Disulfide
In
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 secondary and tertiary structure of proteins.
Compounds of the form R−S−S−H are usually called persulfides instead.
Organic disulfides
Symmetrical disulfides are compounds of the formula R2S2. Most disulfides encountered in organo sulfur chemistry are symmetrical disulfides. Unsymmetrical disulfides (also called heterodisulfides) are compounds of the formula RSSR'. They are less common in organic chemistry, but most disulfides in nature are unsymmetrical.
Properties
The disulfide bonds are strong, with a typical
The disulfide bond is about 2.05
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.[2]
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:
This value is about −250 mV versus the
Synthesis
Disulfide bonds are usually formed from the
The transformation is depicted as follows:A variety of oxidants participate in this reaction including oxygen and
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 polysulfides 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 "RS+" react with thiols to give asymmetrical disulfides:[3]
where R″2N is the phthalimido group. Bunte salts, derivatives of the type RSSO−3Na+are also used to generate unsymmetrical disulfides:[5]
Reactions
The most important aspect of disulfide bonds is their scission, as the S−S bond is usually the weakest bond in a molecule. Many specialized organic reactions have been developed to cleave the bond.
A variety of reductants reduce disulfides to
In biochemistry labwork, thiols such as β-
In Zincke cleavage, halogens oxidize disulfides to a
More unusually, oxidation of disulfides gives first thiosulfinates and then thiosulfonates:[9]
- RSSR + [O] → RS(=O)SR
- RS(=O)SR + [O] → RS(=O)2SR
Thiol-disulfide exchange
In thiol–disulfide exchange, a thiolate group −S− displaces one sulfur atom in a disulfide bond −S−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.[10][11]
Thiolates, not thiols, attack disulfide bonds. Hence, thiol–disulfide exchange is inhibited at low
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 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.
Occurrence in biology
Occurrence in proteins
Disulfide bonds can be formed under
Disulfide bonds in proteins are formed between the
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 entropy.
- The disulfide bond may form the nucleus of a hydrophobic interactions.
- 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 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,
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.
This section is missing information about intermolecular disulfide bonds of the protein-protein and protein-thiol varieties.(November 2023) |
In bacteria and archaea
Disulfide bonds play an important protective role for
In eukaryotes
In
There are notable exceptions to this rule. For example, many nuclear and cytosolic proteins can become disulfide-crosslinked during necrotic cell death.[15] 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 protamines in the sperm chromatin of many mammalian species.
Disulfides in regulatory proteins
As disulfide bonds can be reversibly reduced and re-oxidized, the redox state of these bonds has evolved into a signaling element. In
In hair and feathers
Over 90% of the dry weight of
Inorganic disulfides
The disulfide
2, or −S−S−. 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− center to form S2−
2 group, similar to elemental chlorine existing as the diatomic Cl2. Oxygen may also behave similarly, e.g. in peroxides
- Hydrogen disulfide (S2H2), the simplest inorganic disulfide
- Disulfur dichloride (S2Cl2), a distillable liquid.
- Iron disulfide (FeS2), or pyrite.
Related compounds
Thiosulfoxides are orthogonally 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−.
Disulfide bonds are analogous but more common than related
Compounds with three sulfur atoms, such as CH3S−S−SCH3, are called trisulfides, or trisulfide bonds.
Misnomers
Disulfide is also used to refer to compounds that contain two sulfide (S2−) centers. The compound carbon disulfide, CS2 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, MoS2, is not a disulfide in the sense again that its sulfur atoms are not linked.
