine are metabolised into acetoacetyl-CoA and further into acetyl-CoA.

Metabolism of the carbon skeleton of both ketogenic and glucogenic amino acids

Tyrosine and phenylalanine are metabolised to both fumarate and acetyl-CoA.

Tryptophan is metabolised to both alanine and acetyl-CoA. Tryptophan is also a precursor for important biomolecules like niacin and serotonin.

Isoleucine is metabolised to both succinyl-CoA and acetyl-CoA.

Threonine can be metabolised by two routes. The glucogenic route yields succinyl-CoA or pyruvate, while the ketogenic route yields acetyl-CoA.

Metabolism of branched-chain amino acids

Unlike most amino acids, branched-chain amino acids are not metabolised in the liver. These amino acids are rather metabolised in skeletal muscle, adipose tissue, kidney, and brain.

These amino acids are metabolised in multiple steps. The first step is by branched-chain aminotransferase, an enzyme which is absent from the liver. The next step is by branched-chain α-keto acid dehydrogenase complex.

This mouthful of an enzyme belongs to a family of dehydrogenase enzyme complexes. This family of three have similar structure, use the same cofactors, same reaction mechanism, and catalyse similar reactions. The other two are pyruvate dehydrogenase complex and α-ketoglutarate dehydrogenase complex.

D-amino acid oxidase

All amino acids have two forms, the L and the D form. The L form is the one that our body uses and is composed of. They are drawn with the amino-group to the left. However, the D form also exists and can be ingested. This is drawn with the amino-group to the right. These amino acids cannot be used, and are degraded in the kidney by D-amino acid oxidase.

D-amino acid oxidase metabolises all D-amino acids, the most important of which being D-serine and D-glycine. The enzyme is present in large amounts in the kidney and the brain.

Summary

  • What does it mean that an amino acid is ketogenic?
    • It means that the carbon skeleton of the amino acid is metabolised to acetyl-CoA
  • What does it mean that an amino acid is glucogenic?
    • It means that the carbon skeleton of the amino acid is metabolised to a gluconeogenetic substrate
  • Which amino acids are purely ketogenic?
    • Lysine and leucine
  • Which amino acids are purely glucogenic?
    • Arginine, asparagine, aspartate, glutamate, glutamine, histidine, methionine, proline, and valine
  • Which amino acids are both ketogenic and glucogenic?
    • Alanine, cysteine, glycine, isoleucine, phenylalanine, serine, threonine, tryptophan, and tyrosine
  • What is the function of biotin as a cofactor?
    • Biotin transfers the most oxidized (lowest energy) 1-carbon group, the -COO group
  • What is the function of THF as a cofactor?
    • THF transfers the intermediate oxidized 1-carbon groups, including methylene, formyl, and methyl
  • What is the function of AdoMet as a cofactor?
    • AdoMet transfers the most reduced 1-carbon groups, including methyl
  • Where are most amino acids metabolised?
    • In the liver
  • Where are branched-chain amino acids metabolised?
    • Skeletal muscle, adipose tissue, kidney, and brain
  • What is the function of D-amino acid oxidase?
    • To degrade ingested D-amino acids

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12. Urea cycle and ammonium metabolism

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14. Synthesis of non-essential amino acids

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