Synthesis of Nonessential Amino Acids

Overview

Amino acids Amino acids Organic compounds that generally contain an amino (-NH2) and a carboxyl (-COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. Basics of Amino Acids are building blocks for proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis and metabolic intermediates for reactions. Amino acids Amino acids Organic compounds that generally contain an amino (-NH2) and a carboxyl (-COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. Basics of Amino Acids are classified as essential or nonessential. Essential amino acids Essential amino acids Amino acids that are not synthesized by the human body in amounts sufficient to carry out physiological functions. They are obtained from dietary foodstuffs. Basics of Amino Acids must be incorporated into the diet because the body cannot produce them at sufficient levels to meet physiologic demands; nonessential amino acids Amino acids Organic compounds that generally contain an amino (-NH2) and a carboxyl (-COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. Basics of Amino Acids can be produced by the body. 

• Essential amino acids Essential amino acids Amino acids that are not synthesized by the human body in amounts sufficient to carry out physiological functions. They are obtained from dietary foodstuffs. Basics of Amino Acids include:
  • Phenylalanine
  • Valine
  • Threonine
  • Tryptophan
  • Methionine
  • Leucine
  • Isoleucine
  • Lysine
  • Histidine
• Nonessential amino acids Amino acids Organic compounds that generally contain an amino (-NH2) and a carboxyl (-COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. Basics of Amino Acids include:
  • Alanine
  • Arginine Arginine An essential amino acid that is physiologically active in the l-form. Urea Cycle
  • Asparagine
  • Aspartic acid (aspartate)
  • Cysteine
  • Glutamine
  • Glutamic acid Glutamic acid A non-essential amino acid naturally occurring in the l-form. Glutamic acid is the most common excitatory neurotransmitter in the central nervous system. Urea Cycle (glutamate)
  • Glycine
  • Proline
  • Serine
  • Tyrosine
• Amino acid Amino acid Amino acids (AAs) are composed of a central carbon atom attached to a carboxyl group, an amino group, a hydrogen atom, and a side chain (R group). Basics of Amino Acids synthesis Synthesis Polymerase Chain Reaction (PCR) reactions can be grouped by biosynthetic families, named according to their common starting metabolite.

Biosynthetic families

α-Ketoglutarate Biosynthetic Family

Overview

• Glutamate, glutamine, proline, and arginine Arginine An essential amino acid that is physiologically active in the l-form. Urea Cycle are synthesized from α-ketoacids, which are produced by the citric acid cycle Citric acid cycle The citric acid cycle, also known as the tricarboxylic acid (TCA) cycle or the Krebs cycle, is a cyclic set of reactions that occurs in the mitochondrial matrix. The TCA cycle is the continuation of any metabolic pathway that produces pyruvate, which is converted into its main substrate, acetyl-CoA. Citric Acid Cycle.
  • Transamination Transamination Transamination is the transfer of an amino group from an alpha-AA to an alpha-keto acid, which is an AA with an alpha-keto group (=O) instead of an alpha-amino group (NH2). Catabolism of Amino Acids is an essential reaction in the production of these amino acids Amino acids Organic compounds that generally contain an amino (-NH2) and a carboxyl (-COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. Basics of Amino Acids.
  • The enzyme involved in this reaction is an aminotransferase.
• Glutamate serves as a precursor for the production of many amino acids Amino acids Organic compounds that generally contain an amino (-NH2) and a carboxyl (-COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. Basics of Amino Acids, such as glutamine, proline, and arginine Arginine An essential amino acid that is physiologically active in the l-form. Urea Cycle.
  • α-ketoacid + glutamate ⇄ amino acid Amino acid Amino acids (AAs) are composed of a central carbon atom attached to a carboxyl group, an amino group, a hydrogen atom, and a side chain (R group). Basics of Amino Acids + α-ketoglutarate
  • Glutamate itself is formed by amination of α-ketoglutarate: α-ketoglutarate + NH₄⁺ ⇄ glutamate

Glutamate synthesis Synthesis Polymerase Chain Reaction (PCR)

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 Arginine An essential amino acid that is physiologically active in the l-form. Urea Cycle.

Glutamine synthesis Synthesis Polymerase Chain Reaction (PCR)

Glutamate serves as the precursor for glutamine.

