Cysteine

Cysteine, symbolised as Cys or C, is a semi-essential, proteinogenic amino acid distinguished by its reactive thiol side chain. This sulphur-containing functional group allows cysteine to form disulphide bonds, participate in redox chemistry, and act as a nucleophilic centre in numerous enzymatic processes. Both D-cysteine and L-cysteine occur naturally, though only the latter is incorporated into proteins. Cysteine derives its name from its initial identification in urine, linked to the Greek word for bladder. It is coded genetically by the codons UGU and UGC, and when used as a food additive it carries the designation E920.

Structure and Chemical Characteristics

As with other amino acids in free form, cysteine exists as a zwitterion at physiological pH. Its chiral centre gives rise to two stereoisomers; in the traditional Fischer system, these correspond to dextrorotatory and levorotatory forms, while in the modern R/S nomenclature, cysteine is classified as R. This arises because sulphur has a higher atomic number than oxygen, reversing the usual priority order observed in most amino acids, which predominantly exhibit S chirality.
A defining structural feature of cysteine is its thiol (–SH) group. This moiety is readily oxidised to form cystine, a disulphide-linked dimer containing two cysteine residues. Disulphide bonds contribute strongly to protein stability by creating covalent crosslinks that reinforce tertiary or quaternary structures. The thiol can also undergo further oxidation to sulfinic or sulfonic acid under strongly oxidising conditions. Specialised symbols such as Cyx for oxidised cystine and Cym for deprotonated thiolate forms are sometimes used in structural descriptions.

Dietary Sources and Industrial Production

Cysteine occurs naturally in high-protein foods. Dietary sources include:

• poultry and other meats
• eggs
• dairy products
• whole grains and legumes

Although generally classified as non-essential, cysteine can become conditionally essential in infants, older individuals, or those with metabolic or gastrointestinal disorders. Under normal conditions, humans can synthesise cysteine if adequate methionine is available.
On an industrial scale, cysteine is commonly produced by hydrolysing materials rich in keratin such as poultry feathers or hog hair. Human hair is sometimes mistakenly believed to be a source, but its use is prohibited in many jurisdictions. Because animal-based production methods conflict with kosher, halal, vegan, and vegetarian dietary guidelines, several synthetic routes have been developed. These include:

• microbial fermentation using engineered Escherichia coli
• biocatalysis via Pseudomonas thiazolinophilum acting on substituted thiazolines

Synthetic cysteine is widely used in baking, flavour enhancement, and industrial chemistry.

Biosynthesis Pathways

Cysteine biosynthesis differs between animals and plants or bacteria.
In animals, the pathway begins with serine. Sulphur is supplied via methionine, which is converted to homocysteine through S-adenosylmethionine intermediates. The enzyme cystathionine β-synthase combines homocysteine and serine to form cystathionine, which is subsequently cleaved by cystathionine γ-lyase to yield cysteine and α-ketobutyrate.
In plants and bacteria, serine is acetylated to O-acetylserine via serine transacetylase. Cysteine synthase then replaces the acetyl group with sulphide, producing cysteine and acetate.

Biological Functions

The thiol group of cysteine is highly reactive, giving the amino acid a key role in metabolism, antioxidant defence, and metal binding.
Antioxidant role and glutathione precursorCysteine is essential for the synthesis of glutathione (GSH), a tripeptide central to redox balance within cells. Because dietary glutathione has negligible systemic bioavailability, cysteine availability can limit endogenous GSH synthesis.
Sulphur donation and iron–sulphur cluster assemblyCysteine serves as a major source of sulphide in metabolic processes. Iron–sulphur clusters, vital cofactors in electron transport and enzymatic catalysis, derive their sulphur atoms from cysteine, which is converted to alanine during the reaction.
Metal ion coordinationThe thiolate anion of cysteine binds strongly to metal ions. Metalloproteins including zinc-finger proteins, alcohol dehydrogenase, copper plastocyanins, cytochrome P450 enzymes, and NiFe-hydrogenases rely on cysteine residues for metal cofactor stabilisation. Cysteine-rich proteins such as metallothioneins bind heavy metals including cadmium, mercury, and lead with high affinity.

Role in Protein Structure and Stability

Within polypeptides, cysteine contributes to structural integrity, folding, and function. Historically considered polar due to its thiol group, cysteine is now frequently classified as hydrophobic, as its side chain stabilises hydrophobic interactions and is commonly found in nonpolar regions of proteins. Hydrophobicity scales consistently rank cysteine among the more hydrophobic amino acids.
Disulphide bond formationMost extracellular proteins contain disulphide bonds that arise through oxidation of cysteine residues. These covalent links:

• enhance protein rigidity
• increase resistance to proteolysis
• help maintain tertiary and quaternary structures

Insulin is a classic example, comprising two peptides joined by disulphide bridges. Within the endoplasmic reticulum, protein disulphide isomerases ensure correct disulphide pairing under the organelle’s oxidising conditions.
Post-translational modificationsCysteine participates in numerous intracellular modifications, including:

• prenylation
• ubiquitination
• enzymatic cleavage by cysteine-dependent caspases
• intein-mediated peptide splicing

These roles rely on the nucleophilicity of the thiolate form, which predominates in the cell’s reducing environment.

Evolutionary Considerations

Cysteine is thought to be a relatively late addition to the canonical set of proteinogenic amino acids. Estimates place it as the seventeenth amino acid incorporated into the genetic code. Its emergence likely coincided with evolutionary pressures demanding greater redox regulation, metal coordination, and structural stability in proteins.