Cysteine (/ˈsɪstɪiːn/;[5] symbolCys orC[6]) is a semiessential[7]proteinogenic amino acid with theformulaHOOC−CH(−NH2)−CH2−SH. Thethiol side chain in cysteine enables the formation ofdisulfide bonds, and often participates inenzymatic reactions as anucleophile. Cysteine is chiral, but bothD andL-cysteine are found in nature.L‑Cysteine is a protein monomer in all biota, andD-cysteine acts as a signaling molecule in mammalian nervous systems.[8] Cysteine is named after its discovery in urine, which comes from the urinary bladder or cyst, fromGreek κύστιςkýstis, "bladder".[9]
The thiol is susceptible to oxidation to give thedisulfide derivativecystine, which serves an important structural role in manyproteins. In this case, the symbolCyx is sometimes used.[10][11] The deprotonated form can generally be described by the symbolCym as well.[11][12]
When used as a food additive, cysteine has theE number E920.
Like other amino acids (not as a residue of a protein), cysteine exists as azwitterion. Cysteine haslchirality in the olderd/l notation based on homology tod- andl-glyceraldehyde. In the newerR/S system of designating chirality, based on the atomic numbers of atoms near the asymmetric carbon, cysteine (and selenocysteine) haveR chirality, because of the presence of sulfur (or selenium) as a second neighbor to the asymmetric carbon atom. The remaining chiral amino acids, having lighter atoms in that position, haveS chirality. Replacing sulfur withselenium givesselenocysteine.
(R)-Cysteine (left) and (S)-Cysteine (right) in zwitterionic form at neutral pH
Cysteinyl is a residue in high-protein foods. Some foods considered rich in cysteine include poultry, eggs, beef, and whole grains. In high-protein diets, cysteine may be partially responsible for reduced blood pressure and stroke risk.[13] Although classified as a nonessential amino acid,[14] in rare cases, cysteine may be essential for infants, the elderly, and individuals with certain metabolic diseases or who suffer frommalabsorptionsyndromes. Cysteine can usually be synthesized by the human body under normal physiological conditions if a sufficient quantity ofmethionine is available.
The majority ofl-cysteine is obtained industrially byhydrolysis of animal materials, such as poultry feathers or hog hair. Despite widespread rumor,[15] human hair is rarely a source material.[16] Indeed, food additive or cosmetic product manufactures may not legally source from human hair in the European Union.[17][18]
Some animal-originating sources ofl-cysteine as a food additive contravene kosher, halal, vegan, or vegetarian diets.[15] To avoid this problem, syntheticl-cysteine, compliant with Jewishkosher and Muslimhalal laws, is also available, albeit at a higher price.[19] The typical synthetic route involves fermentation with an artificialE. coli strain.[20]
Alternatively,Evonik (formerly Degussa) introduced a route from substitutedthiazolines.[21]Pseudomonas thiazolinophilum hydrolyzes racemic 2‑amino-Δ2‑thiazoline-4‑carboxylic acid tol‑cysteine.[20]
The cysteine sulfhydryl group isnucleophilic and easily oxidized. The reactivity is enhanced when the thiol is ionized, and cysteineresidues in proteins havepKa values close to neutrality, so are often in their reactivethiolate form in the cell.[23] Because of its high reactivity, the sulfhydryl group of cysteine has numerous biological functions.
Due to the ability of thiols to undergo redox reactions, cysteine and cysteinyl residues haveantioxidant properties. Its antioxidant properties are typically expressed in the tripeptideglutathione, which occurs in humans and other organisms. The systemic availability of oral glutathione (GSH) is negligible; so it must be biosynthesized from its constituent amino acids, cysteine,glycine, andglutamic acid. While glutamic acid is usually sufficient because amino acid nitrogen is recycled through glutamate as an intermediary, dietary cysteine and glycine supplementation can improve synthesis of glutathione.[24]
In the translation of messenger RNA molecules to produce polypeptides, cysteine is coded for by the UGU and UGCcodons.
