Amino acid

Amino acids are organic molecules containing at least one amino group and one carboxyl group, and they serve most famously as the structural monomers of proteins, while also participating in metabolism, signaling, and the synthesis of many essential biomolecules.

General definition and scope

In biochemistry, the term “amino acid” most often refers to α-amino acids, compounds in which the amino group is attached to the carbon atom adjacent to the carboxyl group. This carbon is called the α-carbon. The general structure of a common α-amino acid is H₂N–CH(R)–COOH, where R represents a variable side chain that determines the chemical identity and biological behavior of the amino acid.

Amino acids are central to life because they are the building blocks of proteins. In proteins, amino acids are joined by peptide bonds to form linear chains that fold into specific three-dimensional structures. Beyond protein synthesis, individual amino acids function as neurotransmitters, metabolic intermediates, precursors of hormones and cofactors, regulators of nitrogen balance, and signaling molecules.

Although hundreds of amino acids occur in nature, only a limited set is routinely incorporated into proteins by the standard genetic code. Other amino acids occur as free metabolites, components of cell walls, toxins, antibiotics, and specialized biomolecules.

Chemical structure

Most biologically important amino acids are α-amino acids. They contain four main structural features:

1. An amino group, usually –NH₂ in the uncharged form and –NH₃⁺ under physiological conditions.
2. A carboxyl group, usually –COOH in the uncharged form and –COO⁻ under physiological conditions.
3. A central α-carbon atom.
4. A variable side chain, often designated R.

The side chain may be as simple as a hydrogen atom, as in glycine, or may contain complex aromatic, sulfur-containing, acidic, basic, or branched structures. The properties of the side chain determine whether an amino acid is nonpolar, polar, acidic, basic, aromatic, sulfur-containing, or conformationally restricted.

Amino acids can also be classified according to the position of the amino group relative to the carboxyl group. α-Amino acids have the amino group on the α-carbon, β-amino acids on the next carbon, and γ-amino acids one carbon farther still. γ-Aminobutyric acid, or GABA, is a well-known γ-amino acid that functions as a neurotransmitter but is not a protein-building amino acid.

Stereochemistry

With the exception of glycine, the α-carbon of standard amino acids is chiral, meaning that it can exist in two mirror-image forms. These forms are designated L and D. The amino acids used in ribosomal protein synthesis are almost exclusively L-amino acids.

The preference for L-amino acids in proteins is one of the major examples of biological homochirality. D-amino acids do occur in nature, especially in bacterial cell walls, certain peptide antibiotics, and some specialized peptides. For example, D-alanine and D-glutamate are found in bacterial peptidoglycan.

The L/D designation is based on the configuration relative to glyceraldehyde. In most cases, L-amino acids correspond to the S configuration under the Cahn–Ingold–Prelog system, but cysteine is an important exception because its side chain contains sulfur, which changes the priority order of substituents.

Zwitterions and acid–base behavior

Amino acids are amphoteric molecules because they contain both acidic and basic functional groups. In aqueous solution near neutral pH, most α-amino acids exist predominantly as zwitterions, also called dipolar ions. In this form, the carboxyl group is deprotonated and negatively charged, while the amino group is protonated and positively charged:

H₃N⁺–CH(R)–COO⁻

Because of this internal charge separation, amino acids often have high melting points, good solubility in water, and limited solubility in nonpolar solvents.

Each amino acid has characteristic acid dissociation constants, usually expressed as pKa values. The α-carboxyl group typically has a pKa near 2, while the α-amino group usually has a pKa between 9 and 10. Ionizable side chains have additional pKa values. For example, aspartic acid and glutamic acid have acidic side chains, lysine and arginine have basic side chains, and histidine has an imidazole side chain with a pKa near physiological pH.

At a specific pH called the isoelectric point, an amino acid carries no net electrical charge. At this pH, amino acids often show minimum solubility and do not migrate in an electric field. The isoelectric point depends on the pKa values of the ionizable groups and is especially important in techniques such as isoelectric focusing and protein purification.

