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Cystine
Cystine
Cystine
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Cystine
Identifiers
3D model (JSmol)
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ECHA InfoCard 100.000.270 Edit this at Wikidata
KEGG
UNII
  • InChI=1S/C6H12N2O4S2/c7-3(5(9)10)1-13-14-2-4(8)6(11)12/h3-4H,1-2,7-8H2,(H,9,10)(H,11,12) checkY
    Key: LEVWYRKDKASIDU-UHFFFAOYSA-N checkY
  • InChI=1/C6H12N2O4S2/c7-3(5(9)10)1-13-14-2-4(8)6(11)12/h3-4H,1-2,7-8H2,(H,9,10)(H,11,12)
    Key: LEVWYRKDKASIDU-UHFFFAOYAA
  • C(C(C(=O)O)N)SSCC(C(=O)O)N
Properties
C6H12N2O4S2
Molar mass 240.29 g·mol−1
Hazards
Safety data sheet (SDS) External MSDS
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 ?)

Cystine is the oxidized derivative of the amino acid cysteine and has the formula (SCH2CH(NH2)CO2H)2. It is a white solid that is poorly soluble in water. As a residue in proteins, cystine serves two functions: a site of redox reactions and a mechanical linkage that allows proteins to retain their three-dimensional structure.[1]

Formation and reactions

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Structure

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Cystine is the disulfide derived from the amino acid cysteine. The conversion can be viewed as an oxidation:

2 HO2CCH(NH2)CH2SH + 0.5 O2 → (HO2CCH(NH2)CH2S)2 + H2O

Cystine contains a disulfide bond, two amine groups, and two carboxylic acid groups. As for other amino acids, the amine and carboxylic acid groups exist in rapid equilibrium with the ammonium-carboxylate tautomer. The great majority of the literature concerns l,l-cystine, derived from l-cysteine. Other isomers include d,d-cystine and the meso isomer d,l-cystine, neither of which is biologically significant.

Occurrence

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Cystine is common in many foods such as eggs, meat, dairy products, and whole grains as well as skin, horns and hair. It was not recognized as being derived of proteins until it was isolated from the horn of a cow in 1899.[2] Human hair and skin contain approximately 10–14% cystine by mass.[3]

History

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Cystine was discovered in 1810 by the English chemist William Hyde Wollaston, who called it "cystic oxide".[4][5] In 1833, the Swedish chemist Jöns Jacob Berzelius named the amino acid "cystine".[6] The Norwegian chemist Christian J. Thaulow determined, in 1838, the empirical formula of cystine.[7] In 1884, the German chemist Eugen Baumann found that when cystine was treated with a reducing agent, cystine revealed itself to be a dimer of a monomer which he named "cysteïne".[8][5] In 1899, cystine was first isolated from protein (horn tissue) by the Swedish chemist Karl A. H. Mörner (1855-1917).[9] The chemical structure of cystine was determined by synthesis in 1903 by the German chemist Emil Erlenmeyer.[10][11][12]

The history of cystine and cysteine is complicated by the dimer-monomer relationship of the two.[5] The cysteine monomer was proposed as the actual unit by Embden in 1901.

The sulfur within the structure of cysteine and cystine has been subject of historical interest.[5] In 1902, Osborne partially succeeded in analysing cystine content via lead compounds. An improved colorimetric method was developed in 1922 by Folin and Looney. An iodometric analysis method was developed by Okuda in 1925.

Redox

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It is formed from the oxidation of two cysteine molecules, which results in the formation of a disulfide bond. In cell biology, cystine residues (found in proteins) only exist in non-reductive (oxidative) organelles, such as the secretory pathway (endoplasmic reticulum, Golgi apparatus, lysosomes, and vesicles) and extracellular spaces (e.g., extracellular matrix). Under reductive conditions (in the cytoplasm, nucleus, etc.) cysteine is predominant. The disulfide link is readily reduced to give the corresponding thiol cysteine. Typical thiols for this reaction are mercaptoethanol and dithiothreitol:

(SCH2CH(NH2)CO2H)2 + 2 RSH → 2 HSCH2CH(NH2)CO2H + RSSR

Because of the facility of the thiol-disulfide exchange, the nutritional benefits and sources of cystine are identical to those for the more-common cysteine. Disulfide bonds cleave more rapidly at higher temperatures.[13]

Cystine-based disorders

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Comparison of different types of urinary crystals.