• Glutamate is converted to glutamine by glutamine synthetase.
• Glutamine synthetase uses:
  • ATP
  • NH₄⁺: helps prevent ammonia Ammonia A colorless alkaline gas. It is formed in the body during decomposition of organic materials during a large number of metabolically important reactions. Note that the aqueous form of ammonia is referred to as ammonium hydroxide. Acid-Base Balance build-up
• Glutamine synthetase inhibitors:
  • Amino acids Amino acids Organic compounds that generally contain an amino (-NH2) and a carboxyl (-COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. Basics of Amino Acids: glycine, alanine, serine, histidine, tryptophan
  • Nucleotides Nucleotides The monomeric units from which DNA or RNA polymers are constructed. They consist of a purine or pyrimidine base, a pentose sugar, and a phosphate group. Nucleic Acids: AMP, cytidine triphosphate ( CTP CTP Purine and Pyrimidine Metabolism)
  • Other: carbamoyl phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes, glucosamine-6-phosphate
  • These inhibitors rely on glutamine for production, providing negative feedback Negative feedback Hypothalamic and Pituitary Hormones when glutamine levels are high.
• Glutamine synthetase activation:
  • Glutamine synthetase is active in the deadenylated form.
  • Adenylyl transferase is responsible for adenylation and deadenylation.

Proline synthesis Synthesis Polymerase Chain Reaction (PCR)

Glutamate also serves as the precursor for proline. 

3 steps to produce proline from glutamate:

1. Phosphorylation Phosphorylation The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. Post-translational Protein Processing:
   • Catalyzed by glutamate-5-kinase and glutamate-5-semialdehyde dehydrogenase 
   • Requires ATP and nicotinamide adenine dinucleotide Nicotinamide adenine dinucleotide A coenzyme composed of ribosylnicotinamide 5′-diphosphate coupled to adenosine 5′-phosphate by pyrophosphate linkage. It is found widely in nature and is involved in numerous enzymatic reactions in which it serves as an electron carrier by being alternately oxidized (NAD+) and reduced (NADH). Pentose Phosphate Pathway (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

Arginine Arginine An essential amino acid that is physiologically active in the l-form. Urea Cycle synthesis Synthesis Polymerase Chain Reaction (PCR)

Arginine Arginine An essential amino acid that is physiologically active in the l-form. Urea Cycle is also derived from glutamate.

4 pathways to make arginine Arginine An essential amino acid that is physiologically active in the l-form. Urea Cycle:

1. Reversible 2-step reaction
   • From citrulline Citrulline Urea Cycle, aspartate, and ATP
   • Argininosuccinate Argininosuccinate This amino acid is formed during the urea cycle from citrulline, aspartate and ATP. This reaction is catalyzed by argininosuccinic acid synthetase. Urea Cycle serves as an intermediate compound.
2. Reversible demethylation from asymmetric dimethylarginine (ADMA)
3. Reversible reaction from ornithine Ornithine An amino acid produced in the urea cycle by the splitting off of urea from arginine. Urea Cycle and urea Urea A compound formed in the liver from ammonia produced by the deamination of amino acids. It is the principal end product of protein catabolism and constitutes about one half of the total urinary solids. Urea Cycle
4. Reversible reaction from citrulline Citrulline Urea Cycle, nitric oxide Nitric Oxide A free radical gas produced endogenously by a variety of mammalian cells, synthesized from arginine by nitric oxide synthase. Nitric oxide is one of the endothelium-dependent relaxing factors released by the vascular endothelium and mediates vasodilation. It also inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion to the vascular endothelium. Nitric oxide activates cytosolic guanylate cyclase and thus elevates intracellular levels of cyclic gmp. Pulmonary Hypertension Drugs, and nicotinamide adenine dinucleotide Nicotinamide adenine dinucleotide A coenzyme composed of ribosylnicotinamide 5′-diphosphate coupled to adenosine 5′-phosphate by pyrophosphate linkage. It is found widely in nature and is involved in numerous enzymatic reactions in which it serves as an electron carrier by being alternately oxidized (NAD+) and reduced (NADH). Pentose Phosphate Pathway (NADP⁺)

3-Phosphoglycerate Biosynthetic Family

Serine, glycine, and cysteine are amino acids Amino acids Organic compounds that generally contain an amino (-NH2) and a carboxyl (-COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. Basics of Amino Acids included in the 3-phosphoglycerate 3-phosphoglycerate Glycolysis (3-PG) biosynthetic family. Serine is the first amino acid Amino acid Amino acids (AAs) are composed of a central carbon atom attached to a carboxyl group, an amino group, a hydrogen atom, and a side chain (R group). Basics of Amino Acids produced in this group, and it subsequently contributes to the production of glycine and cysteine.

