Biosynthesis of Nonessential Amino Acids

Biosynthesis of Nonessential Amino Acids

• Humans cannot synthesize 10 proteogenic amino acids and must obtain them from the diet, known as nutritionally essential amino acids.
• The number of enzymes required to synthesize nutritionally essential amino acids is large compared to nonessential amino acids, suggesting a positive survival advantage in retaining the ability to manufacture 'easy' amino acids while losing the ability to make 'difficult' amino acids.

3 General Mechanisms of Nonessential Amino Acids

1. Transamination

• Formation of nonessential amino acids through transamination reactions.
• Glutamate: Can be synthesized by transamination of α-ketoglutarate, with the amino donor being any amino acid (except lysine, threonine, proline, hydroxylysine, and hydroxyproline).
• Alanine: Transamination of pyruvate forms alanine, with the amino donor being glutamate or aspartate.
• Aspartate: Can be synthesized by transamination of oxaloacetate, with the amino donor being glutamate.
• Serine: Synthesized by the oxidation, transamination, and subsequent dephosphorylation of 3-phosphoglycerate, an intermediate of glycolysis.

2. Assimilation of Free Ammonia

• Glutamine: Formation of glutamine from free ammonia and glutamate, catalyzed by glutamine synthetase, which is an ATP-dependent reaction.

3. Modification of the Carbon Skeletons of Existing Amino Acids

• Cysteine: Contains atoms donated by both methionine and serine, formed from homocysteine and serine through cystathionine, and hydrolyzed by cystathionine lyase.
• Glycine: Three mammalian routes for glycine formation:
  • From serine, which is converted to glycine by the removal of its hydroxymethyl group, catalyzed by serine hydroxymethyl transferase.
  • From glyoxylate and glutamate or alanine, catalyzed by glycine aminotransferase.
  • From choline.
• Tyrosine: Phenylalanine is hydroxylated to form tyrosine, catalyzed by phenylalanine hydroxylase.
• Proline: Glutamate is reduced and cyclized to form proline.
• Asparagine: Synthesized from aspartate, catalyzed by asparagine synthetase, with coupled hydrolysis of pyrophosphate to Pi by pyrophosphatase.

Hydroxyproline and Hydroxylysine

• Occur principally in collagen.
• Neither dietary hydroxyproline nor dietary hydroxylysine is incorporated during protein synthesis.
• Peptidyl hydroxyproline and hydroxylysine arise from proline and lysine, but only after these amino acids have been incorporated into peptides.
• Hydroxylation of peptidyl prolyl and peptidyl lysyl residues, catalyzed by prolyl hydroxylase and lysyl hydroxylase, requires molecular O2, ascorbate, Fe2+, and α-ketoglutarate.

Selenocysteine, the 21st Amino Acid

• Biosynthesis requires serine, selenite, ATP, a specific tRNA, and several enzymes.

• Serine provides the carbon skeleton of selenocysteine.

• Selenophosphate, formed from ATP and selenite, serves as the selenium donor.

• The specific tRNASec is first charged with serine by the ligase that charges tRNASer, and then the serine oxygen is replaced by selenium from selenophosphate.### Biosynthesis of Hydroxyproline and Hydroxylysine

• For every mole of proline or lysine hydroxylated, one mole of α-ketoglutarate is decarboxylated to succinate.

• Ascorbate is required for hydroxyproline and hydroxylysine hydroxylases.

• Deficiency of ascorbate results in scurvy, characterized by: • Bleeding gums • Swelling joints • Impaired wound healing

• Scurvy is due to impaired stability of collagen.

Biosynthesis of Selenocysteine

• Selenocysteine is the 21st amino acid.
• At least 25 human selenoproteins are known.
• Selenocysteine is present at the active site of several human enzymes that catalyze redox reactions.
• Examples of enzymes that use selenocysteine include: • Thioredoxin reductase • Glutathione peroxidase • Deiodinase (converts thyroxine to triiodothyronine)
• Selenocysteine participates in the catalytic mechanism of these enzymes.
• Replacement of selenocysteine by cysteine impairs catalytic activity.
• Impairments in human selenoproteins are implicated in: • Tumorigenesis • Atherosclerosis • Selenium deficiency cardiomyopathy (Keshan disease)
• Selenocysteine arises cotranslationally during its incorporation into peptides, unlike hydroxyproline and hydroxylysine.