The presence of cystine in urine is often indicative of amino acid reabsorption defects. Cystinuria has been reported to occur in dogs.[14] In humans the excretion of high levels of cystine crystals can be indicative of cystinosis, a rare genetic disease. Cystine stones account for about 1-2% of kidney stone disease in adults.[15][16]

Various derivatives of cysteamine are used to address cystinosis.[17] These derivatives convert poorly soluble cystine into more soluble derivatives.[18]

Biological transport

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Cystine serves as a substrate for the cystine-glutamate antiporter. This transport system, which is highly specific for cystine and glutamate, increases the concentration of cystine inside the cell. In this system, the anionic form of cystine is transported in exchange for glutamate. Cystine is quickly reduced to cysteine.[citation needed] Cysteine prodrugs, e.g. acetylcysteine, induce release of glutamate into the extracellular space.

See also

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References

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Revisions and contributorsEdit on WikipediaRead on Wikipedia

Cystine

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Cystine is a nonessential sulfur-containing compound that exists as the oxidized dimer of the amino acid cysteine, consisting of two cysteine molecules linked by a disulfide bond. Its chemical formula is C₆H₁₂N₂O₄S₂, with a molecular weight of 240.3 g/mol, and it appears as a white crystalline solid that is poorly soluble in water (approximately 190 mg/L at 20°C). This disulfide linkage imparts stability to cystine, distinguishing it from the more reduced form of cysteine, and it plays a critical role in biological systems by contributing to protein structure and redox processes. In biochemistry, cystine is essential for the formation of bridges that stabilize the three-dimensional of proteins, particularly in extracellular environments where it enhances resistance to denaturation and proteolytic degradation. It serves as a precursor for the synthesis of , a key that protects cells from , and supports processes such as and the metabolism of vitamin B₆. Cystine is naturally occurring in human tissues, including the and , and is also found in bacteria like , where it acts as a source for metabolic pathways. Medically, cystine is implicated in cystinuria, an autosomal recessive disorder caused by mutations in genes such as SLC3A1 or SLC7A9, leading to excessive urinary excretion and formation of cystine kidney stones, which account for about 1% of adult nephrolithiasis cases and 6% in pediatrics. These stones can cause , obstruction, and potential if untreated. Additionally, cystine has applications in for conditioning due to its role in keratin cross-linking and as a food additive to improve strength and flavor, though its therapeutic uses, such as in anti-inflammatory contexts, remain under investigation.

Structure and nomenclature

Chemical formula and structure

Cystine has the molecular formula and a molecular weight of 240.30 g/mol. As a symmetric dimer derived from two residues, cystine features a central bond (-S-S-) that links the atoms of their respective s, forming a -CH2-S-S-CH2- bridge between the α-carbons of the two units. Each half of the molecule consists of a group (-COOH), an amino group (-NH2), an α-hydrogen, and the side chain -CH2-S- connected via the disulfide. The overall structure can be represented as:

H | H₃N⁺-CH-CH₂-S-S-CH₂-CH-NH₃⁺ | | COO⁻ COO⁻

H | H₃N⁺-CH-CH₂-S-S-CH₂-CH-NH₃⁺ | | COO⁻ COO⁻

This depiction highlights the zwitterionic form common in physiological conditions, with the disulfide linkage providing rigidity to the dimer. In the disulfide linkage, the S-S bond length is typically approximately 2.04 Å, as determined from crystallographic studies of cystine. The bond angles around the sulfur atoms, such as the C-S-S angle, are around 100-105°, contributing to the torsional flexibility of the bridge. Cystine exhibits chirality at the two α-carbons, with the naturally occurring form being L-cystine, which has the (R,R) configuration and is levorotatory. The enantiomer, D-cystine, possesses the (S,S) configuration but is not found in biological systems.