Serine

Produced by a 3-step pathway:

1. Oxidation of 3-phosphoglycerate 3-phosphoglycerate Glycolysis
   • Catalyzed by phosphoglycerate dehydrogenase
   • Produces 3-phosphohydroxypyruvate
   • Inhibited by high concentrations of serine
2. Transamination Transamination Transamination is the transfer of an amino group from an alpha-AA to an alpha-keto acid, which is an AA with an alpha-keto group (=O) instead of an alpha-amino group (NH2). Catabolism of Amino Acids of 3-phosphohydroxypyruvate
   • Catalyzed by phosphoserine transaminase Transaminase A subclass of enzymes of the transferase class that catalyze the transfer of an amino group from a donor (generally an amino acid) to an acceptor (generally a 2-keto acid). Most of these enzymes are pyridoxyl phosphate proteins. Catabolism of Amino Acids
   • Produces O-phosphoserine
3. Hydrolysis Hydrolysis The process of cleaving a chemical compound by the addition of a molecule of water. Proteins and Peptides of O-phosphoserine
   • Catalyzed by phosphoserine phosphatase
   • Produces serine

Glycine

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

• Catalyzed by serine hydroxymethyltransferase
• Requires tetrahydrofolate Tetrahydrofolate Sulfonamides and Trimethoprim

Cysteine

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

Oxaloacetate Biosynthetic Family

Overview

Aspartate, lysine, threonine, asparagine, methionine, and isoleucine are amino acids Amino acids Organic compounds that generally contain an amino (-NH2) and a carboxyl (-COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. Basics of Amino Acids that have oxaloacetate Oxaloacetate Derivatives of oxaloacetic acid. Included under this heading are a broad variety of acid forms, salts, esters, and amides that include a 2-keto-1, 4-carboxy aliphatic structure. Citric Acid Cycle as a common precursor.

• Aspartate and asparagine are the only nonessential amino acids Amino acids Organic compounds that generally contain an amino (-NH2) and a carboxyl (-COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. Basics of Amino Acids in this family.
• Oxaloacetate Oxaloacetate Derivatives of oxaloacetic acid. Included under this heading are a broad variety of acid forms, salts, esters, and amides that include a 2-keto-1, 4-carboxy aliphatic structure. Citric Acid Cycle is first converted to aspartate.
• Aspartate is then converted to asparagine.

Aspartate

Aspartate is produced by a transamination Transamination Transamination is the transfer of an amino group from an alpha-AA to an alpha-keto acid, which is an AA with an alpha-keto group (=O) instead of an alpha-amino group (NH2). Catabolism of Amino Acids reaction.

• Catalyzed by an aminotransferase: transfers an amine group from another amino acid Amino acid Amino acids (AAs) are composed of a central carbon atom attached to a carboxyl group, an amino group, a hydrogen atom, and a side chain (R group). Basics of Amino Acids
• Produces aspartate from oxaloacetate Oxaloacetate Derivatives of oxaloacetic acid. Included under this heading are a broad variety of acid forms, salts, esters, and amides that include a 2-keto-1, 4-carboxy aliphatic structure. Citric Acid Cycle

Asparagine

Asparagine is also produced by a transamination Transamination Transamination is the transfer of an amino group from an alpha-AA to an alpha-keto acid, which is an AA with an alpha-keto group (=O) instead of an alpha-amino group (NH2). Catabolism of Amino Acids reaction.

• Catalyzed by asparagine synthetase 
• Produces asparagine from aspartate

Pyruvate Biosynthetic Family

Overview

Alanine, valine, and leucine share pyruvate Pyruvate Derivatives of pyruvic acid, including its salts and esters. Glycolysis as a common precursor. Alanine is the only amino acid Amino acid Amino acids (AAs) are composed of a central carbon atom attached to a carboxyl group, an amino group, a hydrogen atom, and a side chain (R group). Basics of Amino Acids in the pyruvate Pyruvate Derivatives of pyruvic acid, including its salts and esters. Glycolysis biosynthetic family that can be produced by humans.

• Pyruvate Pyruvate Derivatives of pyruvic acid, including its salts and esters. Glycolysis is an end product of glycolysis Glycolysis Glycolysis is a central metabolic pathway responsible for the breakdown of glucose and plays a vital role in generating free energy for the cell and metabolites for further oxidative degradation. Glucose primarily becomes available in the blood as a result of glycogen breakdown or from its synthesis from noncarbohydrate precursors (gluconeogenesis) and is imported into cells by specific transport proteins. Glycolysis.
• Feedback inhibition is provided by the final product (e.g., alanine).

Alanine

Alanine is produced through a 2-step reaction. 

