Editing Disulfide

{{split| Disulfide | Disulfide (biochemistry)|date=February 2025}}

{{short description|Functional group with the chemical structure R−S−S−R′}}
{{dist|Bisulfide}}

In [[chemistry]], a '''disulfide''' (or '''disulphide''' in [[British English]]) is a compound containing a {{chem2|R\s'''S\sS'''\sR′}} [[functional group]] or the {{chem|S|2|2−}} [[anion]].  The linkage is also called an '''SS-bond''' or sometimes a '''disulfide bridge''' and usually derived from two [[thiol]] groups.

In [[inorganic chemistry]], the anion appears in a few rare minerals, but the functional group has tremendous importance in [[biochemistry]]. Disulfide bridges formed between thiol groups in two [[cysteine]] residues are an important component of the tertiary and quaternary structure of [[protein]]s.

Compounds of the form {{chem2|R\sS\sS\sH}} are usually called ''[[persulfide]]s'' instead.

==Organic disulfides==
{{Multiple image
| align             =
| direction         = vertical
| total_width       =
| image1            = Cystine-from-xtal-Mercury-3D-balls-thin.png
| image2            = Lipoic-acid-from-xtal-3D-bs-17.png
| image3            = Diphenyl-disulfide-from-xtal-3D-balls.png
| caption1          = [[Cystine]], crosslinker in many proteins
| caption2          = [[Lipoic acid]], an enyzme cofactor
| caption3          = [[Diphenyl disulfide]], {{chem2|(C6H5)2S2}}, a common organic disulfide
| alt1              =
| header            = A selection of organic disulfides
}}

===Structure===
Disulfides have a C–S–S–C [[dihedral angle]] approaching 90°.  The S–S bond length is 2.03 Å in [[diphenyl disulfide]],<ref>{{cite journal|doi=10.1107/S0567740869005188 |title=The Crystal Structure of Diphenyl Disulphide |date=1969 |last1=Lee |first1=J. D. |last2=Bryant |first2=M. W. R. |journal=Acta Crystallographica Section B Structural Crystallography and Crystal Chemistry |volume=25 |issue=10 |pages=2094–2101 |bibcode=1969AcCrB..25.2094L }}</ref>  similar to that in elemental sulfur.

Disulfides are usually symmetric but they can also be unsymmetric. Symmetrical disulfides are compounds of the formula {{chem2|RSSR}}. Most disulfides encountered in organosulfur chemistry are symmetrical disulfides.  '''Unsymmetrical disulfides''' (also called '''heterodisulfides''' or '''mixed disulfides''') are compounds of the formula {{chem2|RSSR'}}.  Unsymmetrical disulfide are less common in organic chemistry, but many disulfides in nature are unsymmetrical.  Illustrative of a symmetric disulfide is [[cystine]]. 

====Cyclic disulfides====
Disulfides can be components of rings.  [[Lipoic acid]], a [[1,2-Dithiolane|1,2-dithiolane]] is a major example.  Rings with more than one disulfide usually tend to polymerize.<ref>{{cite journal |doi=10.1016/0040-4020(89)80036-5 |title=Characterization and stability of cyclic disulfides and cyclic dimeric bis(disulfides) |date=1989 |last1=Houk |first1=Janette |last2=Whitesides |first2=George M. |journal=Tetrahedron |volume=45 |pages=91–102 }}</ref>

====Other specialized organic disulfides====
[[Thiuram disulfide]]s, with the formula (R<sub>2</sub>NCSS)<sub>2</sub>, are disulfides but they behave distinctly because of the [[thiocarbonyl]] group.

===Properties===
Disulfide bonds are strong, with a typical [[bond dissociation energy]] of 60&nbsp;kcal/mol (251&nbsp;kJ&nbsp;mol<sup>−1</sup>). However, being about 40% weaker than {{chem2|[[C–C bond|C\sC]]}} and {{chem2|[[Carbon–hydrogen bond|C\sH]]}} bonds, the disulfide bond is often the "weak link" in many molecules. Furthermore, reflecting the [[polarizability]] of divalent sulfur, the {{chem2|S\sS}} bond is susceptible to scission by polar reagents, both [[electrophile]]s and especially [[nucleophile]]s (Nu):<ref>{{cite book|first=R. J.|last=Cremlyn|title=An Introduction to Organosulfur Chemistry|publisher=John Wiley and Sons|location=Chichester|date=1996|isbn=0-471-95512-4}}</ref> <chem display=block>RS-SR + Nu- -> RS-Nu + RS-</chem> 

The disulfide bond is about 2.05&nbsp;[[ångström|Å]] in length, about 0.5&nbsp;Å longer than a {{chem2|C\sC}} bond. Rotation about the {{chem2|S\sS}} axis is subject to a low barrier. Disulfides show a distinct preference for [[dihedral angle]]s approaching 90°. When the angle approaches 0° or 180°, then the disulfide is a significantly better oxidant.