Naming and isomers

Cystine, commonly known as the oxidized dimer of the amino acid cysteine, consists of two cysteine molecules linked by a disulfide bond, distinguishing it from its monomeric precursor cysteine, which features a free thiol group. This nomenclature reflects cystine's role as a stable, symmetrical derivative, often encountered in biological contexts where cysteine oxidation occurs. The systematic IUPAC name for the naturally occurring form is (2R)-2-amino-3-{[(2R)-2-amino-2-carboxyethyl]disulfanyl}propanoic acid, specifying the configuration at the chiral centers. Historically, the compound was first isolated in from urinary calculi by , who named it "cystic oxide" due to its origin in bladder stones; it was later redesignated cystine in to reflect its chemical nature more accurately. The term evolved alongside the recognition of its relationship to , with the monomer's name derived by altering "cystine" in the late to highlight the functionality. Cystine exhibits due to the two chiral carbon atoms, yielding three principal forms: L-cystine ((2R,2'R)), the biologically predominant found in proteins; D-cystine ((2S,2'S)), its with limited natural occurrence; and meso-cystine ((2R,2'S)), an achiral resulting from one L- and one D-cysteine unit. The L-form is prevalent in disulfide bridges of biomolecules, while the D- and meso-forms are rarely encountered . Rare cyclic forms, such as those in specialized plant-derived peptides featuring a cystine motif, represent constrained variants but are not typical of free cystine. In biochemical nomenclature, cystine does not have a unique standard three-letter or one-letter abbreviation distinct from cysteine. Cysteine is abbreviated as Cys (three-letter code) or C (one-letter code). Cystine is typically represented as Cys-Cys, (Cys)₂, or simply referred to as "cystine" in biochemical contexts to avoid confusion.

Physical and chemical properties

Physical characteristics

Cystine appears as a , crystalline solid at . It exhibits a range of 247–260 °C, during which the compound decomposes rather than fully melting. Cystine demonstrates low in water, approximately 0.11 g/L (or 0.011 g/100 mL) at 25 °C, rendering it poorly soluble under neutral conditions; it is insoluble in but shows increased solubility in dilute acids due to effects. The L-enantiomer of cystine displays optical activity with a specific rotation of [α]_D = -218° measured in 6 N HCl. In terms of , L-cystine adopts a with P6_122 (or P6_522 for the ), characterized by parameters a = b ≈ 5.422 and c ≈ 56.275 , containing six molecules per and featuring helical arrangements of the dimer units.

Reactivity

Cystine exhibits notable stability toward , particularly under acidic conditions commonly used in protein and , where the bond remains intact without significant degradation. This resistance contrasts with the sensitivity of free thiols to oxidation, allowing cystine to serve as a stable form during such processes. However, cystine is highly susceptible to reducing agents that target the linkage, leading to its cleavage into two molecules. The primary reactive feature of cystine is the central (-S-S-), which undergoes cleavage via reduction. Thiols, such as , facilitate this through thiol- exchange, where the donates hydrogen equivalents to break the bond, regenerating the and producing two equivalents of . Similarly, metallic reducing agents like sodium in liquid achieve reductive cleavage by providing electrons to the atoms, yielding as the product. The general balanced equation for disulfide reduction is: (R-S-S-R)+2H→2(R-SH)\text{(R-S-S-R)} + 2\text{H} \rightarrow 2(\text{R-SH}) This reaction underscores the reversible chemistry inherent to the moiety, though non-biological reductions typically require specific conditions to proceed efficiently. Further reactivity involves oxidation of the bond under strong oxidative conditions. Treatment with converts cystine to cysteic acid (HO₃S-CH₂-CH(NH₂)COOH), where each sulfur atom is oxidized to a group, rendering the product highly polar and stable. Alternative strong oxidants can lead to formation, depending on reaction conditions, highlighting cystine's vulnerability to over-oxidation in oxidative environments. Cystine's acid-base properties are governed by its ionizable groups: the two carboxyl groups (pKa 1.0 and 2.1) and the two amino groups (pKa 8.02 and 8.71) at 25 °C. These values indicate that cystine predominantly exists as a under physiological , with the bond modulating the overall acidity compared to monomeric .