1. α-ketoglutarate is converted to glutamate:
   • Catalyzed by glutamate dehydrogenase
   • Requires ammonia Ammonia A colorless alkaline gas. It is formed in the body during decomposition of organic materials during a large number of metabolically important reactions. Note that the aqueous form of ammonia is referred to as ammonium hydroxide. Acid-Base Balance and NADH
2. Glutamate transfers an amino group to pyruvate Pyruvate Derivatives of pyruvic acid, including its salts and esters. Glycolysis to form alanine:
   • Catalyzed by an aminotransferase enzyme Aminotransferase enzyme A subclass of enzymes of the transferase class that catalyze the transfer of an amino group from a donor (generally an amino acid) to an acceptor (generally a 2-keto acid). Most of these enzymes are pyridoxyl phosphate proteins. Catabolism of Amino Acids
   • Requires preformed pyruvate Pyruvate Derivatives of pyruvic acid, including its salts and esters. Glycolysis from glycolysis Glycolysis Glycolysis is a central metabolic pathway responsible for the breakdown of glucose and plays a vital role in generating free energy for the cell and metabolites for further oxidative degradation. Glucose primarily becomes available in the blood as a result of glycogen breakdown or from its synthesis from noncarbohydrate precursors (gluconeogenesis) and is imported into cells by specific transport proteins. Glycolysis

Phosphoenolpyruvate Biosynthetic Family

Overview

The aromatic amino acids Aromatic amino acids Amino acids containing an aromatic side chain. Basics of Amino Acids phenylalanine, tryptophan, and tyrosine are included in the phosphoenolpyruvate Phosphoenolpyruvate A monocarboxylic acid anion derived from selective deprotonation of the carboxy group of phosphoenolpyruvic acid. It is a metabolic intermediate in glycolysis; gluconeogenesis; and other pathways. Glycolysis family. Phenylalanine and tryptophan are essential amino acids Essential amino acids Amino acids that are not synthesized by the human body in amounts sufficient to carry out physiological functions. They are obtained from dietary foodstuffs. Basics of Amino Acids; tyrosine is a nonessential amino acid Amino acid Amino acids (AAs) are composed of a central carbon atom attached to a carboxyl group, an amino group, a hydrogen atom, and a side chain (R group). Basics of Amino Acids.

Tyrosine

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 Dopamine One of the catecholamine neurotransmitters in the brain. It is derived from tyrosine and is the precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. Receptors and Neurotransmitters of the CNS
  • Noradrenaline
  • Adrenaline

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 Maple syrup urine disease An autosomal recessive inherited disorder with multiple forms of phenotypic expression, caused by a defect in the oxidative decarboxylation of branched-chain amino acids. These metabolites accumulate in body fluids and render a ‘maple syrup’ odor. The disease is divided into classic, intermediate, intermittent, and thiamine responsive subtypes. The classic form presents in the first week of life with ketoacidosis, hypoglycemia, emesis, neonatal seizures, and hypertonia. The intermediate and intermittent forms present in childhood or later with acute episodes of ataxia and vomiting. Disorders of Amino Acid Metabolism: defect in the branched-chain α-ketoacid dehydrogenase complex that results in the accumulation of branched-chain amino acids Amino acids Organic compounds that generally contain an amino (-NH2) and a carboxyl (-COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. Basics of Amino Acids. Individuals present with cognitive disabilities, sweet-smelling urine, and dystonia Dystonia Dystonia is a hyperkinetic movement disorder characterized by the involuntary contraction of muscles, resulting in abnormal postures or twisting and repetitive movements. Dystonia can present in various ways as may affect many different skeletal muscle groups. Dystonia. The primary treatment is avoidance of branched-chain amino acids Amino acids Organic compounds that generally contain an amino (-NH2) and a carboxyl (-COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. Basics of Amino Acids. Severe cases may require a liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy transplant.
• Homocystinuria: defect in the enzyme cystathionine β-synthase, which leads to an accumulation of homocysteine. Individuals present with flushing, developmental delay, downward lens Lens A transparent, biconvex structure of the eye, enclosed in a capsule and situated behind the iris and in front of the vitreous humor (vitreous body). It is slightly overlapped at its margin by the ciliary processes. Adaptation by the ciliary body is crucial for ocular accommodation. Eye: Anatomy dislocation, vascular disease, and osteoporosis Osteoporosis Osteoporosis refers to a decrease in bone mass and density leading to an increased number of fractures. There are 2 forms of osteoporosis: primary, which is commonly postmenopausal or senile; and secondary, which is a manifestation of immobilization, underlying medical disorders, or long-term use of certain medications. 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 Fumarate Citric Acid Cycle. Individuals present with a bluish-black discoloration of connective tissues, arthritis Arthritis Acute or chronic inflammation of joints. Osteoarthritis, and calcifications of various tissues. There is currently no treatment for alkaptonuria, but the life expectancy Life expectancy Based on known statistical data, the number of years which any person of a given age may reasonably expected to live. Population Pyramids remains normal in these individuals.