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l-Cysteine
Skeletal formula of L-cysteine
Names
IUPAC name
Cysteine
Systematic IUPAC name
2-Amino-3-sulfanylpropanoic acid
Other names
  • 2-Amino-3-sulfhydrylpropanoic acid
  • 2-Amino-3-mercaptopropanoic acid
Identifiers
3D model (JSmol)
Abbreviations Cys, C
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 45.00.20 Edit this at Wikidata
EC Number
  • 200-158-2
E number E920 (glazing agents, ...)
KEGG
UNII
  • InChI=1S/C3H7NO2S/c4-2(1-7)3(5)6/h2,7H,1,4H2,(H,5,6) checkY
    Key: XUJNEKJLAYXESH-UHFFFAOYSA-N checkY
  • InChI=1/C3H7NO2S/c4-2(1-7)3(5)6/h2,7H,1,4H2,(H,5,6)/t2-/m0/s1
    Key: XUJNEKJLAYXESH-REOHCLBHBU
  • InChI=1/C3H7NO2S/c4-2(1-7)3(5)6/h2,7H,1,4H2,(H,5,6)
    Key: XUJNEKJLAYXESH-UHFFFAOYAC
  • C([C@@H](C(=O)O)N)S
  • Zwitterion: C([C@@H](C(=O)[O-])[NH3+])S
Properties[4]
C3H7NO2S
Molar mass 121.15 g·mol−1
Appearance white crystals or powder
Melting point 240 °C (464 °F; 513 K) decomposes
277g/L (at 25 °C)[1]
Solubility 1.5g/100g ethanol 19 °C [2]
Acidity (pKa) 1.71 (conjugate acid), 8.33 (thiol), 10.78[3]
+9.4° (H2O, c = 1.3)
Supplementary data page
Cysteine (data page)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)
Cysteine ball and stick model spinning

Cysteine (/ˈsɪstɪiːn/;[5] symbol Cys or C[6]) is a semiessential[7] proteinogenic amino acid with the formula HS−CH2−CH(NH2)−COOH. The thiol side chain in cysteine enables the formation of disulfide bonds, and often participates in enzymatic reactions as a nucleophile. Cysteine is chiral, but both D and L-cysteine are found in nature. L‑Cysteine is a protein monomer in all biota, and D-cysteine acts as a signaling molecule in mammalian nervous systems.[8] Cysteine is named after its discovery in urine, which comes from the urinary bladder or cyst, from Greek κύστις kýstis, "bladder".[9]

The thiol is susceptible to oxidation to give the disulfide derivative cystine, which serves an important structural role in many proteins. In this case, the symbol Cyx is sometimes used.[10][11] The deprotonated form can generally be described by the symbol Cym as well.[11][10]

When used as a food additive, cysteine has the E number E920.

Cysteine is encoded by the codons UGU and UGC.

Structure

[edit]

Like other amino acids (not as a residue of a protein), cysteine exists as a zwitterion. Cysteine has l chirality in the older d/l notation based on homology to d- and l-glyceraldehyde. In the newer R/S system of designating chirality, based on the atomic numbers of atoms near the asymmetric carbon, cysteine (and selenocysteine) have R chirality, because of the presence of sulfur (or selenium) as a second neighbor to the asymmetric carbon atom. The remaining chiral amino acids, having lighter atoms in that position, have S chirality. Replacing sulfur with selenium gives selenocysteine.

(R)-Cysteine (left) and (S)-Cysteine (right) in zwitterionic form at neutral pH

Dietary sources

[edit]

Cysteinyl is a residue in high-protein foods. Some foods considered rich in cysteine include poultry, eggs, beef, and whole grains. In high-protein diets, cysteine may be partially responsible for reduced blood pressure and stroke risk.[12] Although classified as a nonessential amino acid,[13] in rare cases, cysteine may be essential for infants, the elderly, and individuals with certain metabolic diseases or who suffer from malabsorption syndromes. Cysteine can usually be synthesized by the human body under normal physiological conditions if a sufficient quantity of methionine is available.

Industrial sources

[edit]

The majority of l-cysteine is obtained industrially by hydrolysis of animal materials, such as poultry feathers or hog hair. Despite widespread rumor,[14] human hair is rarely a source material.[15] Indeed, food additive or cosmetic product manufactures may not legally source from human hair in the European Union.[16][17]

Some animal-originating sources of l-cysteine as a food additive contravene kosher, halal, vegan, or vegetarian diets.[14] To avoid this problem, synthetic l-cysteine, compliant with Jewish kosher and Muslim halal laws, is also available, albeit at a higher price.[18] The typical synthetic route involves fermentation with an artificial E. coli strain.[19]

Alternatively, Evonik (formerly Degussa) introduced a route from substituted thiazolines.[20] Pseudomonas thiazolinophilum hydrolyzes racemic 2‑amino-Δ2‑thiazoline-4‑carboxylic acid to l‑cysteine.[19]

Biosynthesis

[edit]
Cysteine synthesis: Cystathionine beta synthase catalyzes the upper reaction and cystathionine gamma-lyase catalyzes the lower reaction.

In animals, biosynthesis begins with the amino acid serine. The sulfur is derived from methionine, which is converted to homocysteine through the intermediate S-adenosylmethionine. Cystathionine beta-synthase then combines homocysteine and serine to form the asymmetrical thioether cystathionine. The enzyme cystathionine gamma-lyase converts the cystathionine into cysteine and alpha-ketobutyrate. In plants and bacteria, cysteine biosynthesis also starts from serine, which is converted to O-acetylserine by the enzyme serine transacetylase. The enzyme cysteine synthase, using sulfide sources, converts this ester into cysteine, releasing acetate.[21]

Biological functions

[edit]

The cysteine sulfhydryl group is nucleophilic and easily oxidized. The reactivity is enhanced when the thiol is ionized, and cysteine residues in proteins have pKa values close to neutrality, so are often in their reactive thiolate form in the cell.[22] Because of its high reactivity, the sulfhydryl group of cysteine has numerous biological functions.

Precursor to the antioxidant glutathione

[edit]

Due to the ability of thiols to undergo redox reactions, cysteine and cysteinyl residues have antioxidant properties. Its antioxidant properties are typically expressed in the tripeptide glutathione, which occurs in humans and other organisms. The systemic availability of oral glutathione (GSH) is negligible; so it must be biosynthesized from its constituent amino acids, cysteine, glycine, and glutamic acid. While glutamic acid is usually sufficient because amino acid nitrogen is recycled through glutamate as an intermediary, dietary cysteine and glycine supplementation can improve synthesis of glutathione.[23]

Precursor to iron-sulfur clusters

[edit]

Cysteine is an important source of sulfide in human metabolism. The sulfide in iron-sulfur clusters and in nitrogenase is extracted from cysteine, which is converted to alanine in the process.[24]

Metal ion binding

[edit]

Beyond the iron-sulfur proteins, many other metal cofactors in enzymes are bound to the thiolate substituent of cysteinyl residues. Examples include zinc in zinc fingers and alcohol dehydrogenase, copper in the blue copper proteins, iron in cytochrome P450, and nickel in the [NiFe]-hydrogenases.[25] The sulfhydryl group also has a high affinity for heavy metals, so that proteins containing cysteine, such as metallothionein, will bind metals such as mercury, lead, and cadmium tightly.[26]

Roles in protein structure

[edit]

In the translation of messenger RNA molecules to produce polypeptides, cysteine is coded for by the UGU and UGC codons.

Cysteine has traditionally been considered to be a hydrophilic amino acid, based largely on the chemical parallel between its sulfhydryl group and the hydroxyl groups in the side chains of other polar amino acids. However, the cysteine side chain has been shown to stabilize hydrophobic interactions in micelles to a greater degree than the side chain in the nonpolar amino acid glycine and the polar amino acid serine.[27] In a statistical analysis of the frequency with which amino acids appear in various proteins, cysteine residues were found to associate with hydrophobic regions of proteins. Their hydrophobic tendency was equivalent to that of known nonpolar amino acids such as methionine and tyrosine (tyrosine is polar aromatic but also hydrophobic[28]), those of which were much greater than that of known polar amino acids such as serine and threonine.[29] Hydrophobicity scales, which rank amino acids from most hydrophobic to most hydrophilic, consistently place cysteine towards the hydrophobic end of the spectrum, even when they are based on methods that are not influenced by the tendency of cysteines to form disulfide bonds in proteins. Therefore, cysteine is now often grouped among the hydrophobic amino acids,[30][31] though it is sometimes also classified as slightly polar,[32] or polar.[7]

Most cysteine residues are covalently bonded to other cysteine residues to form disulfide bonds, which play an important role in the folding and stability of some proteins, usually proteins secreted to the extracellular medium.[33] Since most cellular compartments are reducing environments, disulfide bonds are generally unstable in the cytosol with some exceptions as noted below.

