Synthesis of Nonessential Amino Acids

An essential amino acid is an amino acid that must come from the diet. Alternatively, a nonessential amino acid can be produced by cells and does not require dietary intake. Various substrates undergo a series of processes to make amino acids. There are 11 amino acids that can be completely synthesized; the other 9 are considered essential and must be included in an individual’s diet. Nonessential amino acids are alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, proline, serine, and tyrosine. Deficiency in the enzymes required for amino acid metabolism lead to serious conditions that often present early in life, such as maple syrup urine disease and phenylketonuria.

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Amino acids are building blocks for proteins and metabolic intermediates for reactions. Amino acids are classified as essential or nonessential. Essential amino acids must be incorporated into the diet because the body cannot produce them at sufficient levels to meet physiologic demands; nonessential amino acids can be produced by the body. 

  • Essential amino acids include: 
    • Phenylalanine
    • Valine
    • Threonine
    • Tryptophan
    • Methionine
    • Leucine
    • Isoleucine
    • Lysine
    • Histidine
  • Nonessential amino acids include:
    • Alanine
    • Arginine
    • Asparagine
    • Aspartic acid (aspartate)
    • Cysteine
    • Glutamine
    • Glutamic acid (glutamate)
    • Glycine
    • Proline
    • Serine
    • Tyrosine
  • Amino acid synthesis reactions can be grouped by biosynthetic families, named according to their common starting metabolite.

Biosynthetic families

Table: Comparison of biosynthetic families
Biosynthetic family Amino acid Catabolic product
α-Ketoglutarate Glutamate Glucogenic AA
Glutamine Glucogenic AA
Proline Glucogenic AA
Arginine Glucogenic AA
3-Phosphoglycerate Serine Glucogenic AA
Glycine Glucogenic AA
Cysteine Glucogenic AA
Oxaloacetate Aspartate Glucogenic AA
Asparagine Glucogenic AA
Methionine* Glucogenic AA
Threonine* Ketogenic or glucogenic AA
Lysine* Ketogenic AA
Isoleucine* Ketogenic or glucogenic AA
Pyruvate Alanine Glucogenic AA
Valine* Glucogenic AA
Leucine* Ketogenic AA
Phosphoenolpyruvate & erythrose 4-phosphate Tryptophan* Ketogenic or glucogenic AA
Phenylalanine* Ketogenic or glucogenic AA
Tyrosine Ketogenic or glucogenic AA
*Essential amino acids that must be incorporated into the diet. Production of these amino acids commonly occurs in prokaryotic organisms and plants.
AA: amino acid
Amino acid biosynthesis synthesis of nonessential amino acids

Amino acid biosynthesis overview
CoA: coenzyme A

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α-Ketoglutarate Biosynthetic Family


  • Glutamate, glutamine, proline, and arginine are synthesized from α-ketoacids, which are produced by the citric acid cycle.
    • Transamination is an essential reaction in the production of these amino acids.
    • The enzyme involved in this reaction is an aminotransferase.
  • Glutamate serves as a precursor for the production of many amino acids, such as glutamine, proline, and arginine.
    • α-ketoacid + glutamate ⇄ amino acid + α-ketoglutarate
    • Glutamate itself is formed by amination of α-ketoglutarate: α-ketoglutarate + NH4+ ⇄ glutamate

Glutamate synthesis

Glutamate is produced from α-ketoglutarate through the process of amination.

  • α-ketoglutarate + NH4+ ⇄ glutamate
  • Glutamate serves as the primary precursor for glutamine, proline, and arginine.

Glutamine synthesis

Glutamate serves as the precursor for glutamine.