Disulfides where the two R groups are the same are called symmetric, examples being [[diphenyl disulfide]] and [[dimethyl disulfide]]. When the two R groups are not identical, the compound is said to be an asymmetric or mixed disulfide.<ref name=Sevier>{{cite journal | doi = 10.1038/nrm954 |last1=Sevier |first1=C. S. |last2=Kaiser |first2=C. A. | title = Formation and transfer of disulphide bonds in living cells | journal = [[Nature Reviews Molecular Cell Biology]]  | year = 2002 | volume = 3 | issue = 11 | pages = 836–847 | pmid = 12415301|s2cid=2885059 | doi-access = free }}</ref>

Although the [[hydrogenation]] of disulfides is usually not practical, the equilibrium constant for the reaction provides a measure of the standard redox potential for disulfides:
:<chem>RSSR + H2 -> 2 RSH</chem>
This value is about −250&nbsp;mV versus the [[standard hydrogen electrode]] (pH&nbsp;=&nbsp;7). By comparison, the standard reduction potential for [[ferrodoxin]]s is about −430&nbsp;mV.

===Synthesis===
Disulfide bonds are usually formed from the [[oxidation]] of [[thiol]] ({{chem2|\sSH}}) groups, especially in biological contexts.<ref name=Witt>{{cite journal | last = Witt | first = D. | title = Recent developments in disulfide bond formation | journal = [[Synthesis (journal)|Synthesis]] | volume = 2008 | year = 2008 | issue = 16 | pages = 2491–2509 | doi = 10.1055/s-2008-1067188}}</ref> The transformation is depicted as follows:
:<chem>2 RSH <=> RS-SR + 2 H+ + 2 e-</chem>
A variety of oxidants participate in this reaction including oxygen and [[hydrogen peroxide]]. Such reactions are thought to proceed via [[sulfenic acid]] intermediates. In the laboratory, [[iodine]] in the presence of base is commonly employed to oxidize thiols to disulfides. Several metals, such as copper(II) and iron(III) [[metal complex|complex]]es affect this reaction.<ref>{{cite journal |last1=Kreitman |first1=Gal Y. |title=Copper(II)-Mediated Hydrogen Sulfide and Thiol Oxidation to Disulfides and Organic Polysulfanes and Their Reductive Cleavage in Wine: Mechanistic Elucidation and Potential Applications |journal=Journal of Agricultural and Food Chemistry |date=March 5, 2017 |volume=65 |issue=12 |pages=2564–2571 |doi=10.1021/acs.jafc.6b05418 |pmid=28260381 |bibcode=2017JAFC...65.2564K |url=https://pubs.acs.org/doi/10.1021/acs.jafc.6b05418 |access-date=31 May 2021|url-access=subscription }}</ref> Alternatively, disulfide bonds in proteins often formed by [[thiol-disulfide exchange]]:
: <chem>RS-SR + R'SH <=> R'S-SR + RSH</chem>
Such reactions are mediated by enzymes in some cases and in other cases are under equilibrium control, especially in the presence of a catalytic amount of base.

The [[alkylation]] of alkali metal di- and [[polysulfide]]s gives disulfides. "Thiokol" polymers arise when [[sodium polysulfide]] is treated with an alkyl dihalide. In the converse reaction, carbanionic reagents react with elemental sulfur to afford mixtures of the thioether, disulfide, and higher polysulfides. These reactions are often unselective but can be optimized for specific applications.

===Synthesis of unsymmetrical disulfides (heterodisulfides)===
Many specialized methods have been developed for forming unsymmetrical disulfides. Reagents that deliver the equivalent of "{{chem2|RS+}}" react with thiols to give asymmetrical disulfides:<ref name=Witt/>
: <chem>RSH + R'SNR''_2 -> RS-SR' + HNR''_2</chem>
where {{chem2|R{{pprime}}2N}} is the [[phthalimide|phthalimido]] group.
[[Bunte salt]]s, derivatives of the type {{chem2|RSSO3(-)Na+}}are also used to generate unsymmetrical disulfides:<ref>{{cite journal|title=Sulfide Synthesis in Preparation of Unsymmetrical Dialkyl Disulfides: Sec-butyl Isopropyl Disulfide|journal=Org. Synth.|year=1978|volume=58|page=147|doi=10.15227/orgsyn.058.0147|author1=M. E. Alonso |author2=H. Aragona }}</ref>
:<chem>Na[O3S2R] + NaSR' -> RSSR' + Na2SO3</chem>

===Reactions===
The most important aspect of disulfide bonds is their scission, as the {{chem2|S\sS}} bond is usually the weakest bond in an organic molecule (missing citation).  Many specialized [[organic reaction]]s have been developed to cleave the bond. 