Applications
Rubber manufacturing
The vulcanization of 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.[17] 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.[17][18] 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 thermoset material.[17][19]
Covalent adaptable networks
Due to their relatively weak bond dissociation energy (in comparison to C−C bonds and the like), disulfides have been employed in covalent adaptable network (CAN) systems in order to allow for dynamic breakage and reformation of crosslinks.[20] By incorporating disulfide functional groups as crosslinks between polymer chains, materials can be produced which are stable at room temperature while also allowing for reversible crosslink dissociation upon application of elevated temperature.[18] The mechanism behind this reaction can be attributed to the cleavage of disulfide linkages (RS−SR) into thiyl radicals (2 RS•) which can subsequently reassociate into new bonds, resulting in reprocessability and self-healing characteristics for the bulk material.[20] However, since the bond dissociation energy of the disulfide bond is still fairly high, it is typically necessary to augment the bond with adjacent chemistry that can stabilize the unpaired electron of the intermediate state.[19][20] As such, studies usually employ aromatic disulfides or disulfidediamine (RNS−SNR) functional groups to encourage the dynamic dissociation of the S−S bond; these chemistries can result in the bond dissociation energy being reduced to half (or even less) of its prior magnitude.[18][19][20]
In practical terms, disulfide-containing CANs can be used to impart recyclability to polymeric materials while still exhibiting physical properties similar to that of thermosets.[19][20] Typically, recyclability is restricted to thermoplastic materials, as said materials consist of polymer chains which are not bonded to each other at the molecular level; as a result, they can be melted down and reformed (as the addition of thermal energy allows the chains to untangle, move past each other, and adopt new configurations), but this comes at the expense of their physical robustness.[20] Meanwhile, conventional thermosets contain permanent crosslinks which bolster their strength, toughness, creep resistance, and the like (as the bonding between chains provides resistance to deformation at the macroscopic level), but due to the permanence of said crosslinks, these materials cannot be reprocessed akin to thermoplastics.[19][20] However, due to the dynamic nature of the crosslinks in disulfide CANs, they can be designed to exhibit the best attributes of both of the aforementioned material types. Studies have shown that disulfide CANs can be reprocessed multiple times with negligible degradation in performance while also exhibiting creep resistance, glass transition, and dynamic modulus values comparable to those observed in similar conventional thermoset systems.[18][19]
See also
- Thiosulfinate – Functional group
- Diselenides in organoselenium chemistry
References
- ISBN 0-471-95512-4.
- ^ S2CID 2885059.
- ^ .
- PMID 28260381. Retrieved 31 May 2021.
- .
- ^ Hervé This. Can a cooked egg white be uncooked? The Chemical Intelligencer (Springer Verlag), 1996 (14), 51.
- ^ TCEP technical information, from Interchim
- .
{{cite journal}}
: CS1 maint: multiple names: authors list (linkFurther reading
- Sela, M.; Lifson, S. (1959). "The reformation of disulfide bridges in proteins". Biochimica et Biophysica Acta. 36 (2): 471–478. PMID 14444674.
- Stark, G. R.; Stern, K.; Atala, A.; Yoo, J. (1977). Cleavage at cysteine after cyanylation. Methods in Enzymology. Vol. 47. pp. 129–132. PMID 927170.
- Thornton, J. M. (1981). "Disulphide bridges in globular proteins". Journal of Molecular Biology. 151 (2): 261–287. PMID 7338898.
- Thannhauser, T. W.; Konishi, Y.; Scheraga, H. A. (1984). "Sensitive quantitative analysis of disulfide bonds in polypeptides and proteins". Analytical Biochemistry. 138 (1): 181–188. PMID 6547275.
- Wu, J.; Watson, J. T. (1998). "Optimization of the cleavage reaction for cyanylated cysteinyl proteins for efficient and simplified mass mapping". Analytical Biochemistry. 258 (2): 268–276. PMID 9570840.
- Futami, J.; Tada, H.; Seno, M.; Ishikami, S.; Yamada, H. (2000). "Stabilization of human RNAse 1 by introduction of a disulfide bond between residues 4 and 118". Journal of Biochemistry. 128 (2): 245–250. PMID 10920260.
- Wittenberg, G.; Danon, A. (2008). "Disulfide bond formation in chloroplasts: Formation of disulfide bonds in signaling chloroplast proteins". Plant Science. 175 (4): 459–466. .
- Kadokura, Hiroshi; Katzen, Federico; Beckwith, Jon (2003). "Protein Disulfide Bond Formation in Prokaryotes". Annual Review of Biochemistry. 72 (1): 111–135. PMID 12524212.
- Tu, B. P.; Weissman, J. S. (2004). "Oxidative protein folding in eukaryotes: mechanisms and consequences". The Journal of Cell Biology. 164 (3): 341–346. PMID 14757749.
- Ellgaard, Lars; Ruddock, Lloyd W. (2005). "The human protein disulphide isomerase family: substrate interactions and functional properties". EMBO Reports. 6 (1): 28–32. PMID 15643448.
External links
- Media related to Disulfides at Wikimedia Commons