Biosynthesis and sources

Formation from cysteine

Cystine is formed through the oxidation of two L-cysteine molecules, where each thiol group (-SH) loses a , resulting in the creation of a covalent bond (-S-S-) between the atoms. This two-electron oxidation process increases the of each from -2 to -1. The simplified representing this reaction is: 2\ceHS−CH2−CH(NH2)−COOH→\ce(S−CH2−CH(NH2)−COOH)2+2\ceH2 \ce{HS-CH2-CH(NH2)-COOH} \rightarrow \ce{(S-CH2-CH(NH2)-COOH)2} + 2\ce{H} In vivo, cystine formation predominantly takes place in the endoplasmic reticulum (ER) during the oxidative folding of proteins, where nascent polypeptides containing free cysteine residues are directed for disulfide bond establishment to stabilize tertiary and quaternary structures. This process is enzymatically mediated by protein disulfide isomerase (PDI), a resident ER chaperone that catalyzes the oxidation of substrate cysteine thiols using its own active-site CXXC motifs, which shuttle oxidizing equivalents to form the disulfide. PDI activity is supported by upstream oxidants such as endoplasmic reticulum oxidoreductin 1 (Ero1), which reoxidizes PDI via flavin adenine dinucleotide (FAD)-dependent transfer of electrons to molecular oxygen, or oxidized glutathione (GSSG), which directly oxidizes PDI's active-site sulfhydryls. Non-enzymatic oxidation of cysteine to cystine can also occur spontaneously in oxidizing cellular compartments or extracellular environments, though it is less efficient and more prone to off-target modifications. In laboratory settings, cystine is chemically synthesized from via mild oxidation methods suitable for preserving the amino acid's integrity. Air oxidation in neutral aqueous solutions at ambient temperatures promotes dimerization by allowing dissolved oxygen to act as the oxidant, typically requiring several hours to days for completion depending on and . Alternatively, iodine in acidic or aqueous media provides a rapid and selective oxidation, often used in to form disulfides directly from protected residues without significant side reactions. serves as another effective oxidant in aqueous buffers, facilitating controlled two-electron transfer to yield cystine while minimizing over-oxidation products. The oxidation of cysteine to cystine is thermodynamically spontaneous under aerobic conditions, driven by the favorable redox potential difference between the cysteine/cystine couple (E_h ≈ -145 mV at physiological pH) and the oxygen/water couple (E° ≈ +815 mV), resulting in a negative Gibbs free energy change (ΔG < 0). This exergonic process underpins its prevalence in oxidizing biological niches like the ER, where the ambient redox environment (E_h ≈ -180 to -220 mV) supports efficient disulfide formation.

Natural occurrence

Cystine occurs naturally primarily in the form of disulfide bonds within proteins, where it stabilizes structure and function, particularly in extracellular and structural contexts. In eukaryotes, these bonds are most abundant in structural proteins such as keratins, which form the basis of hair, nails, and skin. Hard keratins in hair and nails contain up to 14% cystine residues, contributing to their mechanical strength and resistance to environmental stress. Soft keratins in skin have lower levels, around 2% cystine. Cystine is also integral to functional proteins like insulin, which features three disulfide bonds—two interchain and one intrachain—to maintain its active conformation. Similarly, antibodies (immunoglobulins) incorporate multiple intra- and interchain disulfide bonds to ensure proper folding and assembly of their domains. Free cystine exists in rare, trace amounts in biological fluids such as plasma and urine, where it typically represents less than 0.4% of filtered cystine under normal conditions, as most is incorporated into proteins or rapidly metabolized. In microorganisms, cystine contributes to stability through disulfide bonds in bacterial cell envelope proteins, such as those involved in outer membrane assembly (e.g., LptD and BamA), aiding in protection against oxidative stress and maintaining envelope integrity. Fungi similarly utilize cysteine-rich proteins with disulfide bonds for structural reinforcement, including in extracellular components that enhance spore resilience during dispersal. The prevalence of disulfide bonds reflects an evolutionary adaptation, providing extracellular proteins with enhanced stability in oxidizing environments outside the reducing cytosol, which has facilitated the diversification of protein functions across species. In human proteins overall, cystine equivalents (accounting for disulfide-linked cysteines) comprise about 1-2% of total amino acid residues, underscoring its selective role despite being a relatively rare component.

