Editing Disulfide (section)

== 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.