A variety of reductants reduce disulfides to [[thiols]].  Hydride agents are typical reagents, and a common laboratory demonstration "uncooks" eggs with [[sodium borohydride]].<ref>Hervé This. Can a cooked egg white be uncooked? The Chemical Intelligencer (Springer Verlag), 1996 (14), 51.  </ref>  Alkali metals affect the same reaction more aggressively: <chem display=block>RS-SR + 2 Na -> 2 NaSR,</chem> followed by protonation of the resulting metal thiolate: <chem display=block>NaSR + HCl -> HSR + NaCl</chem> 

In biochemistry labwork, thiols such as β-[[mercaptoethanol]] (β-ME) or [[dithiothreitol]] (DTT) serve as reductants through [[#Thiol-disulfide exchange|thiol-disulfide exchange]].  The thiol reagents are used in excess to drive the equilibrium to the right: <chem display=block>RS-SR + 2 HOCH2CH2SH <=> HOCH2CH2S-SCH2CH2OH + 2 RSH</chem>
The reductant [[TCEP|tris(2-carboxyethyl)phosphine]] (TCEP) is useful, beside being odorless compared to β-ME and DTT, because it is selective, working at both alkaline and acidic conditions (unlike DTT), is more hydrophilic and more resistant to oxidation in air. Furthermore, it is often not needed to remove TCEP before modification of protein thiols.<ref name=FT-242214>[http://www.interchim.fr/ft/2/242214.pdf TCEP technical information], from [[Interchim]]</ref>

In Zincke cleavage, halogens oxidize disulfides to a [[sulfenyl halide]]:<ref>{{multiref|
{{OrgSynth | first = Max H. | last = Hubacher | year = 1935 | title = ''o''-Nitrophenylsulfur Chloride| volume= 15|
doi= 10.15227/orgsyn.015.00452 | page = 45}}
|{{OrgSynth | first1 = Irwin B. | last1 = Douglass | first2 = Richard V. | last2 = Norton | year = 1960| title = Methanesulfinyl Chloride| volume = 40 | page = 62| doi=10.15227/orgsyn.040.0062}}
}}</ref><chem display=block>ArSSAr  +  Cl2  ->  2 ArSCl</chem>

More unusually, oxidation of disulfides gives first [[thiosulfinate]]s and then [[thiosulfonate]]s:<ref name=review>{{cite journal|title=Thiosulfonates: Synthesis, Reactions and Practical Applications|author=Nikolai S. Zefirov, Nikolai V. Zyk, Elena K. Beloglazkina, Andrei G. Kutateladze|journal=Sulfur Reports|year=1993|volume=14|pages=223–240|doi=10.1080/01961779308055018}}</ref>
:RSSR&nbsp;+ [O]&nbsp;→ RS(=O)SR
:RS(=O)SR&nbsp;+ [O]&nbsp;→ RS(=O)<sub>2</sub>SR

====Thiol-disulfide exchange====
In thiol–disulfide exchange, a [[thiol]]ate group {{chem2|\sS-}} displaces one [[sulfur]] [[atom]] in a disulfide bond {{chem2|\sS\sS\s}}. The original disulfide bond is broken, and its other sulfur atom is released as a new thiolate, carrying away the negative charge. Meanwhile, a new disulfide bond forms between the attacking thiolate and the original sulfur atom.<ref>{{cite book | last = Gilbert | first = H. F. | year = 1990 | chapter = Molecular and Cellular Aspects of Thiol–Disulfide Exchange | volume = 63 | pages = 69–172 | pmid = 2407068 | doi = 10.1002/9780470123096.ch2| title = Advances in Enzymology and Related Areas of Molecular Biology | isbn = 9780470123096 }}</ref><ref>{{cite book | last = Gilbert | first = H. F. | year = 1995 | doi = 10.1016/0076-6879(95)51107-5 | chapter = Thiol/disulfide exchange equilibria and disulfide bond stability | title = Biothiols, Part A: Monothiols and Dithiols, Protein Thiols, and Thiyl Radicals | series = [[Methods in Enzymology]] | volume = 251 | pages = 8–28 | pmid=7651233| isbn = 9780121821524 }}</ref>
[[File:Thiol disulfide exchange.png|center|frame|Thiol–disulfide exchange showing the linear intermediate in which the charge is shared among the three sulfur atoms. The thiolate group (shown in red) attacks a sulfur atom (shown in blue) of the disulfide bond, displacing the other sulfur atom (shown in green) and forming a new disulfide bond.]]
Thiolates, not thiols, attack disulfide bonds. Hence, thiol–disulfide exchange is inhibited at low [[pH]] (typically, below 8) where the protonated thiol form is favored relative to the deprotonated thiolate form. (The [[pKa|p''K''<sub>a</sub>]] of a typical thiol group is roughly 8.3, but can vary due to its environment.)