Figure 2: Cystine (shown here in its neutral form), two cysteines bound together by a disulfide bond

Disulfide bonds in proteins are formed by oxidation of the sulfhydryl group of cysteine residues. The other sulfur-containing amino acid, methionine, cannot form disulfide bonds. More aggressive oxidants convert cysteine to the corresponding sulfinic acid and sulfonic acid. Cysteine residues play a valuable role by crosslinking proteins, which increases the rigidity of proteins and also functions to confer proteolytic resistance (since protein export is a costly process, minimizing its necessity is advantageous). Inside the cell, disulfide bridges between cysteine residues within a polypeptide support the protein's tertiary structure. Insulin is an example of a protein with cystine crosslinking, wherein two separate peptide chains are connected by a pair of disulfide bonds.

Protein disulfide isomerases catalyze the proper formation of disulfide bonds; the cell transfers dehydroascorbic acid to the endoplasmic reticulum, which oxidizes the environment. In this environment, cysteines are, in general, oxidized to cystine and are no longer functional as a nucleophiles.

Aside from its oxidation to cystine, cysteine participates in numerous post-translational modifications. The nucleophilic sulfhydryl group allows cysteine to conjugate to other groups, e.g., in prenylation. Ubiquitin ligases transfer ubiquitin to its pendant, proteins, and caspases, which engage in proteolysis in the apoptotic cycle. Inteins often function with the help of a catalytic cysteine. These roles are typically limited to the intracellular milieu, where the environment is reducing, and cysteine is not oxidized to cystine.

Evolutionary role of cysteine

[edit]

Cysteine is considered a "newcomer" amino acid, being the 17th amino acid incorporated into the genetic code.[34][35] Similar to other later-added amino acids such as methionine, tyrosine, and tryptophan, cysteine exhibits strong nucleophilic and redox-active properties.[36][37] These properties contribute to the depletion of cysteine from respiratory chain complexes, such as Complexes I and IV,[38] since reactive oxygen species (ROS) produced by the respiratory chain can react with the cysteine residues in these complexes, leading to dysfunctional proteins and potentially contributing to aging. The primary response of a protein to ROS is the oxidation of cysteine and the loss of free thiol groups,[39] resulting in increased thiyl radicals and associated protein cross-linking.[40][41] In contrast, another sulfur-containing, redox-active amino acid, methionine, does not exhibit these biochemical properties and its content is relatively upregulated in mitochondrially encoded proteins.[42]

Applications

[edit]

Cysteine, mainly the l-enantiomer, is a precursor in the food, pharmaceutical, and personal-care industries. One of the largest applications is the production of flavors. For example, the reaction of cysteine with sugars in a Maillard reaction yields meat flavors.[43] l-Cysteine is also used as a processing aid for baking.[44]

In the field of personal care, cysteine is used for permanent-wave applications, predominantly in Asia. Again, the cysteine is used for breaking up the disulfide bonds in the hair's keratin.

Cysteine is a very popular target for site-directed labeling experiments to investigate biomolecular structure and dynamics. Maleimides selectively attach to cysteine using a covalent Michael addition. Site-directed spin labeling for EPR or paramagnetic relaxation-enhanced NMR also uses cysteine extensively.

Reducing toxic effects of alcohol

[edit]

Cysteine has been proposed as a preventive or antidote for some of the negative effects of alcohol, including liver damage and hangover. It counteracts the poisonous effects of acetaldehyde.[45] It binds to acetaldehyde to form the low-toxicity heterocycle methylthioproline.[46]

In a rat study, test animals received an LD90 dose of acetaldehyde. Those that received cysteine had an 80% survival rate; when both cysteine and thiamine were administered, all animals survived. The control group had a 10% survival rate.[47]

In 2020 an article was published that suggests L-cysteine might also work in humans.[48]

N-Acetylcysteine

[edit]

N-Acetyl-l-cysteine is a derivative of cysteine wherein an acetyl group is attached to the nitrogen atom. This compound is sold as a dietary supplement, and used as an antidote in cases of acetaminophen overdose.[49]

Sheep

[edit]

Cysteine is required by sheep to produce wool. It is an essential amino acid that is taken in from their feed. As a consequence, during drought conditions, sheep produce less wool; however, transgenic sheep that can make their own cysteine have been developed.[50]

Chemical reactions

[edit]

Being multifunctional, cysteine undergoes a variety of reactions. Much attention has focused on protecting the sulfhydryl group.[51] Methylation of cysteine gives S-methylcysteine. Treatment with formaldehyde gives the thiazolidine thioproline. With phosgene and related carbonylating agents, cysteine gives procysteine.

Cysteine forms a variety of coordination complexes upon treatment with metal ions.[52] This coordination behavior is seen in many metal-cysteine metalloenzymes.

Safety

[edit]

Relative to most other amino acids, cysteine is much more toxic.[53]

History

[edit]
Main article: Cystine

In 1884 German chemist Eugen Baumann found that reduction of cystine with zinc gave monomer, which he named "cysteïne".[54] The easy redox interconversion of cysteine and cystine has "provided more puzzles to protein chemists than any of the other amino acids.[55]

See also

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Wikimedia Commons has media related to Cysteine.

References

[edit]

Further reading

[edit]
[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Cysteine

View on Grokipedia
from Grokipedia
Cysteine is a semi-essential with the molecular formula C₃H₇NO₂S, featuring a (-SH) group in its that distinguishes it among the standard and enables unique reactivity. This sulfhydryl moiety allows cysteine residues to form covalent bonds, which are critical for stabilizing the three-dimensional structures of proteins, particularly in extracellular environments where oxidative conditions prevail. As a building block of proteins, cysteine is encoded by the genetic codons UGU and UGC and contributes to diverse biological roles, including enzymatic , , and metal coordination due to its nucleophilic properties. Beyond protein synthesis, cysteine serves as a precursor for essential biomolecules such as , the primary cellular antioxidant that mitigates , and , involved in conjugation and . Although humans can synthesize cysteine from dietary through the transsulfuration pathway, it is considered conditionally essential during periods of rapid growth, metabolic stress, or impaired metabolism, necessitating dietary sources like , eggs, and to meet demands.

Chemical Structure and Properties

Molecular Structure

Cysteine is an α-amino acid with the molecular formula C₃H₇NO₂S and a of 121.16 g/mol. Its structure features a central chiral α-carbon atom bonded to four distinct groups: a , an amino group (-NH₂), a group (-COOH), and a consisting of a attached to a (-CH₂SH). The imparts unique reactivity, enabling bond formation with other cysteine residues. The biologically relevant is L-cysteine, designated as (2R)-2-amino-3-sulfanylpropanoic acid in IUPAC . This (R) configuration arises because the atom in the has a higher than the oxygen in the carboxyl group, altering the Cahn-Ingold-Prelog priority assignment at the α-carbon compared to other L-amino acids, which are typically (S). The SMILES notation for L-cysteine is NC@@HC(O)=O, reflecting its . In crystalline form, cysteine adopts a zwitterionic structure with proton transfer from the carboxyl to the amino group, though the neutral form is depicted in standard structural formulas.

Physical and Chemical Properties

L-Cysteine possesses the molecular C₃H₇NO₂S and a of 121.16 g/mol. It manifests as white crystals or powder. Key physical properties are summarized in the following table:
PropertyValue
Melting point240 °C (decomposes)
solubility≈280 g/L at 20 °C
+8.8° (c=8, 1 M HCl)
L-Cysteine exhibits three ionizable groups with pKₐ values of 1.71 (carboxyl), 8.33 (), and 10.78 (amino), enabling zwitterionic behavior at physiological and partial . The moiety confers nucleophilicity and activity, facilitating disulfide bond formation with another cysteine residue to produce cystine upon oxidation. This reactivity underpins its role in protein stabilization and functions, though in isolation, it is susceptible to air oxidation in solution. decreases in non-polar solvents like , reflecting its polar nature.

Sources and Production

Dietary Sources

Cysteine, typically quantified in foods as its oxidized dimer cystine, is primarily obtained from high-protein animal sources, which provide bioavailable forms essential for meeting needs. Meats such as , , and ; ; eggs; and products like cheese and low-fat rank among the highest contributors per serving. For instance, beef liver offers about 388 mg of cystine per slice, while , , and eggs commonly deliver 200–400 mg per 100 g depending on preparation. Plant-based foods supply cysteine through , grains, and , though their density is generally lower, necessitating higher intake volumes for equivalent . Notable examples include lentils, soybeans, , sunflower , and whole grains like teff or , with values ranging from 140–200 mg per cup cooked. These sources support cysteine's role in synthesis and , with animal products offering more complete profiles compared to . Dietary guidelines emphasize balanced protein intake, as cysteine requirements (approximately 4.1 mg/kg body weight daily) are often met alongside .