  • Glutamate is converted to glutamine by glutamine synthetase.
  • Glutamine synthetase uses:
    • ATP
    • NH4+: helps prevent ammonia build-up
  • Glutamine synthetase inhibitors:
    • Amino acids: glycine, alanine, serine, histidine, tryptophan
    • Nucleotides: AMP, cytidine triphosphate (CTP)
    • Other: carbamoyl phosphate, glucosamine-6-phosphate
    • These inhibitors rely on glutamine for production, providing negative feedback when glutamine levels are high.
  • Glutamine synthetase activation: 
    • Glutamine synthetase is active in the deadenylated form.
    • Adenylyl transferase is responsible for adenylation and deadenylation.
Glutamine synthesis

Glutamine synthesis is mediated by glutamine synthetase:
This reaction requires ATP.

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Proline synthesis

Glutamate also serves as the precursor for proline. 

3 steps to produce proline from glutamate:

  1. Phosphorylation: 
    • Catalyzed by glutamate-5-kinase and glutamate-5-semialdehyde dehydrogenase 
    • Requires ATP and nicotinamide adenine dinucleotide (NADH)
    • Produces glutamate-5-semialdehyde
  2. Oxidation and dephosphorylation: 
    • Spontaneous cyclization reaction
    • Produces 1-pyrroline-5-carboxylic acid
  3. Reduction: 
    • Catalyzed by pyrroline-5-carboxylate reductase
    • Requires NADH
    • Generates proline
Reactions contributing to proline synthesis

Cyclization and reduction reactions contributing to proline synthesis:
These steps require ATP, NADH, and a cyclization intermediate.

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Arginine synthesis

Arginine is also derived from glutamate.

4 pathways to make arginine:

  1. Reversible 2-step reaction
    • From citrulline, aspartate, and ATP
    • Argininosuccinate serves as an intermediate compound.
  2. Reversible demethylation from asymmetric dimethylarginine (ADMA)
  3. Reversible reaction from ornithine and urea
  4. Reversible reaction from citrulline, nitric oxide, and nicotinamide adenine dinucleotide (NADP+)
The 4 ways to produce arginine

The 4 ways to produce arginine
ADMA: asymmetric dimethylarginine
NADPH and NADP+: nicotinamide adenine dinucleotide
Pi: inorganic phosphate

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3-Phosphoglycerate Biosynthetic Family

Serine, glycine, and cysteine are amino acids included in the 3-phosphoglycerate (3-PG) biosynthetic family. Serine is the first amino acid produced in this group, and it subsequently contributes to the production of glycine and cysteine.


Produced by a 3-step pathway:

  1. Oxidation of 3-phosphoglycerate 
    • Catalyzed by phosphoglycerate dehydrogenase
    • Produces 3-phosphohydroxypyruvate
    • Inhibited by high concentrations of serine
  2. Transamination of 3-phosphohydroxypyruvate
    • Catalyzed by phosphoserine transaminase
    • Produces O-phosphoserine
  3. Hydrolysis of O-phosphoserine
    • Catalyzed by phosphoserine phosphatase
    • Produces serine
Serine is made via 3 reactions

Serine is made via 3 reactions, beginning with 3-phosphoglycerate (PG) and nicotinamide adenine dinucleotide (NAD+)

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Glycine is produced from serine with the removal of a hydroxymethyl group.

  • Catalyzed by serine hydroxymethyltransferase
  • Requires tetrahydrofolate
Glycine is produced from serine

Glycine is produced from serine:
This 1-step reaction depends on the removal of a hydroxymethyl group.

Image by Lecturio. License: CC BY-NC-SA 4.0


Cysteine is produced from serine and homocysteine through a 2-step pathway:

  1. Homocysteine and serine combine to form cystathionine
    • Catalyzed by cystathionine beta-synthase
    • Homocysteine contributes sulfur group
  2. Cystathionine converted to cysteine
    • Catalyzed by cystathionine gamma-lyase
    • Also produces α-ketobutyrate
Formation of cysteine from serine and homocysteine

The formation of cysteine from serine and homocysteine

Image: “Cysteine biosynthesis” by David E. License: Public Domain

Oxaloacetate Biosynthetic Family


Aspartate, lysine, threonine, asparagine, methionine, and isoleucine are amino acids that have oxaloacetate as a common precursor.