Thiol–disulfide exchange is the principal reaction by which disulfide bonds are formed and rearranged in a [[protein]]. The rearrangement of disulfide bonds within a protein generally occurs via intra-protein thiol–disulfide exchange reactions; a thiolate group of a [[cysteine]] residue attacks one of the protein's own disulfide bonds. This process of disulfide rearrangement (known as ''disulfide shuffling'') does not change the number of disulfide bonds within a protein, merely their location (i.e., which cysteines are bonded). Disulfide reshuffling is generally much faster than oxidation/reduction reactions, which change the number of disulfide bonds within a protein. The oxidation and reduction of protein disulfide bonds ''in vitro'' also generally occurs via thiol–disulfide exchange reactions. Typically, the thiolate of a redox reagent such as [[glutathione]], [[dithiothreitol]] attacks the disulfide bond on a protein forming a ''mixed disulfide bond'' between the protein and the reagent. This mixed disulfide bond when attacked by another thiolate from the reagent, leaves the cysteine oxidized. In effect, the disulfide bond is transferred from the protein to the reagent in two steps, both thiol–disulfide exchange reactions.

The ''in vivo'' oxidation and reduction of protein disulfide bonds by thiol–disulfide exchange is facilitated by a protein called [[thioredoxin]]. This small protein, essential in all known organisms, contains two cysteine amino acid residues in a [[vicinal (chemistry)|vicinal]] arrangement (i.e., next to each other), which allows it to form an internal disulfide bond, or disulfide bonds with other proteins. As such, it can be used as a repository of reduced or oxidized disulfide bond moieties.

===Nomenclature and misnomers===
{{Multiple image
| align =
| direction = vertical
| total_width =
| image1 = Carbon-disulfide-3D-balls.png
| alt1 =
| caption1 = CS<sub>2</sub>
| image2 = Molybdenite-3D-balls.png
| caption2 = MoS<sub>2</sub>
}}
[[Thiosulfoxide]]s are isomeric with disulfides, having the second sulfur branching from the first and not partaking in a continuous chain, i.e. >S=S rather than −S−S−.

Compounds with three sulfur atoms, such as CH<sub>3</sub>S−S−SCH<sub>3</sub>, are called trisulfides.  More extended species are well known, especially in rings.

Disulfide is also used to refer to compounds that contain two sulfide (S<sup>2−</sup>) centers. The compound [[carbon disulfide]], CS<sub>2</sub> is described with the structural formula i.e. S=C=S. This molecule is not a disulfide in the sense that it lacks a S-S bond. Similarly, [[molybdenum disulfide]], MoS<sub>2</sub>, is not a disulfide in the sense again that its sulfur atoms are not linked.

Disulfide bonds are analogous but more common than related [[peroxide]], [[thioselenide]], and [[diselenide]] bonds. Intermediate compounds of these also exist, for example thioperoxides such as [[hydrogen thioperoxide]], have the formula R<sup>1</sup>OSR<sup>2</sup> (equivalently R<sup>2</sup>SOR<sup>1</sup>). These are isomeric to [[sulfoxide]]s in a similar manner to the above; i.e. >S=O rather than −S−O−.

== Occurrence in biology ==
[[File:Disulfide Bridges (SCHEMATIC) V.1.svg|thumb|right|150px|Schematic of disulfide bonds crosslinking regions of a protein]]

===Occurrence in proteins===
Disulfide bonds can be formed under [[oxidising conditions]] and play an important role in the folding and stability of some proteins, usually proteins secreted to the extracellular medium.<ref name=Sevier/> Since most cellular compartments are [[reducing environment]]s, in general, disulfide bonds are unstable in the [[cytosol]], with some exceptions as noted below, unless a [[sulfhydryl oxidase]] is present.<ref name="Hatahet">{{cite journal|last1=Hatahet|first1=F.|last2=Nguyen|first2=V. D.|last3=Salo|first3=K. E.|last4=Ruddock|first4=L. W.|year=2010|title=Disruption of reducing pathways is not essential for efficient disulfide bond formation in the cytoplasm of ''E. coli''|journal=Microbial Cell Factories|volume=9|issue=67|pages=67|doi=10.1186/1475-2859-9-67|pmc=2946281|pmid=20836848 |doi-access=free }}</ref>

[[File:Cystine-skeletal.png|thumb|right|150px|[[Cystine]] is composed of two [[cysteine]]s linked by a disulfide bond (shown here in its neutral form).]]