Classification by side-chain properties

Amino acids are commonly classified according to the chemical nature of their side chains. This classification is useful because side-chain properties strongly influence protein folding, enzyme function, membrane interactions, and molecular recognition.

Nonpolar aliphatic amino acids

These amino acids have hydrophobic side chains that tend to cluster away from water in folded proteins. They include glycine, alanine, valine, leucine, isoleucine, and proline. Glycine is the smallest amino acid and is conformationally flexible. Proline has a cyclic side chain that bonds back to the amino nitrogen, restricting backbone motion and often introducing bends or kinks in protein structures.

Aromatic amino acids

Phenylalanine, tyrosine, and tryptophan contain aromatic rings. These side chains are largely hydrophobic but can participate in π-stacking interactions and absorb ultraviolet light. Tryptophan and tyrosine are especially important contributors to the ultraviolet absorbance of proteins near 280 nm. Tyrosine also contains a hydroxyl group and can be phosphorylated in cell signaling.

Polar uncharged amino acids

Serine, threonine, asparagine, glutamine, and cysteine have side chains capable of forming hydrogen bonds. Serine and threonine contain hydroxyl groups and are common sites of phosphorylation. Asparagine and glutamine contain amide groups. Cysteine contains a thiol group that can form disulfide bonds with another cysteine, producing cystine. Disulfide bonds are important for the stability of many extracellular proteins.

Negatively charged amino acids

Aspartic acid and glutamic acid have carboxyl groups in their side chains that are negatively charged at physiological pH. They are often called aspartate and glutamate in biochemical contexts. These residues participate in metal binding, catalysis, salt bridges, and pH-sensitive interactions.

Positively charged amino acids

Lysine, arginine, and histidine have basic side chains that can carry positive charge under physiological conditions. Lysine has a terminal amino group, arginine has a guanidinium group, and histidine has an imidazole group. These amino acids are often found in active sites, nucleic acid-binding regions, and protein–protein interaction surfaces.

The standard proteinogenic amino acids

The standard genetic code specifies 20 common amino acids that are directly encoded by codons in messenger RNA. These are often called the canonical or standard proteinogenic amino acids.

The 20 common amino acids are:

| Amino acid | Three-letter code | One-letter code | General side-chain type |
|---|---:|---:|---|
| Alanine | Ala | A | Nonpolar aliphatic |
| Arginine | Arg | R | Positively charged, basic |
| Asparagine | Asn | N | Polar uncharged |
| Aspartic acid | Asp | D | Negatively charged, acidic |
| Cysteine | Cys | C | Sulfur-containing, polar |
| Glutamic acid | Glu | E | Negatively charged, acidic |
| Glutamine | Gln | Q | Polar uncharged |
| Glycine | Gly | G | Nonpolar, smallest |
| Histidine | His | H | Positively charged, basic |
| Isoleucine | Ile | I | Nonpolar aliphatic, branched |
| Leucine | Leu | L | Nonpolar aliphatic, branched |
| Lysine | Lys | K | Positively charged, basic |
| Methionine | Met | M | Sulfur-containing, nonpolar |
| Phenylalanine | Phe | F | Aromatic, nonpolar |
| Proline | Pro | P | Cyclic, conformationally restricted |
| Serine | Ser | S | Polar uncharged |
| Threonine | Thr | T | Polar uncharged |
| Tryptophan | Trp | W | Aromatic |
| Tyrosine | Tyr | Y | Aromatic, polar |
| Valine | Val | V | Nonpolar aliphatic, branched |

Two additional amino acids are incorporated into proteins by specialized translational mechanisms. Selenocysteine is encoded by the UGA codon in the presence of a SECIS element and other specialized factors. It contains selenium in place of sulfur and occurs in certain enzymes such as glutathione peroxidases. Pyrrolysine is encoded by UAG in some methanogenic archaea and bacteria and is involved in methane metabolism.