Biosynthesis in Biological Systems

In and , cysteine is synthesized de novo from serine and inorganic through a two-step pathway. The initial step involves the of L-serine to form O-acetylserine, catalyzed by serine . This is followed by the sulfhydrylation of O-acetylserine with , yielding L-cysteine, mediated by O-acetylserine thiol lyase (OASTL). These reactions integrate and , with SAT activity regulated by feedback inhibition from cysteine to prevent overaccumulation. In , the enzymes are encoded by cysE (SAT) and cysK/cysM (OASTL), forming a cysteine synthase complex that enhances efficiency. Plants localize these enzymes in , plastids, and mitochondria, with the mitochondrial isoform regulating levels to balance and . This pathway is absent in mammals, rendering cysteine non-essential under normal conditions but conditionally essential during high demand, such as for synthesis in . Mammalian cysteine derives primarily from methionine via the transsulfuration pathway in the liver and other tissues. is converted to , which condenses with serine to form cystathionine via cystathionine β-synthase (), requiring as cofactor. Cystathionine is then cleaved by cystathionine γ-lyase (CSE) to produce cysteine, α-ketobutyrate, and . This unidirectional pathway (opposite to some microbes) supports cysteine availability for protein synthesis and defense, with flux upregulated under methionine excess or cysteine limitation. Deficiencies in or CSE, as in , impair cysteine production and elevate levels.

Industrial Synthesis Methods

The predominant industrial method for L-cysteine production involves the acid hydrolysis of keratin-rich byproducts, such as feathers or hog hair. In this process, the raw material is boiled in concentrated (typically requiring about 27 kg of HCl per kg of cysteine produced) at around 100°C for several hours to degrade proteins into constituent , primarily yielding L-cystine as an oxidized dimer of L-cysteine. The is then treated with activated to selectively adsorb cystine, followed by desorption, filtration, and purification steps to isolate L-cystine crystals. L-Cystine is subsequently reduced to L-cysteine via electrolytic reduction in an or chemical reduction agents, achieving high purity (up to 98%) in batch operations. This method accounts for the majority of global L-cysteine supply due to its cost-effectiveness and scalability, though it generates significant acidic waste and relies on animal-derived feedstocks, raising environmental and ethical concerns. An alternative enzymatic bioconversion method converts DL-2-amino-Δ²-thiazoline-4-carboxylic acid (ATC), a chemically synthesized precursor, to L-cysteine using microbial enzymes such as ATC racemase, thiazole synthase, and cysteine synthase expressed in bacteria like . This process avoids direct animal sourcing and has been commercialized by companies like , offering higher specificity and reduced byproducts compared to , though it requires precise control of , , and substrate concentrations to minimize from accumulated intermediates. Fermentative production via microbial represents an emerging, sustainable approach, utilizing genetically engineered bacteria such as Pantoea ananatis or E. coli to overproduce L-cysteine from glucose and sources under aerobic conditions. Strains are modified to enhance flux through the serine-acetyl-CoA pathway, delete feedback inhibitions (e.g., on serine acetyltransferase), and mitigate via exporters or antioxidants, achieving titers up to several grams per liter in fed-batch fermentations. This method supports vegan production and reduces chemical waste but faces challenges from metabolic stress and lower yields compared to traditional , with ongoing research focusing on thermophilic enzymes or systems for further optimization.

Biological Functions

Structural Roles in Proteins

Cysteine residues contribute to primarily through the formation of bonds, covalent linkages between the thiol groups of two cysteine side chains that stabilize tertiary and structures. These bonds form via oxidation of the sulfhydryl (-SH) groups, creating a cystine residue with a -S-S- bridge that links spatially separated regions of the polypeptide chain. bonds are particularly prevalent in extracellular and secreted proteins, where they enhance resistance to proteolytic degradation and maintain structural integrity in oxidizing environments. The stabilizing effect of disulfide bonds arises from their ability to reduce the conformational entropy of the unfolded protein state, thereby increasing the free energy difference between folded and denatured forms and promoting thermodynamic stability. In globular proteins, these cross-links constrain backbone flexibility, facilitating proper folding and preventing misfolding under physiological stresses such as heat or denaturation. For instance, disruption of bonds correlates with loss of structural rigidity and functional activity, underscoring their role in maintaining native conformations. Beyond entropy reduction, disulfide bonds can impose geometric constraints that guide oxidative pathways, where enzymes like protein disulfide isomerases catalyze thiol- exchange to achieve the correct pairing. In intracellular compartments, the reducing milieu limits disulfide formation, confining structural cysteines largely to periplasmic or extracellular locales, which reflects evolutionary adaptation for domain-specific stability. Cysteine's low abundance yet high conservation in proteins highlights the precision required for disulfide positioning to avoid aberrant linkages that could destabilize folds.

Antioxidant and Redox Roles

The thiol (-SH) group in cysteine confers high nucleophilicity and reactivity, enabling it to function as a by donating electrons to (ROS) and other oxidants, thereby undergoing oxidation to , , or forms. This reversible oxidation, particularly to disulfides like cystine, supports , stability, and dynamic signaling without permanent damage. Cysteine serves as the biosynthetic precursor for (GSH), a antioxidant comprising cysteine, glutamate, and , which constitutes the primary intracellular defense against by reducing and lipid hydroperoxides via enzymes. The cysteine-derived in GSH directly participates in these electron-transfer reactions, with oxidized GSSG recycled back to GSH by NADPH-dependent , maintaining the cellular GSH/GSSG ratio as a key buffer. Depletion of cysteine limits GSH production, exacerbating vulnerability to ROS-induced damage in conditions like . At the protein level, cysteine residues act as sensors through posttranslational modifications such as S-glutathionylation—formation of a mixed with GSH—which protects thiols from irreversible over-oxidation and enables reversible of activity and signaling pathways. Sulfenylation, an initial oxidation step, further propagates signals, influencing metabolic s and transcription factors in response to fluctuating ROS levels. These mechanisms underscore cysteine's role in to oxidative challenges, with evidence from studies showing cysteine supplementation enhances GSH levels and mitigates ROS-mediated in neuronal cells.

Metal Binding and Cofactor Functions

Cysteine residues facilitate metal binding in proteins through their (-SH) side chains, which can deprotonate to form nucleophilic thiolates capable of coordinating soft metal ions such as , iron, , and . This coordination often stabilizes protein structures or enables catalytic functions, with the thiolate's electron-donating properties allowing tight binding to metals that prefer s over harder ones like oxygen or nitrogen. In biological contexts, these interactions support cofactor roles where cysteine acts as a rather than a standalone cofactor, modulating activity via redox-sensitive metal-thiolate bonds. A prominent example is in zinc finger proteins, where cysteine residues in motifs such as C2H2 (two cysteines and two histidines) or C4 (four cysteines) provide tetrahedral coordination to Zn²⁺ ions, essential for DNA recognition and transcriptional regulation. These structures, found in up to 1% of human genes, rely on cysteine's ability to form stable Zn-S bonds, with disruptions in cysteine coordination leading to loss of DNA-binding affinity. Similarly, in type 1 copper centers of enzymes like azurin, a conserved cysteine thiolate coordinates Cu(I)/Cu(II), enabling electron transfer with rapid redox kinetics due to the soft ligand environment. Cysteine thiolates also ligate iron-sulfur (Fe-S) clusters, ubiquitous cofactors in proteins across all domains of , where four cysteine residues typically coordinate [4Fe-4S] or [2Fe-2S] clusters in or ferredoxin-like geometries. These clusters, with potentials tuned by the protein environment, participate in mitochondrial respiration, , and radical SAM enzyme catalysis; for instance, in complex I of the , cysteine-ligated Fe-S clusters mediate multi-electron transfers essential for ATP synthesis. Sulfur for these clusters derives from cysteine via desulfurase enzymes, underscoring cysteine's dual role in providing both ligands and cluster atoms. In metallothioneins, cysteine-rich proteins (up to 30% cysteine content), thiolates form polynuclear metal-thiolate clusters binding 7-12 atoms of Zn²⁺, Cd²⁺, or Cu⁺ per molecule, functioning in metal , of , and buffering through thiolate-metal charge transfer. These proteins exhibit high affinity for d¹⁰ metals (e.g., dissociation constants in the femtomolar range for Zn²⁺), with cysteine coordination enabling rapid metal exchange and protection against . Such binding prevents free metal toxicity while reserving ions for apoenzymes, as evidenced by knockout models showing disrupted distribution and increased sensitivity to exposure.