Disulfide bonds in proteins are formed between the [[thiol]] groups of [[cysteine]] residues by the process of [[oxidative folding]]. The other sulfur-containing amino acid, [[methionine]], cannot form disulfide bonds. A disulfide bond is typically denoted by hyphenating the abbreviations for cysteine, e.g., when referring to [[ribonuclease A]] the "Cys26–Cys84 disulfide bond", or the "26–84 disulfide bond", or most simply as "C26–C84"<ref name="Ruoppolo">{{cite journal|last1=Ruoppolo|first1=M.|last2=Vinci|first2=F.|last3=Klink|first3=T. A.|last4=Raines|first4=R. T.|last5=Marino|first5=G.|year=2000|title=Contribution of individual disulfide bonds to the oxidative folding of ribonuclease A|journal=Biochemistry|volume=39|issue=39|pages=12033–12042|doi=10.1021/bi001044n|pmid=11009618}}</ref> where the disulfide bond is understood and does not need to be mentioned. The prototype of a protein disulfide bond is the two-amino-acid peptide [[cystine]], which is composed of two [[cysteine]] amino acids joined by a disulfide bond. The structure of a disulfide bond can be described by its ''χ''<sub>ss</sub> [[dihedral angle]] between the C<sup>β</sup>−S<sup>γ</sup>−S<sup>γ</sup>−C<sup>β</sup> atoms, which is usually close to ±90°.

The disulfide bond stabilizes the folded form of a protein in several ways:

# It holds two portions of the protein together, biasing the protein towards the folded topology. That is, the disulfide bond ''destabilizes the unfolded form'' of the protein by lowering its [[loop entropy|entropy]].
# The disulfide bond may form the nucleus of a [[hydrophobic core]] of the folded protein, i.e., local hydrophobic residues may condense around the disulfide bond and onto each other through [[hydrophobic interaction]]s.
# Related to 1 and 2, the disulfide bond ''links'' two segments of the protein chain, ''increases'' the effective local concentration of protein residues, and ''lowers'' the effective local concentration of water molecules. Since water molecules attack amide-amide [[hydrogen bond]]s and break up [[secondary structure]], a disulfide bond stabilizes secondary structure in its vicinity. For example, researchers have identified several pairs of peptides that are unstructured in isolation, but adopt stable secondary and tertiary structure upon formation of a disulfide bond between them.

A ''disulfide species'' is a particular pairing of cysteines in a disulfide-bonded protein and is usually depicted by listing the disulfide bonds in parentheses, e.g., the "(26–84, 58–110) disulfide species". A ''disulfide ensemble'' is a grouping of all disulfide species with the same number of disulfide bonds, and is usually denoted as the 1S ensemble, the 2S ensemble, etc. for disulfide species having one, two, etc. disulfide bonds. Thus, the (26–84) disulfide species belongs to the 1S ensemble, whereas the (26–84, 58–110) species belongs to the 2S ensemble. The single species with no disulfide bonds is usually denoted as R for "fully reduced". Under typical conditions, [[thiol-disulfide exchange|disulfide reshuffling]] is much faster than the formation of new disulfide bonds or their reduction; hence, the disulfide species within an ensemble equilibrate more quickly than between ensembles.

The native form of a protein is usually a single disulfide species, although some proteins may cycle between a few disulfide states as part of their function, e.g., [[thioredoxin]]. In proteins with more than two cysteines, non-native disulfide species may be formed, which are almost always misfolded. As the number of cysteines increases, the number of nonnative species increases factorially.
{{missing information|section|intermolecular disulfide bonds of the protein-protein and protein-thiol varieties|date=November 2023}}

====In bacteria and archaea====
Disulfide bonds play an important protective role for [[bacteria]] as a reversible switch that turns a protein on or off when bacterial cells are exposed to [[oxidation]] reactions. [[Hydrogen peroxide]] ([[hydrogen|H]]<sub>2</sub>[[oxygen|O]]<sub>2</sub>) in particular could severely damage [[DNA]] and kill the [[bacteria|bacterium]] at low concentrations if not for the protective action of the SS-bond. [[Archaea]] typically have fewer disulfides than higher organisms.<ref>{{cite journal|last1=Ladenstein|first1=R.|last2=Ren|first2=B.|year=2008|title=Reconsideration of an early dogma, saying "there is no evidence for disulfide bonds in proteins from archaea"|journal=[[Extremophiles (journal)|Extremophiles]]|volume=12|issue=1|pages=29–38|doi=10.1007/s00792-007-0076-z|pmid=17508126|s2cid=11491989}}</ref>

====In eukaryotes====
In [[eukaryote|eukaryotic]] cells, in general, stable disulfide bonds are formed in the lumen of the [[rough endoplasmic reticulum|RER]] (rough endoplasmic reticulum) and the [[mitochondrial intermembrane space]] but not in the [[cytosol]]. This is due to the more oxidizing environment of the aforementioned compartments and more reducing environment of the cytosol (see [[glutathione]]). Thus disulfide bonds are mostly found in secretory proteins, lysosomal proteins, and the exoplasmic domains of membrane proteins.