  • Aspartate and asparagine are the only nonessential amino acids in this family.
  • Oxaloacetate is first converted to aspartate.
  • Aspartate is then converted to asparagine.


Aspartate is produced by a transamination reaction.

  • Catalyzed by an aminotransferase: transfers an amine group from another amino acid
  • Produces aspartate from oxaloacetate


Asparagine is also produced by a transamination reaction.

  • Catalyzed by asparagine synthetase 
  • Produces asparagine from aspartate

Pyruvate Biosynthetic Family


Alanine, valine, and leucine share pyruvate as a common precursor. Alanine is the only amino acid in the pyruvate biosynthetic family that can be produced by humans.

  • Pyruvate is an end product of glycolysis.
  • Feedback inhibition is provided by the final product (e.g., alanine).


Alanine is produced through a 2-step reaction. 

  1. α-ketoglutarate is converted to glutamate:
    • Catalyzed by glutamate dehydrogenase
    • Requires ammonia and NADH
  2. Glutamate transfers an amino group to pyruvate to form alanine:
    • Catalyzed by an aminotransferase enzyme
    • Requires preformed pyruvate from glycolysis

Phosphoenolpyruvate Biosynthetic Family


The aromatic amino acids phenylalanine, tryptophan, and tyrosine are included in the phosphoenolpyruvate family. Phenylalanine and tryptophan are essential amino acids; tyrosine is a nonessential amino acid.


Phenylalanine serves as the precursor for tyrosine

  • The reaction is catalyzed by biopterin-dependent phenylalanine hydroxylase.
  • Phenylalanine hydroxylase deficiency results in phenylketonuria.
  • Tyrosine is the precursor for important neurotransmitters:
    • Dopamine
    • Noradrenaline
    • Adrenaline
The conversion of l-phenylalanine into l-tyrosine

The conversion of L-phenylalanine into L-tyrosine is the 1st step in the upper left.
Tyrosine and phenylalanine are precursors to a number of crucial neurotransmitters and hormones.

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Clinical Relevance

  • Phenylketonuria (PKU): defect of phenylalanine hydroxylase that results in impairment of the conversion of phenylalanine to tyrosine and subsequent accumulation of phenylalanine. Individuals will present with psychomotor delay and seizures, and their sweat will classically have a “mousy” odor. It is critical for these individuals to avoid ingestion of phenylalanine.
  • Maple syrup urine disease: defect in the branched-chain α-ketoacid dehydrogenase complex that results in the accumulation of branched-chain amino acids. Individuals present with cognitive disabilities, sweet-smelling urine, and dystonia. The primary treatment is avoidance of branched-chain amino acids. Severe cases may require a liver transplant.
  • Homocystinuria: defect in the enzyme cystathionine β-synthase, which leads to an accumulation of homocysteine. Individuals present with flushing, developmental delay, downward lens dislocation, vascular disease, and osteoporosis. It is recommended that these individuals maintain a diet low in sulfur.
  • Alkaptonuria: deficiency of homogentisic acid dioxygenase, which impairs the normal degradation of tyrosine to fumarate. Individuals present with a bluish-black discoloration of connective tissues, arthritis, and calcifications of various tissues. There is currently no treatment for alkaptonuria, but the life expectancy remains normal in these individuals.


  1. Reitzer, L. (2009). Amino acid synthesis. In: Encyclopedia of Microbiology, 3rd ed. Academic Press, pp. 1–17.
  2. Rose A. J. (2019). Amino acid nutrition and metabolism in health and disease. Nutrients 11:2623.
  3. Young V.R. (2000). Protein and amino acids. In: Gershwin M.E., German J.B., Keen C.L. (Eds.), Nutrition and Immunology. Totowa, NJ: Humana Press.
  4. Hou, Y., Wu, G. (2018). Nutritionally essential amino acids. Advances in Nutrition 9:849–851.

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