Emerging Roles in Metabolism and Tissue Repair

Recent investigations have elucidated cysteine's involvement in , a form of iron-dependent characterized by , where cysteine serves as a precursor for synthesis to maintain balance and suppress peroxidation. Depletion of extracellular cysteine induces ferroptosis in various cell types, including cells, which cannot compensate via transsulfuration, highlighting cysteine's non-redundant role in ferroptotic resistance. In cancer metabolism, cysteine restriction sensitizes gliomas and pancreatic tumors to ferroptosis by elevating lipid peroxides and altering , positioning cysteine pathways as potential therapeutic targets. Cysteine metabolism intersects with , as its depletion in during caloric restriction triggers and fat mobilization in humans and mice, independent of classic pathways. This effect stems from reduced thiol-containing , which modulate mitochondrial function and signaling. Furthermore, inhibits cysteine dioxygenase 1 (CDO1) via glutathionylation, linking radiation-induced perturbations in cysteine to disrupted metabolic and cellular damage. In tissue repair, cysteine supplementation counters in irradiated fibroblasts, enhancing proliferation and migration to accelerate closure in preclinical models. N-acetylcysteine (NAC), a cysteine , boosts manganese superoxide dismutase activity, recruiting quiescent fibroblasts into the and comparable to advanced dermal substitutes in promoting epithelialization and deposition. Dietary cysteine emerges as a regulator of intestinal regeneration, activating + T cells to secrete interleukin-22 (IL-22), which stimulates + stem cell proliferation and crypt-villus renewal in mice subjected to injury or . In a 2025 study, cysteine-rich diets rejuvenated the small intestinal lining by 20-30% faster than controls, via this immune-stem cell axis, without altering overall nutrient absorption. D-ribose-L-cysteine conjugates further enhance dermal wound strength by day 14 post-injury in , reducing early through elevated intracellular . These findings underscore cysteine's causal role in bridging metabolic control with reparative processes, though human trials remain limited.

Evolutionary Significance

Conservation in Early Life Forms

Cysteine's utilization is conserved in the proteomes of early life forms, as demonstrated by its presence in protein domains attributable to the (LUCA), estimated to have existed around 4.2 billion years ago. Analyses of ancient protein domains show enrichment of cysteine in LUCA-derived sequences, particularly for roles in metal coordination, such as binding iron and other transition metals in primordial electron transfer proteins like . This suggests cysteine was recruited into the early, alongside and , due to the selective advantage of sulfur-containing and metal-binding functionalities in anaerobic, reducing environments typical of . The of cysteine, primarily via serine and sulfhydrylation using or , represents a foundational metabolic step likely operative in proto-metabolic networks predating LUCA. Experimental and computational studies indicate this pathway enabled the incorporation of cysteine into primitive peptides through of serine, addressing challenges in direct prebiotic synthesis of the group under oxidizing conditions. Such mechanisms provided catalytic versatility, including nucleophilic attacks and modulation, essential for early enzymatic activities like radical-based reactions in iron-sulfur world hypotheses. Across bacterial and archaeal lineages—proxies for early diversification—cysteine residues are retained in conserved motifs of universal proteins, such as ribosomal components and chaperones, despite lower overall frequencies (around 0.5–1% in prokaryotes) compared to later eukaryotes. This selective conservation correlates with functional demands, where cysteine's enables bridges and cofactor assembly in core metabolic enzymes, outweighing risks of oxidative damage in evolving atmospheres. Degeneration occurs only when reactivity disrupts stability, as in some hyperthermophilic proteins, but essential sites remain invariant, underscoring cysteine's irreplaceable role from life's .

Implications for Protein Evolution

Cysteine's group enables the formation of bonds, which provide covalent stabilization to protein structures beyond non-covalent interactions, facilitating the of more rigid and functional folds in oxidizing environments. This capability likely contributed to the diversification of extracellular proteins in eukaryotes, where disulfide acquisition increased protein stability and enabled to aerobic conditions, with approximately 50% of cysteines in eukaryotic proteins forming such bonds compared to lower frequencies in prokaryotes. bonds are strongly conserved across species, suggesting their role in preserving functional connectivity during protein , particularly in secreted and proteins requiring resilience against and denaturation. The relative scarcity of cysteine in proteomes—typically 1-2% in most organisms, rising to 2.26% in mammals—reflects evolutionary pressures favoring its avoidance in solvent-exposed regions to minimize aberrant oxidation and aggregation, while concentrating it in buried or paired positions for precise reactivity. This selective positioning, often conserved across distant taxa, implies that cysteine's incorporation imposed constraints on mutational tolerance, promoting co-evolution of chaperone systems and machinery to manage its reactivity. Such patterns indicate cysteine acted as a "" for -sensitive functions, enabling regulatory innovations like and enzyme activation in response to environmental oxygen levels during the transition from anaerobic to aerobic . Cysteine's underrepresentation correlates with organismal complexity, from 0.5% in some to higher levels in multicellular eukaryotes, suggesting its expanded use supported proteome elaboration, including metal coordination and catalytic sites essential for advanced metabolic networks. Evidence from expansion studies posits cysteine as a later addition among coded , with its single codon pair (UGU/UGC) limiting abundance and favoring precise evolutionary recruitment for specialized roles, such as in primordial catalysts predating full protein synthesis pathways. This scarcity-driven selectivity likely accelerated adaptive by reducing off-target reactivity, allowing cysteines to drive innovations in protein and allostery without pervasive deleterious effects.

Therapeutic and Medical Applications

N-Acetylcysteine in Clinical Use

N-acetylcysteine (NAC), the N-acetyl derivative of cysteine, is approved by the U.S. (FDA) for the treatment of acetaminophen () overdose to prevent or mitigate . It functions as an by serving as a precursor to , which detoxifies the toxic metabolite N-acetyl-p-benzoquinone imine () generated from acetaminophen metabolism. Intravenous NAC regimens, such as the 21-hour protocol involving a of 150 mg/kg followed by infusions, are standard and highly effective, with near-100% prevention of when initiated within 8 hours of ingestion. is an alternative, though it may cause more gastrointestinal side effects like and . NAC is also FDA-approved as a mucolytic agent for respiratory conditions involving viscous , such as (COPD), , and acute lung injuries, where it cleaves disulfide bonds in mucoproteins to reduce mucus and promote clearance. Nebulized or oral NAC at doses of 600–1200 mg daily has demonstrated efficacy in reducing frequency in chronic bronchitis and COPD patients, with meta-analyses showing a significant decrease in exacerbation rates compared to . Long-term use up to 1200 mg/day is generally well-tolerated, with adverse effects primarily limited to mild gastrointestinal upset or in nebulized form. In clinical practice, NAC's safety profile supports its use across diverse patient populations, including and , for acetaminophen overdose, with over 50 years of data confirming low toxicity at therapeutic doses. Dosing adjustments are recommended for hepatic or renal impairment, and anaphylactoid reactions to intravenous NAC occur in 10–20% of cases but are typically manageable with antihistamines or dose slowing. While primarily indicated for these core uses, NAC's properties underpin ongoing evaluations for adjunctive roles, though evidence for broader approvals remains limited to these established applications.

Applications in Toxicology and Overdose Treatment

N-acetylcysteine (NAC), the acetylated form of L-cysteine, functions as a cysteine prodrug to replenish (GSH) stores depleted during acetaminophen () overdose, serving as the standard for this common toxicological . In overdose, acetaminophen shifts toward enzymes, producing excess N-acetyl-p-benzoquinone imine (), a reactive that conjugates with GSH for detoxification; GSH exhaustion allows NAPQI to bind cellular proteins, causing centrilobular hepatic . NAC provides substrate for GSH synthesis via cysteine delivery after deacetylation, while also exhibiting direct effects and improving microcirculatory oxygenation in affected liver tissue. This mechanism restores redox balance and mitigates , with efficacy approaching 100% in preventing when administered within 8 hours of ingestion. Clinical protocols emphasize prompt NAC initiation based on serum acetaminophen levels plotted on the Rumack-Matthew , which stratifies risk from 4 hours post-ingestion; treatment is indicated for levels above the treatment line, even in patients. The U.S. FDA-approved oral regimen consists of a 140 mg/kg followed by 70 mg/kg every 4 hours for 17 doses, totaling approximately 21 hours, though intravenous (IV) administration is preferred in or delayed presentations to ensure . Standard IV dosing involves 150 mg/kg over 60 minutes, then 50 mg/kg over 4 hours, and 100 mg/kg over 16 hours, with continuation beyond 21 hours if transaminases rise or acetaminophen persists. (1 g/kg) is recommended within 1-2 hours of ingestion to reduce absorption, without contraindicating NAC. Adverse effects, including anaphylactoid reactions (rash, hypotension) in up to 20% of IV recipients, are managed by slowing infusion rates, as they stem from release rather than IgE mediation. Beyond acetaminophen, NAC has investigational roles in other overdoses, though evidence is less robust and not FDA-approved for these indications. In or mushroom () poisoning, NAC may attenuate via GSH restoration, with case series reporting reduced mortality when combined with supportive care. Limited studies suggest benefit in acute from non-acetaminophen etiologies, such as or ischemia, by improving transplant-free survival, but randomized trials are lacking and guidelines restrict routine use outside acetaminophen toxicity. Direct administration of free cysteine is rarely employed due to its instability, rapid oxidation to cystine, and poor oral absorption compared to NAC, which undergoes hepatic first-pass metabolism to yield bioavailable cysteine. Overall, NAC's toxicology applications underscore cysteine's pivotal role in countering electrophilic toxin-induced oxidative damage, with ongoing research exploring its utility in emerging threats like agents.