There are notable exceptions to this rule. For example, many nuclear and cytosolic proteins can become disulfide-crosslinked during necrotic cell death.<ref>{{Cite journal |last1=Samson |first1=Andre L. |last2=Knaupp |first2=Anja S. |last3=Sashindranath |first3=Maithili |last4=Borg |first4=Rachael J. |last5=Au |first5=Amanda E.-L. |last6=Cops |first6=Elisa J. |last7=Saunders |first7=Helen M. |last8=Cody |first8=Stephen H. |last9=McLean |first9=Catriona A. |date=2012-10-25 |title=Nucleocytoplasmic coagulation: an injury-induced aggregation event that disulfide crosslinks proteins and facilitates their removal by plasmin |journal=[[Cell Reports]] |volume=2 |issue=4 |pages=889–901 |doi=10.1016/j.celrep.2012.08.026 |issn=2211-1247 |pmid=23041318 |doi-access=free}}</ref> Similarly, a number of cytosolic proteins which have cysteine residues in proximity to each other that function as oxidation sensors or [[redox]] catalysts; when the reductive potential of the cell fails, they oxidize and trigger cellular response mechanisms. The virus ''[[Vaccinia]]'' also produces cytosolic proteins and peptides that have many disulfide bonds; although the reason for this is unknown presumably they have protective effects against intracellular proteolysis machinery.

Disulfide bonds are also formed within and between [[protamine]]s in the [[sperm]] [[chromatin]] of many [[mammal]]ian species.

====Disulfides in regulatory proteins====<!--mention [[Gliotoxin]]-->
As disulfide bonds can be reversibly reduced and re-oxidized, the redox state of these bonds has evolved into a signaling element. In [[chloroplasts]], for example, the enzymatic reduction of disulfide bonds has been linked to the control of numerous metabolic pathways as well as gene expression. The reductive signaling activity has been shown, thus far, to be carried by the [[Ferredoxin-thioredoxin reductase|ferredoxin-thioredoxin system]], channeling electrons from the light reactions of [[photosystem I]] to catalytically reduce disulfides in regulated proteins in a light dependent manner. In this way chloroplasts adjust the activity of key processes such as the [[Calvin-Benson cycle|Calvin–Benson cycle]], [[starch]] degradation, [[Adenosine triphosphate|ATP]] production and gene expression according to light intensity. Additionally, It has been reported that disulfides plays a significant role on redox state regulation of Two-component systems (TCSs), which could be found in certain bacteria including photogenic strain. A unique intramolecular cysteine disulfide bonds in the ATP-binding domain of SrrAB TCs found in ''Staphylococcus aureus'' is a good example of disulfides in regulatory proteins, which the redox state of SrrB molecule is controlled by cysteine disulfide bonds, leading to the modification of SrrA activity including gene regulation.<ref>{{cite journal |last1=Tiwari |first1=Nitija |last2=López-Redondo |first2=Marisa |last3=Miguel-Romero |first3=Laura |last4=Kulhankova |first4=Katarina |last5=Cahill |first5=Michael P. |last6=Tran |first6=Phuong M. |last7=Kinney |first7=Kyle J. |last8=Kilgore |first8=Samuel H. |last9=Al-Tameemi |first9=Hassan |last10=Herfst |first10=Christine A. |last11=Tuffs |first11=Stephen W. |date=19 May 2020 |title=The SrrAB two-component system regulates Staphylococcus aureus pathogenicity through redox sensitive cysteines |journal=[[Proceedings of the National Academy of Sciences]] |volume=117 |issue=20 |pages=10989–10999 |bibcode=2020PNAS..11710989T |doi=10.1073/pnas.1921307117 |pmc=7245129 |pmid=32354997 |doi-access=free |last12=Kirby |first12=John R. |last13=Boyd |first13=Jeffery M. |last14=McCormick |first14=John K. |last15=Salgado-Pabón |first15=Wilmara |last16=Marina |first16=Alberto |last17=Schlievert |first17=Patrick M. |last18=Fuentes |first18=Ernesto J.}}</ref>

====In hair and feathers====
Over 90% of the dry weight of [[hair]] comprises proteins called [[keratin]]s, which have a high disulfide content, from the amino acid cysteine. The robustness conferred in part by disulfide linkages is illustrated by the recovery of virtually intact hair from ancient Egyptian tombs. [[Feather]]s have similar keratins and are extremely resistant to protein digestive enzymes. The stiffness of hair and feather is determined by the disulfide content. Manipulating disulfide bonds in hair is the basis for the [[permanent wave]] in hairstyling. Reagents that affect the making and breaking of S−S bonds are key, e.g., [[ammonium thioglycolate]]. The high disulfide content of feathers dictates the high sulfur content of bird eggs. The high sulfur content of hair and feathers contributes to the disagreeable odor that results when they are burned.