Peptide bonds and protein formation

Amino acids are linked together by peptide bonds. A peptide bond forms when the carboxyl group of one amino acid reacts with the amino group of another, releasing a molecule of water. The resulting covalent bond is an amide linkage.

Because the peptide bond has partial double-bond character due to resonance, it is planar and relatively rigid. Most peptide bonds in proteins adopt the trans configuration, although cis peptide bonds can occur, especially with proline.

A chain of amino acids is called a peptide. Short chains are often called oligopeptides, while longer chains are polypeptides. A functional protein may consist of one or more polypeptide chains, often together with cofactors, metal ions, or other non-protein components.

Protein synthesis in cells occurs on ribosomes. Messenger RNA is read in triplets called codons, and each codon specifies a particular amino acid or a stop signal. Transfer RNAs carry amino acids to the ribosome, where peptide bonds are formed. Polypeptide chains are synthesized from the amino terminus to the carboxyl terminus.

The amino acid sequence of a protein is called its primary structure. This sequence determines how the chain folds into secondary structures such as α-helices and β-sheets, then into tertiary and quaternary structures. Side-chain interactions, including hydrophobic packing, hydrogen bonding, ionic interactions, disulfide bridges, and metal coordination, stabilize the final structure.

Essential and nonessential amino acids

Amino acids are often classified nutritionally as essential, nonessential, or conditionally essential.

Essential amino acids cannot be synthesized in sufficient quantities by the organism and must be obtained from the diet. In humans, the essential amino acids are:

• Histidine
• Isoleucine
• Leucine
• Lysine
• Methionine
• Phenylalanine
• Threonine
• Tryptophan
• Valine

Nonessential amino acids can be synthesized by the human body from metabolic intermediates. Examples include alanine, aspartate, asparagine, glutamate, glutamine, glycine, serine, and, under many conditions, cysteine and tyrosine.

Conditionally essential amino acids are normally synthesized but may become essential during growth, illness, injury, prematurity, or metabolic stress. Examples include arginine, cysteine, glutamine, glycine, proline, serine, and tyrosine. Taurine, although not a proteinogenic amino acid, is also sometimes discussed as a conditionally essential nutrient, especially in infants.

Dietary protein quality depends not only on total protein content but also on amino acid composition and digestibility. Animal proteins such as meat, fish, eggs, and dairy generally provide all essential amino acids in adequate proportions. Many plant proteins may be relatively lower in one or more essential amino acids, such as lysine in cereals or methionine in legumes, but varied plant-based diets can meet amino acid requirements through complementary protein sources.

Biosynthesis

Amino acid biosynthesis varies among organisms. Plants, bacteria, fungi, and archaea generally possess more complete amino acid biosynthetic pathways than animals. Humans can synthesize many amino acids but lack pathways for the essential amino acids.

Amino acid biosynthesis is closely connected to central carbon metabolism. Major precursor metabolites include:

• Pyruvate, giving rise to alanine, valine, leucine, and isoleucine in organisms that synthesize them.
• Oxaloacetate, giving rise to aspartate, asparagine, methionine, threonine, lysine, and isoleucine in many organisms.
• α-Ketoglutarate, giving rise to glutamate, glutamine, proline, and arginine.
• 3-Phosphoglycerate, giving rise to serine, glycine, and cysteine.
• Phosphoenolpyruvate and erythrose-4-phosphate, which combine in the shikimate pathway to produce aromatic amino acids in plants and microorganisms.
• Ribose-5-phosphate, involved in histidine biosynthesis.

Nitrogen is incorporated mainly through glutamate and glutamine. Transamination reactions transfer amino groups from glutamate to keto acids, forming new amino acids. The enzyme family of aminotransferases, which usually requires pyridoxal phosphate, the active form of vitamin B₆, is central to these reactions.