Cysteine has traditionally been considered to be ahydrophilic amino acid, based largely on the chemical parallel between itssulfhydryl group and thehydroxyl groups in the side chains of other polar amino acids. However, the cysteine side chain has been shown to stabilize hydrophobic interactions in micelles to a greater degree than the side chain in the nonpolar amino acid glycine and the polar amino acid serine.[28] In a statistical analysis of the frequency with which amino acids appear in various proteins, cysteine residues were found to associate with hydrophobic regions of proteins. Their hydrophobic tendency was equivalent to that of known nonpolar amino acids such asmethionine andtyrosine (tyrosine is polar aromatic but also hydrophobic[29]), those of which were much greater than that of known polar amino acids such as serine andthreonine.[30]Hydrophobicity scales, which rank amino acids from most hydrophobic to most hydrophilic, consistently place cysteine towards the hydrophobic end of the spectrum, even when they are based on methods that are not influenced by the tendency of cysteines to form disulfide bonds in proteins. Therefore, cysteine is now often grouped among the hydrophobic amino acids,[31][32] though it is sometimes also classified as slightly polar,[33] or polar.[7]
Most cysteine residues are covalently bonded to other cysteine residues to formdisulfide bonds, which play an important role in the folding and stability of some proteins, usually proteins secreted to the extracellular medium.[34] Since most cellular compartments arereducing environments, disulfide bonds are generally unstable in thecytosol with some exceptions as noted below.
Figure 2:Cystine (shown here in its neutral form), two cysteines bound together by a disulfide bond
Disulfide bonds in proteins are formed by oxidation of the sulfhydryl group of cysteine residues. The other sulfur-containing amino acid, methionine, cannot form disulfide bonds. More aggressive oxidants convert cysteine to the correspondingsulfinic acid andsulfonic acid. Cysteine residues play a valuable role by crosslinking proteins, which increases the rigidity of proteins and also functions to confer proteolytic resistance (since protein export is a costly process, minimizing its necessity is advantageous). Inside the cell, disulfide bridges between cysteine residues within a polypeptide support the protein's tertiary structure.Insulin is an example of a protein with cystine crosslinking, wherein two separate peptide chains are connected by a pair of disulfide bonds.
Aside from its oxidation to cystine, cysteine participates in numerouspost-translational modifications. Thenucleophilic sulfhydryl group allows cysteine to conjugate to other groups, e.g., inprenylation.Ubiquitinligases transfer ubiquitin to its pendant, proteins, andcaspases, which engage in proteolysis in the apoptotic cycle.Inteins often function with the help of a catalytic cysteine. These roles are typically limited to the intracellular milieu, where the environment is reducing, and cysteine is not oxidized to cystine.
Cysteine is considered a "newcomer" amino acid, being the 17th amino acid incorporated into thegenetic code.[35][36] Similar to other later-added amino acids such asmethionine,tyrosine, andtryptophan, cysteine exhibits strong nucleophilic and redox-active properties.[37][38] These properties contribute to the depletion of cysteine fromrespiratory chain complexes, such asComplexes I andIV,[39] since reactive oxygen species (ROS) produced by the respiratory chain can react with the cysteine residues in these complexes, leading to dysfunctional proteins and potentially contributing to aging. The primary response of a protein to ROS is the oxidation of cysteine and the loss of free thiol groups,[40] resulting in increasedthiyl radicals and associated protein cross-linking.[41][42] In contrast, another sulfur-containing, redox-active amino acid, methionine, does not exhibit these biochemical properties and its content is relatively upregulated inmitochondrially encoded proteins.[43]
Cysteine, mainly thel-enantiomer, is aprecursor in the food, pharmaceutical, and personal-care industries. One of the largest applications is the production of flavors. For example, the reaction of cysteine with sugars in aMaillard reaction yields meat flavors.[44]l-Cysteine is also used as aprocessing aid for baking.[45]
In the field of personal care, cysteine is used forpermanent-wave applications, predominantly in Asia. Again, the cysteine is used for breaking up the disulfide bonds in thehair'skeratin.
Cysteine is a very popular target for site-directed labeling experiments to investigate biomolecular structure and dynamics.Maleimides selectively attach to cysteine using a covalentMichael addition.Site-directed spin labeling for EPR or paramagnetic relaxation-enhanced NMR also uses cysteine extensively.
Cysteine has been proposed as a preventive or antidote for some of the negative effects of alcohol, including liver damage andhangover. It counteracts the poisonous effects ofacetaldehyde.[46] It binds to acetaldehyde to form the low-toxicity heterocycle methylthioproline.[47]
In arat study, test animals received anLD90 dose of acetaldehyde. Those that received cysteine had an 80% survival rate; when both cysteine andthiamine were administered, all animals survived. Thecontrol group had a 10% survival rate.[48]
In 2020 an article was published that suggests L-cysteine might also work in humans.[49]
Cysteine is required bysheep to produce wool. It is an essential amino acid that is taken in from their feed. As a consequence, during drought conditions, sheep produce less wool; however,transgenic sheep that can make their own cysteine have been developed.[51]
Being multifunctional, cysteine undergoes a variety of reactions. Much attention has focused on protecting the sulfhydryl group.[52]Methylation of cysteine givesS-methylcysteine. Treatment with formaldehyde gives thethiazolidinethioproline. Withphosgene and related carbonylating agents, cysteine givesprocysteine.