====In disease====
[[Cystinosis]] is a condition where cystine precipitates in various organs.  This accumulation interferes with bodily function and can be fatal. This disorder can be resolved by treatment with [[cysteamine]].<ref>{{cite journal |doi=10.1016/j.drudis.2013.02.003 |title=Cysteamine: An Old Drug with new Potential |date=2013 |last1=Besouw |first1=Martine |last2=Masereeuw |first2=Rosalinde |last3=Van Den Heuvel |first3=Lambert |last4=Levtchenko |first4=Elena |journal=Drug Discovery Today |volume=18 |issue=15–16 |pages=785–792 |pmid=23416144 }}</ref> Cysteamine acts to solubilize the cystine by (1) forming the mixed disulfide cysteine-cysteamine, which is more soluble and exportable, and (2) reducing cystine to cysteine.

==Inorganic disulfides==
{{Multiple image
| align             =
| direction         = vertical
| total_width       =
| image1            = Pyrite-unit-cell-3D-balls.png
| image2            = Disulfur-dichloride-3D-balls.png
| caption1          = [[Pyrite]], {{chem2|FeS2}}, "fool's gold".  Color code: yellow = S, violet = Fe
| caption2          = [[Disulfur dichloride]], {{chem2|S2Cl2}}, a common industrial chemical
| alt1              =
| header            = A selection of disulfides
}}

The disulfide [[anion]] is {{chem|S|2|2−}}, or <sup>−</sup>S−S<sup>−</sup>. In disulfide, sulfur exists in the reduced state with oxidation number −1. Its electron configuration then resembles that of a [[chlorine]] atom.  It thus tends to form a covalent bond with another S<sup>−</sup> center to form {{chem|S|2|2−}} group, similar to elemental chlorine existing as the diatomic Cl<sub>2</sub>. [[Oxygen]] may also behave similarly, e.g. in [[peroxide]]s such as H<sub>2</sub>O<sub>2</sub>. Examples:
* [[Hydrogen disulfide]] (S<sub>2</sub>H<sub>2</sub>), the simplest inorganic disulfide
* [[Disulfur dichloride]] (S<sub>2</sub>Cl<sub>2</sub>), a distillable liquid.
* [[Iron]] disulfide (FeS<sub>2</sub>), or [[pyrite]].

==Applications==
Aside from the major role in biology, disulfides are found in rubber that has been vulcanized with sulfur. The [[vulcanization]] of [[Natural rubber|rubber]] results in crosslinking groups which consist of disulfide (and polysulfide) bonds; in analogy to the role of disulfides in proteins, the S−S linkages in rubber strongly affect the stability and [[rheology]] of the material.<ref name=":0">{{Cite journal |last1=Akiba |first1=M. |last2=Hashim |first2=A.S. |date=1997 |title=Vulcanization and crosslinking in elastomers |url=https://www.sciencedirect.com/science/article/pii/S0079670096000159 |journal=[[Progress in Polymer Science]] |volume=22 |issue=3 |pages=475–521 |doi=10.1016/S0079-6700(96)00015-9 |via=[[Elsevier Science Direct]]|url-access=subscription }}</ref> Although the exact mechanism underlying the vulcanization process is not entirely understood (as multiple reaction pathways are present but the predominant one is unknown), it has been extensively shown that the extent to which the process is allowed to proceed determines the physical properties of the resulting rubber—namely, a greater degree of crosslinking corresponds to a stronger and more rigid material.<ref name=":0" /><ref name=":1">{{Cite journal |last1=Mutlu |first1=Hatice |last2=Theato |first2=Patrick |date=2020 |title=Making the Best of Polymers with Sulfur–Nitrogen Bonds: From Sources to Innovative Materials |journal=[[Macromolecular Rapid Communications]] |volume=41 |issue=13 |pages=2000181 |doi=10.1002/marc.202000181 |pmid=32462759 |s2cid=218975603|doi-access=free }}</ref> The current conventional methods of rubber manufacturing are typically irreversible, as the unregulated reaction mechanisms can result in complex networks of sulfide linkages; as such, rubber is considered to be a [[Thermosetting polymer|thermoset]] material.<ref name=":0" /><ref name=":2">{{Cite journal |last1=Bin Rusayyis |first1=Mohammed |last2=Torkelson |first2=John |date=2021 |title=Reprocessable covalent adaptable networks with excellent elevated-temperature creep resistance: facilitation by dynamic, dissociative bis(hindered amino) disulfide bonds |url=https://pubs.rsc.org/en/content/articlelanding/2021/PY/D1PY00187F |journal=[[Polymer Chemistry (journal)|Polymer Chemistry]] |volume=12 |issue=18 |pages=2760–2771 |doi=10.1039/D1PY00187F |s2cid=234925061|url-access=subscription }}</ref>