Investigational Uses in Neurology and Psychiatry

N-acetylcysteine (NAC), a precursor to cysteine that replenishes and modulates glutamate via the cystine-glutamate , has been examined in clinical trials for various neurological and psychiatric conditions, primarily due to its properties and potential to address and . Early studies suggested NAC could mitigate symptoms in disorders involving glutamatergic dysregulation, such as , where adjunctive therapy at doses of 1,200–2,400 mg/day reduced negative symptoms in some randomized controlled trials, though larger trials have yielded inconsistent results, including no significant augmentation effects. In mood disorders, NAC shows promise as an adjunct for bipolar depression, with meta-analyses indicating modest reductions in depressive symptoms when added to standard treatments, potentially linked to its role in normalizing brain balance; however, evidence for unipolar major depression remains preliminary and not uniformly supportive. For obsessive-compulsive disorder (OCD), open-label and small randomized trials reported symptom severity decreases of up to 30–40% at 2,400–3,000 mg/day, attributed to glutamate modulation in cortico-striatal circuits, though larger confirmatory studies are needed. Investigations in neurodevelopmental disorders include autism spectrum disorder, where a 2009 pilot randomized trial (n=33 children) found 900–2,700 mg/day NAC reduced irritability scores by approximately 25% on the Aberrant Behavior Checklist compared to , prompting ongoing trials for repetitive behaviors and social deficits. In addiction psychiatry, NAC has been tested for substance use disorders, with preliminary evidence from 2018 reviews showing reduced cravings and relapse in , , and via restoration of extracellular glutamate , but phase II trials often fail to demonstrate sustained abstinence benefits. Neurological applications remain exploratory, focusing on ; for instance, a 2025 nonrandomized trial in hereditary (n=10) assessed NAC's safety for lowering levels, reporting tolerability but inconclusive efficacy on cerebral burden. In and Alzheimer's, preclinical data support NAC's mitigation of mitochondrial dysfunction and , yet human trials as of 2023 show limited cognitive improvements, hampered by small sample sizes and variable . Recent large-scale trials, such as a 2025 study published in the Journal of Clinical Psychiatry, have highlighted NAC's lack of efficacy in core symptoms of , underscoring the need for biomarker-driven selection to identify responsive subgroups. Overall, while NAC's safety profile supports further investigation, meta-analyses emphasize heterogeneous outcomes, with effect sizes often small (Cohen's d < 0.5) and influenced by dosage, duration (typically 8–24 weeks), and comorbid oxidative stress markers.

Controversies, Regulatory Issues, and Evidence Assessment

The primary regulatory issues pertaining to cysteine derivatives, particularly N-acetylcysteine (NAC), involve its dual status as an approved drug and purported dietary supplement in the United States. The U.S. Food and Drug Administration (FDA) approved NAC as a prescription drug in 1963 for treating acetaminophen overdose, leading to its exclusion from the dietary supplement definition under the Federal Food, Drug, and Cosmetic Act when the agency issued warning letters to manufacturers in July 2020, prompting widespread product delistings from retailers like Amazon. This action sparked industry opposition, with groups such as the Council for Responsible Nutrition arguing that NAC's safe supplemental use for over 25 years, supported by post-market surveillance data showing minimal adverse events, justified grandfathered access rather than retroactive restriction. In March 2022, the FDA responded to citizen petitions by reaffirming NAC's exclusion but announced exploration of rulemaking to potentially permit its lawful inclusion in supplements, citing public health considerations. By August 2022, the agency finalized guidance exercising enforcement discretion for certain over-the-counter NAC products marketed before October 15, 2020, allowing their continued sale while prohibiting new dietary ingredient submissions and scrutinizing unapproved health claims. This policy, while stabilizing market availability, has sustained debates over regulatory overreach, as evidenced by withdrawn lawsuits from trade associations following the guidance, though full rulemaking remains pending as of 2025. Evidence assessment for cysteine and NAC supplementation highlights robust support for specific indications but inconsistencies in broader claims. Intravenous NAC, at doses of 150 mg/kg loading followed by maintenance infusions, reduces hepatotoxicity mortality to under 1% in acetaminophen overdose when initiated within 8 hours, as confirmed by systematic reviews of over 20 studies involving thousands of cases. Oral cysteine supplementation shows preliminary benefits in cysteine-deficient states, such as improving glutathione levels and reducing oxidative markers in small trials of elderly subjects, but lacks large-scale RCTs to establish causality or population-level efficacy. Controversies emerge in investigational uses, where promotional narratives often exceed empirical backing. Meta-analyses of NAC for substance use disorders report modest craving reductions (Hedges' g ≈ -0.48 across 12 RCTs, n=681), yet high heterogeneity (I² > 70%) and risks—common in academic literature incentivized toward positive outcomes—undermine confidence, with null effects in youth trials. Similarly, for obsessive-compulsive disorder, a 2024 of 10 RCTs (n=413) found symptom score improvements (SMD -0.62), but analyses revealed benefits confined to adjunctive at ≥2000 mg/day, with no superiority over in monotherapy. In COVID-19, despite early advocacy, a 2024 review of 7 RCTs (n=651) detected no mortality benefit (RR 0.94, 95% CI 0.68-1.30) or ventilator-free days increase, illustrating how mechanistic plausibility (e.g., mucolytic effects) failed to translate clinically. Further contention involves potential harms from antioxidant supplementation. Preclinical data from models indicate NAC may accelerate in established cancers by quenching that otherwise suppress tumor invasiveness, prompting cautions against routine use in patients absent deficiency confirmation. Overall, while NAC exhibits a favorable safety profile (adverse events <5% at 1200-2400 mg/day, mainly nausea), evidence for non-toxicological applications relies on underpowered studies prone to type I errors, necessitating prioritization of first-line therapies and further pragmatic trials over extrapolated benefits.

Other Practical Applications

Use in Animal Feed and Agriculture

Cysteine, typically provided as L-cystine or its derivatives, serves as a supplemental sulfur-containing amino acid in animal feeds, particularly for monogastric species such as poultry and swine, where methionine plus cysteine often represents the second-limiting amino acid profile after lysine. This supplementation enables the formulation of diets with reduced crude protein content while maintaining adequate sulfur amino acid levels, thereby supporting protein synthesis, growth, and tissue integrity without excess nitrogen excretion. In poultry nutrition, cysteine is critical for keratin production in feathers, with deficiencies linked to impaired feathering and reduced performance; balanced supplementation improves feed intake and weight gain when methionine:cysteine ratios are optimized, typically around 0.5:1 to 0.7:1. Studies in broiler chickens demonstrate that dietary cysteine, often in conjunction with methionine, enhances growth performance and feed conversion ratios, particularly under stress conditions like heat exposure, by bolstering glutathione synthesis and antioxidant defenses. For instance, supplementation at levels providing 0.3-0.5% total sulfur amino acids has been shown to increase body weight gains by 5-10% in trials, though excess L-cysteine (e.g., above 2.5% of diet) can induce toxicity, reducing feed intake and causing mortality in young chicks due to metabolic imbalances like acidosis. In swine, cysteine spares up to 50% of the methionine requirement in both enteral and parenteral feeding, improving nutrient digestibility and offsetting oxidative stress from environmental toxins, as evidenced by enhanced average daily gains in piglets exposed to bisphenol A. For calves, inclusion of methionine plus cysteine at 0.2-0.4% of dry matter supports rumen development and performance in liquid feeds. In ruminant agriculture, such as sheep, cysteine supplementation has niche applications, including a 13% reduction in methane emissions via alterations in rumen fermentation redox potential, though microbial synthesis typically meets requirements, limiting widespread use. Overall, the global demand for synthetic cysteine in animal nutrition, estimated at thousands of tons annually, drives its inclusion to boost immunity, weight gain, and efficiency in intensive production systems, with market growth projected at 5-6% CAGR through 2030 amid rising protein demands. This practice, however, requires precise dosing to avoid imbalances, as peer-reviewed evidence underscores the narrow therapeutic window for sulfur amino acids in feed formulations.

Industrial and Biochemical Applications

L-Cysteine is produced industrially on a scale of approximately 3,000 tons per year, primarily via acid hydrolysis of keratinous materials such as duck feathers or hog bristles, followed by extraction, purification, and conversion of the resulting L-cystine to L-cysteine through electrolytic or catalytic reduction. This method, while cost-effective, yields impurities and racemic byproducts, prompting shifts toward microbial fermentation using genetically engineered strains of Escherichia coli or Pantoea ananatis, which convert serine or O-acetylserine precursors into L-cysteine with yields exceeding 10 g/L under optimized conditions. In vitro enzymatic cascades employing thermophilic enzymes have also demonstrated production of up to 10.5 mM L-cysteine from glucose, offering potential for sustainable, non-animal-derived synthesis. In the food sector, L-cysteine functions as a reducing agent in bakery applications, cleaving disulfide bonds in gluten proteins to enhance dough elasticity, reduce mixing times by up to 30%, and increase loaf volumes in yeast-leavened breads. It also reacts with reducing sugars in Maillard processes to produce savory meat flavors for soups, snacks, and seasonings, leveraging its thiol group's reactivity to generate sulfur-containing volatiles like those in roasted beef. Animal feed formulations incorporate L-cysteine as a sulfur amino acid supplement to address deficiencies in corn-soy diets, improving feather growth and weight gain in poultry by 5-10%. Biochemically, cysteine's nucleophilic thiol enables its use in biotechnology for site-specific protein labeling and engineering, where selective alkylation of cysteine residues introduces tags for purification or fluorescence without disrupting native folds. In peptide synthesis, over 60 distinct protecting groups for the cysteine thiol—such as trityl or acetamidomethyl—facilitate controlled disulfide bond formation, yielding therapeutic peptides like insulin analogs with enhanced stability. As a reducing agent, it supports in vitro protein refolding by preventing aberrant disulfide linkages, with concentrations of 1-5 mM commonly used in recombinant expression systems to recover active enzymes from inclusion bodies. In drug discovery, reactive cysteine profiling identifies hyper-reactive cysteines in proteins for covalent inhibitor design, targeting enzymes like kinases with sub-micromolar potency.