In plants and microorganisms, the synthesis of aromatic amino acids proceeds through the shikimate pathway. This pathway is absent in animals, which is why phenylalanine, tryptophan, and histidine are essential in the human diet. Some herbicides target enzymes of the shikimate pathway.

Catabolism and nitrogen metabolism

Amino acid catabolism involves removal of the amino group and utilization of the remaining carbon skeleton. The amino group can be transferred to α-ketoglutarate by transamination, forming glutamate. Glutamate can then undergo oxidative deamination by glutamate dehydrogenase, releasing ammonium.

Free ammonium is toxic at elevated concentrations, so organisms have evolved mechanisms for its disposal. In many terrestrial vertebrates, ammonium is converted to urea through the urea cycle and excreted by the kidneys. In birds, reptiles, and many insects, nitrogen is often excreted as uric acid. Aquatic organisms may excrete ammonium directly.

The carbon skeletons of amino acids enter central metabolism at several points. Depending on their degradation products, amino acids are classified as glucogenic, ketogenic, or both.

Glucogenic amino acids yield intermediates that can be used for gluconeogenesis, such as pyruvate, oxaloacetate, α-ketoglutarate, succinyl-CoA, or fumarate. Ketogenic amino acids yield acetyl-CoA or acetoacetate, which can be used for ketone body formation or fatty acid synthesis but cannot be converted into glucose in animals.

Leucine and lysine are exclusively ketogenic. Isoleucine, phenylalanine, threonine, tryptophan, and tyrosine are both glucogenic and ketogenic. The remaining standard amino acids are generally glucogenic.

Amino acid catabolism is especially active in the liver, although branched-chain amino acids are also metabolized significantly in skeletal muscle and other tissues.

Functions in proteins

The sequence of amino acids in a protein determines its structure and function. Different amino acids contribute different chemical properties:

• Hydrophobic residues stabilize protein cores and membrane-associated regions.
• Charged residues form salt bridges, bind metals, and participate in catalysis.
• Polar residues form hydrogen-bond networks.
• Cysteine residues form disulfide bonds.
• Proline introduces conformational constraints.
• Glycine provides flexibility and allows tight packing.
• Histidine often functions in enzyme active sites because its side chain can act as both acid and base near physiological pH.

Amino acids also participate in post-translational modifications. These include phosphorylation of serine, threonine, and tyrosine; acetylation and methylation of lysine; methylation of arginine; hydroxylation of proline and lysine in collagen; γ-carboxylation of glutamate in clotting factors; and formation of disulfide bonds from cysteine. Such modifications expand the functional diversity of proteins.

Non-protein amino acids

Many amino acids are not encoded by the standard genetic code but have important biological roles.

Examples include:

• γ-Aminobutyric acid, or GABA, a major inhibitory neurotransmitter.
• Ornithine and citrulline, intermediates of the urea cycle.
• Homocysteine, an intermediate in methionine metabolism.
• β-Alanine, a component of coenzyme A, carnosine, and pantothenic acid.
• Taurine, involved in bile acid conjugation, osmoregulation, and antioxidant defense.
• D-amino acids, found in bacterial cell walls and some bioactive peptides.
• Selenocysteine, incorporated into certain proteins by specialized translation.
• Pyrrolysine, found in some methanogenic microorganisms.

Some non-protein amino acids function as toxins or defense compounds. Plants and microorganisms produce analogs of standard amino acids that can interfere with metabolism if ingested by competing organisms. Examples include canavanine, an arginine analog, and mimosine, a tyrosine-like compound.

Biological roles beyond protein synthesis

Amino acids are precursors for many essential molecules.

Neurotransmitters and neuromodulators

Glutamate is the principal excitatory neurotransmitter in the vertebrate central nervous system. Glycine acts as an inhibitory neurotransmitter in parts of the spinal cord and brainstem. GABA, synthesized from glutamate, is another major inhibitory neurotransmitter. Serotonin is synthesized from tryptophan, and dopamine, norepinephrine, and epinephrine are synthesized from tyrosine. Histamine is produced from histidine.