Dietary sources

Cystine is primarily obtained through the diet as a component of proteins, with animal-based sources generally providing higher concentrations per serving compared to plant-based ones. Foods rich in cystine include animal proteins such as eggs, which contain approximately 250 mg per 100 g; meats like beef and pork, ranging from 200 to 300 mg per 100 g; and dairy products like yogurt and cheese, offering around 100 mg per 100 g. Plant sources tend to have lower levels on a per-weight basis, such as oats (cooked oatmeal approximately 120 mg per 100 g), wheat germ (about 450 mg per 100 g dry), and legumes like lentils (around 150 mg per 100 g cooked).
Food CategoryExample FoodsApproximate Cystine (mg/100 g)
Animal ProteinsEggs (whole, raw)250
Beef (ground, raw)220
Yogurt (plain, low-fat)100
Plant SourcesOats (cooked)120
Wheat germ (crude)450
Lentils (cooked)150
The bioavailability of cystine is higher from animal sources due to their complete amino acid profiles and greater protein digestibility (often exceeding 90%), allowing more efficient absorption of pre-formed cystine. In contrast, plant sources primarily supply cysteine precursors, with lower overall digestibility (typically 70-85%) influenced by anti-nutritional factors like fiber and phytates, though processing can mitigate this. As part of total sulfur amino acids (cysteine + cystine), the World Health Organization recommends an average intake of 15 mg per kg body weight per day, with a safe upper level of 19 mg per kg body weight per day for adults to meet nutritional needs. Food processing, particularly high-heat methods like boiling or baking, can reduce cystine availability by promoting β-elimination reactions in proteins, leading to disulfide bond cleavage; however, cystine itself exhibits relative thermal stability compared to free cysteine under moderate conditions. For vegans, cystine requirements can be met through combinations of grains (e.g., oats, wheat) and legumes (e.g., lentils, soybeans), which together provide complementary sulfur amino acids, ensuring adequacy when total protein intake is sufficient.

Metabolism

Redox reactions

Cystine participates in a dynamic redox cycle central to cellular metabolism, where it is reversibly reduced to cysteine in the reducing environment of the cytosol and reoxidized to form disulfide bonds in the more oxidizing endoplasmic reticulum (ER). This cycle maintains the balance of thiol-disulfide equilibria, supporting protein synthesis and redox homeostasis. In the cytosol, cystine is primarily reduced to two molecules of cysteine by the glutathione system or the thioredoxin system. The glutathione-dependent reaction proceeds via thiol-disulfide exchange, as shown in the equation: Cystine+2 GSH⇌2 Cysteine+GSSG\text{Cystine} + 2 \, \text{GSH} \rightleftharpoons 2 \, \text{Cysteine} + \text{GSSG} where GSSG is glutathione disulfide. Glutathione reductase then regenerates GSH from GSSG using NADPH as the electron donor. Similarly, the thioredoxin system, comprising NADPH, thioredoxin reductase, and thioredoxin (or thioredoxin-related protein 14), catalyzes cystine reduction, with thioredoxin-related protein 14 acting as a dedicated cystine reductase. Recent research has identified thioredoxin-related protein 14 (TRP14) as the evolutionarily conserved primary enzyme for intracellular cystine reduction. In the ER, cysteine residues in unfolded proteins are reoxidized to cystine disulfides by protein disulfide isomerase (PDI) and endoplasmic reticulum oxidoreductin 1 (Ero1), facilitating correct protein folding. The midpoint reduction potential (E°') for the cystine/cysteine couple at pH 7 is approximately -220 mV, positioning it as a key modulator of intracellular redox balance and influencing the directionality of thiol-disulfide exchanges relative to other couples like glutathione/glutathione disulfide (-240 mV at pH 7). This potential ensures efficient cystine reduction under physiological cytosolic conditions while favoring oxidation in the ER. The cystine/cysteine redox couple also regulates cellular signaling processes, including protein folding quality control in the ER and the response to oxidative stress via the Nrf2 pathway. An oxidizing extracellular cystine/cysteine ratio promotes Nrf2 activation by modulating cysteine oxidation in its inhibitor Keap1, thereby inducing expression of antioxidant and detoxifying genes. Disruptions in this balance, particularly excess oxidation, can promote improper disulfide linkages, contributing to protein misfolding and ER stress.