Chemical Reactivity

Oxidation and Disulfide Formation

The thiol group (-SH) in the side chain of cysteine exhibits high reactivity toward oxidants due to the nucleophilic nature of the sulfur atom, enabling facile oxidation under physiological conditions. Oxidation typically proceeds via a two-electron process, converting two cysteine thiols into a disulfide bond (R-S-S-R), accompanied by the release of two protons and two electrons. This reaction is pH-dependent and influenced by the local redox potential, with the cysteine/cystine couple exhibiting a standard reduction potential of approximately -220 mV at neutral pH, favoring disulfide formation in oxidizing environments such as the endoplasmic reticulum. Mechanistically, initial oxidation often yields an unstable sulfenic acid intermediate (R-SOH) from one thiol, which rapidly reacts with a second proximal thiol to form the disulfide, preventing irreversible over-oxidation to sulfinic (R-SO2H) or sulfonic (R-SO3H) acids. In vitro, mild oxidants like or molecular oxygen can drive this process, while in vivo, enzymes such as Ero1 and protein disulfide isomerase (PDI) catalyze disulfide formation and rearrangement during protein folding. Disulfide bonds can also form intermolecularly between protein subunits or with low-molecular-weight thiols like , enabling thiol-disulfide exchange reactions that regulate redox signaling and protein function. In proteins, disulfide bonds covalently cross-link cysteine residues, imparting structural rigidity and resistance to unfolding, particularly in extracellular domains exposed to oxidative stress. For instance, insulin contains three disulfide bridges essential for its activity, while mutations disrupting these bonds in proteins like transthyretin lead to amyloid aggregation diseases. The stability conferred by disulfides arises from their covalent nature, with bond energies around 50-60 kcal/mol, though they remain reversible under reducing conditions mediated by thioredoxins or glutaredoxins in the cytosol. Over-oxidation of cysteines can disrupt these bonds, contributing to oxidative damage in pathologies like neurodegeneration, underscoring the delicate balance between formation and reduction.

Nucleophilic and Electrophilic Reactions

The thiol (-SH) group in cysteine's side chain is highly nucleophilic, especially when deprotonated to the thiolate anion (pKa ≈ 8.3), owing to sulfur's large atomic radius, polarizability, and lone pair availability, which facilitate attacks on electrophiles. This reactivity underpins diverse chemical and biological processes, including nucleophilic substitution (e.g., SN2 reactions with alkyl halides like iodoacetic acid, displacing iodide to form thioethers) and conjugate additions to α,β-unsaturated carbonyls or other Michael acceptors. In proteins, cysteine's nucleophilicity enables thiol-disulfide exchange, where the thiolate attacks the electrophilic sulfur of a disulfide bond, transferring the sulfhydryl group and equilibrating redox states critical for enzyme catalysis and structural stabilization. Cysteine proteases exemplify this, with the thiolate nucleophilically attacking the electrophilic carbonyl carbon of peptide substrates, forming a covalent acyl-enzyme intermediate that hydrolyzes to cleave the bond. Additionally, free cysteine or protein thiols react with endogenous electrophiles (e.g., lipid peroxidation products) or exogenous agents, yielding S-adducts that modulate signaling pathways but risk toxicity if unchecked. Cysteine can also engage in electrophilic reactions when its sulfur acts as an electrophile, typically after oxidation or modification that increases sulfur's electron deficiency. For example, oxidation to (Cys-SOH) imparts electrophilicity at sulfur, enabling nucleophilic attack by proximal thiols or amines to form disulfides or other adducts, a reversible modification in redox sensing. Higher oxidation states, such as sulfinic (Cys-SO₂H) or (Cys-SO₃H), further enhance electrophilicity, reacting irreversibly with strong nucleophiles, though these are less common in native cysteine reactivity. Persulfide derivatives (Cys-SSH) exhibit dual behavior, with the terminal sulfur acting electrophilically toward nucleophiles in some cellular defenses against oxidative stress. These electrophilic modes contrast cysteine's default nucleophilicity, highlighting context-dependent reactivity influenced by pH, redox environment, and proximal residues.

Safety, Toxicology, and Risks

Toxicity Profile and Dosage Considerations

L-Cysteine demonstrates low to moderate acute oral toxicity in animal models, with reported LD50 values ranging from 1,890 mg/kg in rats to greater than 2,000 mg/kg body weight in other rodent studies, classifying it below the threshold for high toxicity but warranting caution for substantial ingestions. In humans, single oral doses of 5–10 grams have elicited adverse effects including nausea, lightheadedness, and dissociation, indicating gastrointestinal and central nervous system sensitivity at elevated acute exposures. Intravenous administration, as in parenteral nutrition, carries risks of aluminum accumulation in formulations, potentially exacerbating toxicity in patients with renal impairment or preterm infants during prolonged use. Subchronic exposure studies in rats over four weeks revealed no-observed-adverse-effect levels below 500 mg/kg/day for L-cysteine, with higher doses associated with renal histopathological changes such as basophilic tubules and eosinophilic luminal material, suggesting potential nephrotoxicity from oxidative stress or metabolic overload. D-Cysteine exhibited comparable toxicity thresholds in similar models. Cellular-level investigations indicate that excess cysteine impairs mitochondrial function through non-vacuolar accumulation, though human relevance remains understudied and primarily inferred from in vitro or animal data.31397-2) Dosage considerations for oral supplementation lack a standardized recommended daily allowance, as cysteine is conditionally essential and derived endogenously or from diet, but typical supplemental ranges of 500–2,000 mg/day are employed in nutritional contexts without established upper limits from major health authorities. Safety assessments for food supplements propose tolerable intakes up to 13 mg/kg body weight per day for L-cysteine equivalents, with lower thresholds (e.g., 10 mg/day) deemed safe for children aged 10–14 years to avoid cumulative risks. Individual factors such as renal function, concurrent medications (e.g., antidiabetics, due to potential hypoglycemia), and oxidation propensity necessitate medical supervision, particularly exceeding 1 gram daily, as gastrointestinal disturbances predominate at higher intakes.

Adverse Effects and Contraindications

L-Cysteine exhibits low acute toxicity when administered orally, with an LD50 value of approximately 1.89 g/kg in rats, indicating a wide margin of safety relative to typical dietary or supplemental doses. The U.S. Food and Drug Administration has affirmed L-cysteine as generally recognized as safe (GRAS) for use as a direct food ingredient in specific applications, such as dough conditioning, at levels not exceeding good manufacturing practices. At supplemental doses up to 1-2 g/day, adverse effects are uncommon in healthy adults, though gastrointestinal disturbances including nausea, vomiting, diarrhea, and abdominal discomfort may occur with higher intakes exceeding 5 g/day. Rare reports include headache, drowsiness, and skin rash, potentially linked to hypersensitivity or sulfur content. Intravenous administration of cysteine hydrochloride, often in , carries additional risks including , , and imbalances, particularly in neonates or patients with hepatic dysfunction. Aluminum contamination in some formulations may contribute to with prolonged use. L-Cysteine may lower blood glucose levels, necessitating caution and monitoring in individuals with or those on hypoglycemic agents to avoid excessive reductions. Contraindications include known to L-cysteine or related , as well as inborn errors of , where supplementation risks exacerbating or other imbalances. In , a impairing renal reabsorption of cystine (the dimer of cysteine), L-cysteine supplementation is inadvisable, as ingested cysteine oxidizes to cystine, potentially elevating urinary cystine concentrations and promoting recurrent nephrolithiasis. Caution is also warranted in severe renal impairment, where impaired clearance may lead to accumulation.

Historical Development

Discovery and Early Characterization

Cystine, the disulfide dimer of cysteine, was first isolated in 1810 by English physician and chemist from a novel type of urinary calculus obtained from a patient. Wollaston designated the hexagonal prisms as "cystic oxide" based on their source in stones and crystalline appearance, later renamed cystine by in 1832 to reflect its etymology from the Greek kystis (bladder). In 1884, German chemist Eugen Baumann achieved the first isolation of cysteine by reducing cystine with zinc dust in acidic conditions, yielding a monomeric compound he named "cysteïne" to denote its derivation from cystine. This reduction cleaved the bond, revealing cysteine's structure as featuring a reactive sulfhydryl (-SH) group, which distinguished it from other and highlighted its propensity for oxidation to reform cystine. Early analyses confirmed cysteine's as C₃H₇NO₂S and its amphoteric properties, though initial structural elucidation faced challenges due to its instability and tendency to oxidize. Subsequent investigations in the late , including of proteins like horn, verified cystine's presence in biological tissues and its equivalence to the urinary compound, establishing cysteine's role as a despite detection difficulties posed by sulfur's interference in early analytical methods. By the 1890s, cysteine's interconversion with cystine was recognized as key to its biochemical function, particularly in forming bridges that stabilize protein structures.