Nitrogen transport and storage

Glutamine and alanine are important carriers of nitrogen between tissues. Glutamine transports ammonia in a relatively nontoxic form and is important in immune cells, intestinal cells, and acid–base regulation. Alanine participates in the glucose–alanine cycle between muscle and liver.

One-carbon metabolism

Glycine, serine, methionine, and histidine contribute to one-carbon metabolism. Serine provides one-carbon units to the folate cycle, while methionine is converted to S-adenosylmethionine, the principal biological methyl donor. One-carbon metabolism is essential for nucleotide synthesis, methylation reactions, and redox balance.

Synthesis of specialized molecules

Amino acids are precursors of many non-protein biomolecules:

• Glycine contributes to heme, purines, creatine, and glutathione.
• Aspartate contributes to pyrimidines, purines, and the urea cycle.
• Glutamine contributes to nucleotide synthesis and amino sugar formation.
• Arginine is a precursor of nitric oxide, creatine, polyamines, and urea.
• Cysteine is required for glutathione synthesis and iron–sulfur cluster metabolism.
• Tyrosine is a precursor of thyroid hormones and catecholamines.
• Tryptophan is a precursor of serotonin, melatonin, and niacin.

Signaling and metabolic regulation

Amino acids are not only metabolites but also signals. Leucine and other amino acids can activate the mechanistic target of rapamycin complex 1, or mTORC1, a key regulator of cell growth and protein synthesis. Amino acid availability influences insulin secretion, autophagy, immune activation, and tissue repair.

Nutrition and dietary sources

Dietary proteins supply amino acids for protein synthesis, energy production, and biosynthesis of nitrogen-containing compounds. Proteins are digested by gastric and pancreatic proteases, and the resulting peptides and amino acids are absorbed mainly in the small intestine by specific transport systems.

Foods of animal origin generally provide high-quality protein because they contain all essential amino acids in proportions suitable for human needs. Soy, quinoa, and some other plant foods also provide relatively balanced amino acid profiles. Diets based heavily on a single plant protein source may require combination with other foods to ensure adequate intake of limiting amino acids.

Protein quality has been assessed by methods such as the Protein Digestibility Corrected Amino Acid Score, or PDCAAS, and the Digestible Indispensable Amino Acid Score, or DIAAS. These methods evaluate both amino acid composition and digestibility.

Amino acid requirements vary with age, body size, pregnancy, lactation, physical activity, injury, infection, and disease. Infants and children require relatively high intakes of essential amino acids to support growth. Older adults may require adequate protein and specific amino acids to maintain muscle mass. Clinical conditions such as trauma, burns, sepsis, renal disease, and liver disease can alter amino acid needs.

Medical significance

Amino acid metabolism is clinically important in nutrition, inherited metabolic disease, critical care, and neurology.

Inherited metabolic disorders

Several genetic diseases result from defects in amino acid metabolism or transport. Examples include:

• Phenylketonuria, caused by deficiency of phenylalanine hydroxylase or related cofactor defects, leading to accumulation of phenylalanine.
• Maple syrup urine disease, caused by impaired degradation of branched-chain amino acids.
• Homocystinuria, often involving defects in methionine metabolism.
• Urea cycle disorders, causing hyperammonemia due to impaired nitrogen disposal.
• Hartnup disease, involving defective neutral amino acid transport.
• Cystinuria, involving defective renal and intestinal transport of cystine and dibasic amino acids.

Dietary management, medical formulas, cofactor supplementation, and in some cases organ transplantation or gene-based therapies may be used depending on the disorder.

Clinical nutrition

Amino acid solutions are used in parenteral nutrition when patients cannot obtain adequate nutrition by mouth or through the gastrointestinal tract. Specialized formulations may be used for renal failure, hepatic failure, critical illness, or premature infants.