Transport mechanisms

Cystine absorption in the small intestine occurs primarily through the apical membrane of enterocytes via a sodium-independent, heterodimeric transporter complex consisting of the heavy chain rBAT (encoded by SLC3A1) and the light chain b⁰,+AT (encoded by SLC7A9). This transporter facilitates the luminal uptake of cystine along with dibasic amino acids, operating through an exchange mechanism that is energy-dependent and mediated. Upon uptake, cystine is rapidly reduced to cysteine intracellularly, and only cysteine appears in the portal blood, highlighting the redox-linked preference for the monomeric form during intestinal transport. In the kidneys, cystine is filtered freely at the glomerulus and undergoes near-complete reabsorption (approximately 99%) in the proximal tubule, again mediated by the SLC3A1/SLC7A9 heterodimer (rBAT/b⁰,+AT) located on the apical membrane of epithelial cells. This high-affinity transporter exchanges extracellular cystine for intracellular neutral amino acids, ensuring efficient conservation and preventing excessive urinary loss under normal conditions. The basolateral efflux of cystine or its reduced form, cysteine, involves additional carriers, though the precise mechanisms remain less characterized compared to apical uptake. At the cellular level, cystine enters most tissues via the sodium-independent system xc- , a heterodimer of the light chain xCT (encoded by SLC7A11) and the heavy chain 4F2hc (encoded by SLC3A2). This chloride-dependent exchanger imports extracellular cystine in a 1:1 stoichiometric ratio with the export of intracellular glutamate, serving as a critical route for supply to support intracellular defenses. Once inside the cell, imported cystine is reduced to , which is essential for biosynthesis. Transport across the blood-brain barrier for cystine is mediated by the system x_c^- antiporter (SLC7A11/SLC3A2), but with limited capacity; is more readily transported via neutral transporters such as the L-type system (LAT1). This restricted access underscores the reliance on peripheral import and local reduction processes to maintain cerebral cystine/ homeostasis. Excretion of cystine primarily occurs through glomerular filtration in the kidneys, where the molecule's free filtration is followed by extensive proximal tubular reabsorption, resulting in minimal urinary output (less than 1% of filtered load) in healthy individuals. Any unreabsorbed cystine contributes to the baseline urinary excretion, which is tightly regulated by the efficiency of the SLC3A1/SLC7A9 system.

Biological roles and health implications

Role in proteins and antioxidants

Cystine plays a crucial structural role in proteins through the formation of disulfide bonds, which covalently link residues to stabilize the tertiary and quaternary structures, particularly in extracellular proteins exposed to oxidative environments. These bonds reduce the of the unfolded state, thereby enhancing overall protein stability. In hormones such as insulin, three disulfide bonds—one intra-chain in the A chain and two inter-chain between the A and B chains—maintain the compact fold essential for . Similarly, in antibodies like immunoglobulins, multiple intra- and inter-chain disulfide bonds reinforce the immunoglobulin domains, ensuring proper assembly and function in immune responses. Disulfide bonds formed from cystine can contribute 5–6 kcal/mol to the free energy of stabilization in folded proteins, significantly lowering the rate of unfolding under thermal or chemical stress. This stabilization is particularly evident in structural proteins such as , where high cystine content—up to 20% of residues—forms extensive cross-links that impart tensile strength and resilience to , , and . Beyond structural roles, cystine serves as a key precursor in defense by being reduced to , the rate-limiting substrate for (GSH) synthesis, which neutralizes (ROS) and maintains cellular balance. The import of cystine via the system xc- transporter supports this pathway by providing a stable, oxidized form of that cells can readily utilize for production. Cystine also influences regulation indirectly through its impact on cellular levels and status, modulating the activity of -sensitive transcription factors such as those regulating the CTNS , which encodes a lysosomal cystine transporter. This modulation helps coordinate the expression of involved in stress responses and protein .