==See also==
* {{anl|Thiosulfinate}}
* Diselenides in [[organoselenium chemistry]]
* [[Covalent adaptable network]]

==References==
{{Reflist|30em}}

==Further reading==<!--specialized stuff-->
{{refbegin|30em}}
* {{cite journal | journal=Biochimica et Biophysica Acta | volume=36 | issue=2 | pages=471–478 | year=1959 |last1=Sela |first1=M. |last2=Lifson |first2=S. | title=The reformation of disulfide bridges in proteins | pmid=14444674 | doi = 10.1016/0006-3002(59)90188-X }}
* {{cite journal | series=Methods in Enzymology | volume=47 | issue=2 | pages=129–132 | last1=Stark | first1 = G. R. | title=In vitro generation of three-dimensional renal structures | pmid=927170 | doi = 10.1016/j.ymeth.2008.09.005 | last2=Stern | first2=K. | last3=Atala | first3=A. | last4=Yoo | first4=J. | journal=Methods | date=2009 }}
* {{cite journal | journal=Journal of Molecular Biology | volume=151 | issue=2 | pages=261–287 | year=1981 | last=Thornton | first = J. M. | title=Disulphide bridges in globular proteins | pmid=7338898 | doi = 10.1016/0022-2836(81)90515-5 }}
* {{cite journal | journal=Analytical Biochemistry | volume=138 | issue=1 | pages=181–188 | year=1984 |last1=Thannhauser |first1=T. W. |last2=Konishi |first2=Y. |last3=Scheraga |first3=H. A. | title=Sensitive quantitative analysis of disulfide bonds in polypeptides and proteins | pmid=6547275 | doi = 10.1016/0003-2697(84)90786-3 }}
* {{cite journal | journal=Analytical Biochemistry | volume=258 | issue=2 | pages=268–276 | year=1998 |last1=Wu |first1=J. |last2=Watson |first2=J. T. | title=Optimization of the cleavage reaction for cyanylated cysteinyl proteins for efficient and simplified mass mapping | pmid=9570840 | doi = 10.1006/abio.1998.2596 }}
* {{cite journal | journal=Journal of Biochemistry | volume=128 | issue=2 | pages=245–250 | year=2000 |last1=Futami |first1=J. |last2=Tada |first2=H. |last3=Seno |first3=M. |last4=Ishikami |first4=S. |last5=Yamada |first5=H. | title=Stabilization of human RNAse 1 by introduction of a disulfide bond between residues 4 and 118 | pmid=10920260 | doi = 10.1093/oxfordjournals.jbchem.a022747}}
* {{cite journal | journal=Plant Science | volume=175 | issue=4 | pages=459–466 | year=2008 |last1=Wittenberg |first1=G. |last2=Danon |first2=A. | title=Disulfide bond formation in chloroplasts: Formation of disulfide bonds in signaling chloroplast proteins | doi = 10.1016/j.plantsci.2008.05.011 | bibcode=2008PlnSc.175..459W }}
* {{cite journal | doi = 10.1146/annurev.biochem.72.121801.161459 | pmid = 12524212 | title = Protein Disulfide Bond Formation in Prokaryotes | year = 2003 | last1 = Kadokura | first1 = Hiroshi | last2 = Katzen | first2 = Federico | last3 = Beckwith | first3 = Jon | journal = Annual Review of Biochemistry | volume = 72 | issue = 1 | pages = 111–135}}
* {{cite journal | doi = 10.1083/jcb.200311055 | pmc = 2172237 | pmid = 14757749 | title = Oxidative protein folding in eukaryotes: mechanisms and consequences | first2 = J. S. | year = 2004 | last2 = Weissman | last1 = Tu | first1 = B. P. | journal = The Journal of Cell Biology | volume = 164 | issue = 3 | pages = 341–346}}
* {{cite journal | doi = 10.1038/sj.embor.7400311 | pmc = 1299221 | pmid = 15643448 | title = The human protein disulphide isomerase family: substrate interactions and functional properties | year = 2005 | last1 = Ellgaard | first1 = Lars | last2 = Ruddock | first2 = Lloyd W. | journal = EMBO Reports | volume = 6 | issue = 1 | pages = 28–32}}
{{refend}}

==External links==
* {{Commonscatinline|Disulfides}}

{{Disulfides}}
{{Functional group}}
{{Protein posttranslational modification}}

{{DEFAULTSORT:Disulfide Bond}}
[[Category:Organic disulfides| ]]
[[Category:Protein structure]]
[[Category:Post-translational modification]]
[[Category:Sulfur]]
[[Category:Functional groups]]