Enteral and parenteral nutrition must provide appropriate amounts of essential and nonessential amino acids to maintain nitrogen balance, support wound healing, preserve lean body mass, and support immune function.

Supplements and therapeutic uses

Individual amino acids or derivatives are used in medicine and nutrition. Examples include N-acetylcysteine as a precursor of glutathione and treatment for acetaminophen overdose, levodopa as a treatment for Parkinson disease, and branched-chain amino acid supplements in certain clinical or athletic contexts. The efficacy and safety of amino acid supplementation vary by indication, dose, and patient population.

Analytical methods

Amino acids can be analyzed by many biochemical techniques.

Classical methods include ninhydrin reactions, which produce colored products with most amino acids. Proline and hydroxyproline give different colors because of their secondary amino group structure.

Modern analytical methods include:

• Ion-exchange chromatography with post-column ninhydrin detection.
• Reverse-phase high-performance liquid chromatography after derivatization.
• Gas chromatography–mass spectrometry after derivatization.
• Liquid chromatography–tandem mass spectrometry.
• Capillary electrophoresis.
• Nuclear magnetic resonance spectroscopy.
• Chiral chromatography for separation of D- and L-amino acids.

Protein amino acid composition can be determined by hydrolyzing the protein and analyzing the released amino acids. Protein sequencing may be performed by Edman degradation, mass spectrometry, or inferred from DNA and RNA sequences.

Industrial, agricultural, and biotechnological applications

Amino acids are produced on a large scale for food, feed, pharmaceutical, and chemical industries.

In animal feed, lysine, methionine, threonine, and tryptophan are commonly added to optimize growth and reduce the need for high-protein feed ingredients. In food, monosodium glutamate is widely used as a flavor enhancer because glutamate produces the umami taste. Glycine and other amino acids are used in flavoring, nutrition, and specialty foods.

Microbial fermentation is a major production method. Organisms such as Corynebacterium glutamicum are used to produce glutamate, lysine, and other amino acids industrially. Some amino acids are produced by enzymatic conversion or chemical synthesis, especially when racemic mixtures or specific derivatives are required.

In biotechnology, amino acids are used as chiral building blocks for pharmaceuticals, agrochemicals, and fine chemicals. Unnatural amino acids are also incorporated into proteins by genetic code expansion, allowing researchers to introduce novel chemical groups for structural studies, drug development, materials science, and synthetic biology.

Amino acids in evolution and origin-of-life studies

Amino acids are central to hypotheses about the origin of life. Experiments simulating prebiotic Earth, such as the Miller–Urey experiment, have shown that simple gases and energy sources can produce amino acids. Amino acids have also been detected in carbonaceous meteorites, comets, and interstellar environments, indicating that they can form under diverse cosmic conditions.

The transition from prebiotic amino acid mixtures to biologically encoded proteins remains an unresolved question. Major issues include the origin of homochirality, the emergence of the genetic code, the formation of early peptides, and the evolution of translation machinery.

History

The study of amino acids began in the late 18th and early 19th centuries with the isolation of compounds from biological materials. Asparagine, discovered in 1806 from asparagus juice, is often regarded as the first amino acid to be identified. Glycine and leucine were isolated in the early 19th century from gelatin and protein hydrolysates.

In the late 19th and early 20th centuries, Emil Fischer and others elucidated many amino acid structures and developed peptide chemistry. Fischer’s work established that proteins are composed of amino acid chains and helped lay the foundation for modern biochemistry.

In the 1930s, William Cumrose and colleagues identified the essential amino acids required in the human diet. In the 1950s, Frederick Sanger determined the complete amino acid sequence of insulin, demonstrating that proteins have defined sequences. The deciphering of the genetic code in the 1960s explained how nucleotide triplets specify amino acids during protein synthesis.

Since then, amino acid research has expanded into structural biology, nutrition, metabolic disease, neuroscience, synthetic biology, and astrobiology, making amino acids among the most extensively studied molecules in the life sciences.