Nutritional significance

Cystine, the oxidized dimer of , is classified as a conditionally in , meaning the body can typically synthesize sufficient from the via the transsulfuration pathway under normal conditions. However, its demand increases during physiological stress such as trauma or , where oxidative demands elevate the need for precursors to support defenses, potentially rendering it indispensable in these scenarios. The recommended dietary allowance (RDA) for total sulfur amino acids ( plus cystine/cysteine) is approximately 19 mg/kg body weight per day for healthy adults, reflecting the combined requirement to meet protein synthesis and metabolic needs. Infants and young children have higher relative needs, with requirements estimated at around 25-30 mg/kg per day or 588 μmol/100 kcal for sulfur amino acids, due to rapid growth and immature metabolic pathways. Deficiency of cystine/cysteine is rare in well-nourished individuals but can occur in conditions of inadequate sulfur amino acid intake or increased catabolism, leading to impaired , , and reduced immune function primarily through diminished (GSH) synthesis, a critical cellular . Low GSH levels exacerbate , weakening immune responses and delaying tissue repair. Cystine supplementation is commonly incorporated into formulations to meet sulfur amino acid needs, particularly in neonates and patients unable to tolerate oral intake, where it helps prevent metabolic imbalances. N-acetylcysteine serves as an effective proxy precursor, enhancing cysteine availability and supporting GSH replenishment in clinical settings. Cystine exhibits a methionine-sparing effect, reducing the dietary requirement by up to 50-80% when provided adequately, which is particularly relevant for vegan diets that may be lower in total sulfur amino acids and warrant monitoring to ensure nutritional sufficiency.

Associated disorders

Cystinuria is an inherited disorder characterized by a defect in the renal reabsorption of cystine and other dibasic , primarily due to mutations in the SLC3A1 or SLC7A9 genes, which encode components of the cystine transporter in the . Type I cystinuria, associated with biallelic SLC3A1 mutations, follows an autosomal recessive inheritance pattern and is the most common form. This impairment leads to excessive urinary cystine excretion, promoting the formation of cystine calculi, which account for 1-2% of adult kidney stones and 6-8% of pediatric stones. Symptoms typically include recurrent nephrolithiasis, , urinary tract obstruction, and potential complications such as or renal impairment if untreated. The prevalence of cystinuria is approximately 1 in 7,000 individuals worldwide, with ethnogeographic variations. Cystinosis, another disorder linked to cystine abnormalities, is an autosomal recessive caused by mutations in the CTNS gene, which encodes cystinosin—a transporter responsible for cystine export from lysosomes. Defective cystinosin results in cystine accumulation within lysosomes of various organs, including the kidneys, eyes, and , leading to cellular damage. The infantile nephropathic form, the most severe and common variant (accounting for about 95% of cases), manifests before age 2 with —characterized by proximal tubular dysfunction causing , , hypophosphatemic , and growth failure—along with corneal cystine crystals causing and renal failure typically by age 10. Less severe juvenile and ocular forms present later with milder renal involvement or isolated eye symptoms. The prevalence of cystinosis is estimated at 1 in 100,000 to 200,000 live births. In due to cystathionine beta-synthase deficiency, cystine is indirectly affected, with secondary elevation of mixed homocysteine-cystine disulfides in urine due to impaired transsulfuration, contributing to urinary abnormalities and potential stone risk. Additionally, in , cystine plays a role in ; reduced cystine availability exacerbates in erythrocytes, promoting S polymerization and vaso-occlusive crises, as cystine serves as a precursor for synthesis. Diagnosis of cystinuria often involves the qualitative cyanide-nitroprusside , which detects elevated cystine levels (>75 mg/L) by producing a color change, followed by quantitative analysis confirming excretion >400 mg/day. For , leukocyte cystine levels and for CTNS mutations are definitive. Treatment for focuses on increasing volume through high fluid intake (≥3 L/day) to maintain output >2-3 L/m² in children, urinary alkalinization to 7.5, and chelating agents like D-penicillamine to solubilize cystine and reduce stone formation. management includes cystine-depleting therapy with to mitigate accumulation, alongside supportive care for renal and ocular complications.

Recent developments (as of 2025)

As of 2025, research has advanced treatment options for these disorders. For cystinuria, the FDA granted Orphan Drug Designation to ADV7103 in March 2024 for sustained-release cystine-binding therapy, and VENXXIVA™ (tiopronin delayed-release tablets) was launched in the in March 2025 to improve patient adherence with reduced dosing. Clinical trials for alpha-lipoic acid and bucillamine are ongoing to enhance cystine solubilization and reduce stone recurrence. For cystinosis, cysteamine remains standard, but trials (initiated 2018, ongoing) and the CF10 small molecule (funded £3.9 million in October 2025) aim to restore CTNS function with fewer side effects and improved efficacy. Emerging combination therapies and approaches are in preclinical and early clinical stages.