Key Milestones in Synthesis and Research

Cystine, the disulfide dimer of cysteine, was first isolated in 1810 by William Hyde Wollaston from human bladder stones, initially termed "cystic oxide" due to its origin in cystic calculi. This marked the initial recognition of a sulfur-containing compound linked to mammalian metabolism, though its structure remained unclear for decades. In 1884, German chemist Eugen Baumann isolated monomeric cysteine by reducing cystine with zinc dust in hydrochloric acid, establishing its thiol nature and naming it "cysteïne" from its cystine precursor. The structure of cystine was confirmed through total synthesis in 1903 by Emil Erlenmeyer, providing foundational insight into the disulfide linkage central to cysteine's reactivity. These early isolations relied on empirical reduction and crystallization techniques, highlighting cysteine's redox lability without advanced spectroscopic tools. Biosynthetic pathways for cysteine were elucidated in the mid-, revealing its formation from serine and in microorganisms. In enteric bacteria like Salmonella typhimurium and , the pathway involves serine acetyltransferase (SAT) and O-acetylserine sulfhydrylase (OASS), converting O-acetylserine to cysteine using ; the SAT-OASS complex was first characterized in 1969. This enzymatic mechanism underscored cysteine's non-essential status in many organisms, dependent on methionine transsulfuration in mammals. Industrial production shifted from acid hydrolysis of sources (e.g., feathers, bristles) in the early 20th century to microbial fermentation in the 1950s, enabling scalable L-cysteine output via engineered bacteria overexpressing pathway genes. Key biochemical research advanced in the with N-acetylcysteine (NAC)'s development as a mucolytic agent and for acetaminophen overdose, leveraging cysteine's in glutathione replenishment. By the 1970s, cysteine's centrality in via disulfide bonds and was firmly established, with studies on thiol-disulfide exchange informing enzymology and . Later milestones include the 1996 clarification of cysteine complexes in and , integrating with nitrogen . These developments, grounded in kinetic assays and genetic knockouts, affirmed cysteine's indispensability despite its semi-essential classification, with ongoing research probing its catabolism in cancer and aging via stable isotope tracing.