History and developments

Discovery and isolation

Cystine was first isolated in by the English chemist and physiologist from a urinary calculus, or , obtained from a patient. Wollaston described the compound as a novel crystalline substance with unique properties, initially naming it "cystic " because it dissolved equally well in acids and alkalis. The name was subsequently shortened to cystine, derived from the Greek word kystis (κύστις), meaning "," in reference to its origin in bladder stones. Early chemical analyses in the mid-19th century confirmed its content, distinguishing it from other organic compounds found in calculi. By 1884, German Eugen Baumann demonstrated that treatment of cystine with reducing agents yielded a new monomeric compound, which he named , thereby establishing cystine as the oxidized dimer of cysteine linked by a bond. In 1899, Swedish biochemist Karl Albert Hermann Mörner achieved the first isolation of cystine from a protein source, animal horn tissue with acid to obtain pure crystals, thus recognizing its role as a component of proteins. Isolation methods at the time relied primarily on acid of sulfur-rich proteins such as keratins, followed by techniques to separate cystine from other . The structure of cystine was definitively confirmed in 1903 through its by German chemist Emil Erlenmeyer Jr., who oxidized to form the dimer, validating the proposed formula. This synthesis marked a key milestone in chemistry, enabling further studies on its properties. A significant advancement in understanding cystine's biological importance came with Frederick Sanger's work on in the 1940s and 1950s, particularly his determination of insulin's sequence, which highlighted the critical role of bonds formed by cystine residues in stabilizing protein tertiary structures; for this, Sanger received the 1958 . The International Union of Pure and Applied Chemistry (IUPAC) later standardized cystine's nomenclature in the mid-20th century as (2R)-2-amino-3-{[(2R)-2-amino-2-carboxyethyl]disulfanyl}propanoic acid.

Recent research

Recent research on cystine has focused on its role in and therapeutic targeting, particularly in and . In cancer therapy, inhibition of the system xc⁻ cystine-glutamate , notably with erastin, has emerged as a strategy to induce in tumors that rely on cystine uptake for (GSH) synthesis and defense. SLC7A11, the core subunit of system xc⁻, is frequently overexpressed in various cancers, promoting tumor growth by suppressing ; targeting it reduces cystine availability, leading to and cell death in cystine-dependent malignancies like and pancreatic tumors. Studies in the 2010s highlighted cystine's involvement in via the cystine-glutamate exchange. In addiction models, chronic exposure downregulates system xc⁻ activity in the , reducing extracellular glutamate and increasing relapse vulnerability during withdrawal; N-acetylcysteine supplementation, which boosts cystine levels and restores exchange, attenuates cue-induced reinstatement in preclinical rodent studies. Similarly, in (), astrocytes upregulate xCT (SLC7A11) under , releasing excess glutamate that exacerbates excitotoxicity; inhibiting this exchange has shown potential to mitigate neurodegeneration in models. Advancements in for , a disorder of cystine accumulation, include /Cas9-based editing of the CTNS in preclinical models as of 2023. Using homology-independent targeted integration (HITI), researchers restored functional cystinosin expression in patient-derived cells, significantly reducing lysosomal cystine buildup and improving cellular function in vitro; kidney organoids from edited induced pluripotent stem cells (iPSCs) integrated into mouse models, demonstrating partial reversal of renal pathology. In , cystine-based self-assembling peptides have gained attention for in the 2020s. Disulfide-linked cysteine-diphenylalanine conjugates form redox-responsive hollow nanospheres that release payloads under reducing conditions, enhancing targeted delivery of antifungals and antioxidants with in cellular models. These structures leverage cystine's bonds for stability and stimuli-responsive disassembly, offering advantages over traditional carriers in tumor and therapies. During the , 2021 investigations explored cystine's redox contributions to storms, linking GSH depletion—via impaired cystine-derived —to excessive and oxidative damage in severe cases. N-acetyl (NAC), a cystine precursor, was tested in clinical trials for its ability to replenish GSH, suppress pro-inflammatory like IL-6, and aid recovery; preliminary data indicated reduced needs and improved oxygenation in NAC-treated patients, though larger randomized studies are ongoing. Updated epidemiological data confirm prevalence at approximately 1 in 100,000–200,000 live births globally, with genetic screening revealing underdiagnosis in diverse populations. Emerging studies also address influences on , showing that gut extensively utilize and cystine pathways for production, which modulates host and may exacerbate cystine-related disorders in dysbiotic states.

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