References

  1. https://pubchem.ncbi.nlm.nih.gov/compound/L-_-Cysteine
  2. https://pmc.ncbi.nlm.nih.gov/articles/PMC4355186/
  3. https://pmc.ncbi.nlm.nih.gov/articles/PMC3268551/
  4. https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/cysteine
  5. https://pubchem.ncbi.nlm.nih.gov/compound/5862
  6. https://www.acs.org/molecule-of-the-week/archive/c/l-cysteine.html
  7. https://chem.libretexts.org/Courses/CSU_Chico/CSU_Chico%253A_CHEM_451_-_Biochemistry_I/CHEM_451_Test/04%253A_Protein_Structure/4.1%253A_Amino_Acids/A2._Amino_Acid_Stereochemistry
  8. https://www.alfa-chemistry.com/product/l-cysteine-cas-52-90-4-292429.html
  9. https://www.chemicalbook.com/ChemicalProductProperty_EN_CB7388480.htm
  10. https://www.myfooddata.com/articles/high-cystine-foods.php
  11. https://purovitalis.com/nac-l-cysteine-foods/
  12. https://pmc.ncbi.nlm.nih.gov/articles/PMC10297691/
  13. https://www.ahajournals.org/doi/10.1161/strokeaha.114.008022
  14. https://pubmed.ncbi.nlm.nih.gov/12624753/
  15. https://www.jbc.org/article/S0021-9258%2819%2937747-6/fulltext
  16. https://portlandpress.com/bioscirep/article/42/10/BSR20220368/231848/Combatting-antimicrobial-resistance-via-the
  17. https://www.kegg.jp/entry/map00270
  18. https://pmc.ncbi.nlm.nih.gov/articles/PMC3431704/
  19. https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/transsulfuration-pathway
  20. https://www.cell.com/cell-metabolism/fulltext/S1550-4131%2819%2930512-1
  21. https://pmc.ncbi.nlm.nih.gov/articles/PMC4005819/
  22. https://jn.nutrition.org/article/S0022-3166%2822%2917597-8/fulltext
  23. https://pmc.ncbi.nlm.nih.gov/articles/PMC5311407/
  24. https://www.myfoodresearch.com/uploads/8/4/8/5/84855864/fr-2020-189.pdf
  25. https://pmc.ncbi.nlm.nih.gov/articles/PMC10821248/
  26. https://patents.google.com/patent/EP0235908A2/en
  27. https://www.scribd.com/document/206299928/Manufacture-of-L-cystine
  28. https://bakerpedia.com/ingredients/l-cysteine/
  29. https://www.mdpi.com/1420-3049/29/2/486
  30. https://journals.asm.org/doi/abs/10.1128/aem.02502-16
  31. https://microbialcellfactories.biomedcentral.com/articles/10.1186/s12934-023-02021-5
  32. https://www.sciencedirect.com/science/article/abs/pii/S1389172321002358
  33. https://pmc.ncbi.nlm.nih.gov/articles/PMC7191308/
  34. https://pubs.acs.org/doi/10.1021/acs.chemrev.7b00123
  35. https://www.metwarebio.com/importance-of-disulfide-bonds-in-proteins/
  36. https://pmc.ncbi.nlm.nih.gov/articles/PMC2142256/
  37. https://www.nature.com/articles/s41598-020-67230-z
  38. https://www.nature.com/articles/srep38572
  39. https://pmc.ncbi.nlm.nih.gov/articles/PMC4076987/
  40. https://pmc.ncbi.nlm.nih.gov/articles/PMC2706539/
  41. https://pmc.ncbi.nlm.nih.gov/articles/PMC10339824/
  42. https://pubs.acs.org/doi/10.1021/cr300163e
  43. https://www.ahajournals.org/doi/10.1161/circresaha.112.268680
  44. https://pmc.ncbi.nlm.nih.gov/articles/PMC3772197/
  45. https://pmc.ncbi.nlm.nih.gov/articles/PMC12384178/
  46. https://jissn.biomedcentral.com/articles/10.1186/1550-2783-2-2-38
  47. https://pmc.ncbi.nlm.nih.gov/articles/PMC5618090/
  48. https://pmc.ncbi.nlm.nih.gov/articles/PMC9455234/
  49. https://www.nature.com/articles/s41467-018-04003-3
  50. https://www.mdpi.com/2218-273X/15/8/1115
  51. https://pubmed.ncbi.nlm.nih.gov/12954327/
  52. https://www.sciencedirect.com/science/article/pii/S1074552103001741
  53. https://pmc.ncbi.nlm.nih.gov/articles/PMC4101490/
  54. https://www.sciencedirect.com/science/article/abs/pii/S0076687902530366
  55. https://onlinelibrary.wiley.com/doi/10.1002/psc.3606
  56. https://academic.oup.com/metallomics/article/16/5/mfae025/7673086
  57. https://www.sciencedirect.com/science/article/pii/S2213231721003244
  58. https://pubmed.ncbi.nlm.nih.gov/12686149/
  59. https://pubmed.ncbi.nlm.nih.gov/19587982/
  60. https://pubs.acs.org/doi/10.1021/jacs.1c05495
  61. https://pubmed.ncbi.nlm.nih.gov/26583802/
  62. https://ashpublications.org/bloodadvances/article/8/1/56/498553/The-nonessential-amino-acid-cysteine-is-required
  63. https://www.nature.com/articles/s41467-023-36630-w
  64. https://pmc.ncbi.nlm.nih.gov/articles/PMC12374342/
  65. https://www.nature.com/articles/s42255-025-01297-8
  66. https://www.sciencedirect.com/science/article/pii/S2213231725001697
  67. https://www.sciencedirect.com/science/article/abs/pii/S0006291X25013154
  68. https://pmc.ncbi.nlm.nih.gov/articles/PMC4822548/
  69. https://pmc.ncbi.nlm.nih.gov/articles/PMC4400934/
  70. https://www.biorxiv.org/content/10.1101/2025.02.15.638423v1.full-text
  71. https://news.mit.edu/2025/cysteine-rich-diet-may-promote-intestinal-lining-regeneration-study-suggests-1001
  72. https://www.sciencedirect.com/science/article/abs/pii/S000296101500135X
  73. https://www.pnas.org/doi/10.1073/pnas.2410311121
  74. https://astrobiology.com/2024/04/identifying-the-last-universal-common-ancestors-protein-domains-resolves-the-order-in-which-the-amino-acids-were-recruited-into-the-genetic-code.html
  75. https://www.ucl.ac.uk/news/2020/nov/cysteine-synthesis-was-key-step-origin-life
  76. https://phys.org/news/2020-11-cysteine-synthesis-key-life.html
  77. https://pmc.ncbi.nlm.nih.gov/articles/PMC3061813/
  78. https://academic.oup.com/mbe/article/17/8/1232/992796
  79. https://academic.oup.com/mbe/article/28/1/327/980888
  80. https://pubmed.ncbi.nlm.nih.gov/20675408/
  81. https://www.nature.com/articles/s41598-024-77056-8
  82. https://www.sciencedirect.com/science/article/pii/S089158491500146X
  83. https://pmc.ncbi.nlm.nih.gov/articles/PMC8048112/
  84. https://www.ncbi.nlm.nih.gov/books/NBK537183/
  85. https://www.jci.org/articles/view/110853
  86. https://emedicine.medscape.com/article/820200-treatment
  87. https://pmc.ncbi.nlm.nih.gov/articles/PMC8234027/
  88. https://publications.ersnet.org/content/errev/24/137/451
  89. https://pmc.ncbi.nlm.nih.gov/articles/PMC7892733/
  90. https://pmc.ncbi.nlm.nih.gov/articles/PMC8211525/
  91. https://www.sciencedirect.com/science/article/pii/S0163725821001182
  92. https://www.amjmed.com/article/0002-9343%2891%2990296-A/fulltext
  93. https://www.aasld.org/liver-fellow-network/core-series/clinical-pearls/getting-knack-nac
  94. https://chemm.hhs.gov/countermeasure_acetylcysteine.htm
  95. https://pmc.ncbi.nlm.nih.gov/articles/PMC3044191/
  96. https://pmc.ncbi.nlm.nih.gov/articles/PMC9095537/
  97. https://www.psychiatrist.com/jcp/antipsychotic-augmentation-with-n-acetylcysteine-in-schizophrenia/
  98. https://www.sciencedirect.com/science/article/abs/pii/S0163834324002238
  99. https://pmc.ncbi.nlm.nih.gov/articles/PMC4423164/
  100. https://pmc.ncbi.nlm.nih.gov/articles/PMC4914359/
  101. https://pmc.ncbi.nlm.nih.gov/articles/PMC5993450/
  102. https://jamanetwork.com/journals/jamaneurology/fullarticle/2831917
  103. https://pmc.ncbi.nlm.nih.gov/articles/PMC10376274/
  104. https://www.psychiatrist.com/news/weekly-mind-reader-n-acetylcysteine-falls-short/
  105. https://www.sciencedirect.com/science/article/pii/S0149763415001190
  106. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/guidance-industry-policy-regarding-n-acetyl-l-cysteine
  107. https://www.webmd.com/diet/health-benefits-nac
  108. https://www.crnusa.org/congress-tell-fda-stop-limiting-consumer-access-safe-beneficial-dietary-supplements
  109. https://www.fda.gov/food/hfp-constituent-updates/fda-issues-response-two-citizen-petitions-nac-dietary-supplements
  110. https://www.fda.gov/food/hfp-constituent-updates/fda-releases-final-guidance-enforcement-discretion-certain-nac-products
  111. https://www.federalregister.gov/documents/2022/08/02/2022-16499/policy-regarding-n-acetyl-l-cysteine-guidance-for-industry-availability
  112. https://www.nutraingredients.com/Article/2022/11/02/npa-withdraws-fda-lawsuit-following-final-nac-guidance-marketplace-stabilization/
  113. https://pmc.ncbi.nlm.nih.gov/articles/PMC6017824/
  114. https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1462612/full
  115. https://www.nature.com/articles/s41386-025-02061-y
  116. https://pmc.ncbi.nlm.nih.gov/articles/PMC11456833/
  117. https://www.cell.com/heliyon/fulltext/S2405-8440%2824%2901210-6
  118. https://www.science.org/content/blog-post/n-acetyl-cysteine-warning-shot
  119. https://pmc.ncbi.nlm.nih.gov/articles/PMC5241507/
  120. https://www.efsa.europa.eu/en/efsajournal/pub/3173
  121. https://www.researchgate.net/publication/352697700_Cysteine_in_Broiler_Poultry_Nutrition
  122. https://www.intechopen.com/chapters/76144
  123. https://pubmed.ncbi.nlm.nih.gov/38100947/
  124. https://www.tandfonline.com/doi/full/10.1080/00071668.2023.2264234
  125. https://www.sciencedirect.com/science/article/pii/S0032579125009861
  126. https://www.sciencedirect.com/science/article/pii/S0022316622090599
  127. https://pubmed.ncbi.nlm.nih.gov/14652375/
  128. https://pmc.ncbi.nlm.nih.gov/articles/PMC10675709/
  129. https://www.sciencedirect.com/science/article/pii/S0022030218302777
  130. https://www.sciencedirect.com/science/article/abs/pii/S0048969797001629
  131. https://www.mordorintelligence.com/industry-reports/cysteine-market
  132. https://straitsresearch.com/report/cysteine-market
  133. https://www.researchgate.net/publication/351881001_APPLICATIONS_OF_CYSTEINE_IN_HEALTH_AND_INDUSTRIES_Complimentary_Contributor_Copy
  134. https://pubs.rsc.org/en/content/articlehtml/2021/cs/d1cs00271f
  135. https://aapep.bocsci.com/resources/cysteine-definition-structure-benefits-sources-and-uses.html
  136. https://pubmed.ncbi.nlm.nih.gov/30105421/
  137. https://pubs.acs.org/doi/10.1021/acs.biochem.2c00349
  138. https://pubs.acs.org/doi/10.1021/bi1008694
  139. https://www.nature.com/articles/s41467-020-19372-x
  140. https://chem.libretexts.org/Bookshelves/Organic_Chemistry/Book%253A_Organic_Chemistry_with_a_Biological_Emphasis_v2.0_%28Soderberg%29/15%253A_Oxidation_and_Reduction_Reactions/15.07%253A_Redox_Reactions_of_Thiols_and_Disulfides
  141. https://pmc.ncbi.nlm.nih.gov/articles/PMC5367942/
  142. https://www.creative-proteomics.com/resource/disulfide-bridges-proteins-formation-function-analysis.htm
  143. https://www.pnas.org/doi/10.1073/pnas.1605363113
  144. https://www.sciencedirect.com/science/article/pii/S0021925819665117
  145. https://pmc.ncbi.nlm.nih.gov/articles/PMC6382561/
  146. https://www.pearson.com/channels/organic-chemistry/asset/e05e9aa8/write-the-mechanism-for-the-reaction-of-a-cysteine-side-chain-with-iodoacetic-ac
  147. https://books.rsc.org/books/monograph/900/chapter/689580/The-Nucleophilic-Thiolate-in-Cysteine-and
  148. https://www.sciencedirect.com/science/article/pii/S2213231721002317
  149. https://pubs.rsc.org/en/content/articlelanding/2016/sc/c5sc02569a
  150. https://www.pnas.org/doi/10.1073/pnas.1321232111
  151. https://pmc.ncbi.nlm.nih.gov/articles/PMC4788399/
  152. https://www.tersusenv.com/images/documents/SDS/08a_L-Cysteine.pdf
  153. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/210660lbl.pdf
  154. https://pmc.ncbi.nlm.nih.gov/articles/PMC5545674/
  155. https://www.rivm.nl/bibliotheek/rapporten/2024-0086.pdf
  156. https://www.webmd.com/vitamins/ai/ingredientmono-1692/l-cysteine
  157. https://louisville.edu/micronano/files/documents/safety-data-sheets-sds/l-cysteine-free-base/
  158. https://www.ecfr.gov/current/title-21/chapter-I/subchapter-B/part-184/subpart-B/section-184.1271
  159. https://synapse.patsnap.com/article/what-are-the-side-effects-of-l-cysteine
  160. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e7652275-1c53-490c-82ad-e63867df5788
  161. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=cbf70fc3-14b3-4c17-8de8-acba1e12ac95
  162. https://www.rxlist.com/cysteine/generic-drug.htm
  163. https://pmc.ncbi.nlm.nih.gov/articles/PMC7915598/
  164. https://www.ncbi.nlm.nih.gov/books/NBK470527/
  165. https://synapse.patsnap.com/article/what-is-l-cysteine-used-for
  166. https://chemtymology.co.uk/2020/11/27/cysteine-and-cystine/
  167. https://www.eurpepsoc.com/cysteine-essential-inessential-amino-acid/
  168. https://www.intechopen.com/chapters/1198180
  169. https://www.researchgate.net/publication/361023915_Thiol_Redox_Regulation_-_A_Brief_Historical_Overview
  170. https://www.eurpepsoc.com/cysteine-essential-inessential-amino-acid/?aid=5111&sa=0
  171. https://www.biorxiv.org/content/10.1101/2022.08.26.505162v1.full.pdf
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