Cysteine forms a variety ofcoordination complexes upon treatment with metal ions.[53] This coordination behavior is seen in many metal-cysteine metalloenzymes.
In 1884 German chemistEugen Baumann found that reduction ofcystine with zinc gavemonomer, which he named "cysteïne".[55] The easy redox interconversion of cysteine and cystine has "provided more puzzles to protein chemists than any of the other amino acids.[56]
^"Nomenclature and symbolism for amino acids and peptides (IUPAC-IUB Recommendations 1983)".Pure and Applied Chemistry.56 (5):595–624. 1984.doi:10.1351/pac198456050595.
^"EU Chemical Requirements". RetrievedMay 24, 2020....L-cysteine hydrochloride or hydrochloride monohydrate. Human hair may not be used as a source for this substance
^abDrauz, Karlheinz; Grayson, Ian; Kleemann, Axel; Krimmer, Hans-Peter; Leuchtenberger, Wolfgang; Weckbecker, Christoph (2007). "Amino Acids".Ullmann's Encyclopedia of Industrial Chemistry.doi:10.1002/14356007.a02_057.pub2.ISBN978-3-527-30673-2.
^Martens, Jürgen;Offermanns, Heribert; Scherberich, Paul (1981). "Facile Synthesis of Racemic Cysteine".Angewandte Chemie International Edition in English.20 (8): 668.doi:10.1002/anie.198106681.
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^Betts, M.J.; R.B. Russell (2003)."Hydrophobic amino acids".Amino Acid Properties and Consequences of Substitutions, In: Bioinformatics for Geneticists. Wiley. Retrieved2012-09-16.
^Moosmann, Bernd; Hajieva, Parvana; Behl, Christian (2006), "The antioxidant function of protein methionine explains about the evolution of a non-standard genetic code in mitochondria",Free Radical Biology and Medicine,41 402: S149–S150,doi:10.1016/j.freeradbiomed.2006.10.015
^Sprince H, Parker CM, Smith GG, Gonzales LJ (April 1974). "Protection against acetaldehyde toxicity in the rat by L-cysteine, thiamin and L-2-methylthiazolidine-4-carboxylic acid".Agents Actions.4 (2):125–30.doi:10.1007/BF01966822.PMID4842541.S2CID5924137.
^Eriksson, C J Peter; Metsälä, Markus; Möykkynen, Tommi; Mäkisalo, Heikki; Kärkkäinen, Olli; Palmén, Maria; Salminen, Joonas E; Kauhanen, Jussi (20 October 2020). "L-Cysteine Containing Vitamin Supplement Which Prevents or Alleviates Alcohol-related Hangover Symptoms: Nausea, Headache, Stress and Anxiety".Alcohol and Alcoholism.55 (6):660–666.doi:10.1093/alcalc/agaa082.hdl:10138/339340.PMID32808029.
^Kanter MZ (October 2006). "Comparison of oral and i.v. acetylcysteine in the treatment of acetaminophen poisoning".Am J Health Syst Pharm.63 (19):1821–7.doi:10.2146/ajhp060050.PMID16990628.S2CID9209528.
^Powell BC, Walker SK, Bawden CS, Sivaprasad AV, Rogers GE (1994). "Transgenic sheep and wool growth: possibilities and current status".Reprod. Fertil. Dev.6 (5):615–23.doi:10.1071/RD9940615.PMID7569041.
^Milkowski, John D.; Veber, Daniel F.; Hirschmann, Ralph (1979). "Thiol Protection with the Acetamidomethyl Group: S-Acetamidomethyl-L-Cysteine Hydrochloride".Organic Syntheses.59: 190.doi:10.15227/orgsyn.059.0190.
^Arnold, Alan P.; Jackson, W. Gregory (1990). "Stereospecificity in the Synthesis of the Tris((R)-Cysteinato-N,S)- and Tris((R)-Cysteinesulfinato-N,S)cobaltate(III) Ions".Inorganic Chemistry.29 (18):3618–3620.doi:10.1021/ic00343a061.
^Baumann, E. (1884)."Ueber Cystin und Cysteïn" [On cystine and cysteine].Zeitschrift für physiologische Chemie (in German).8:299–305. From pp. 301-302:"Die Analyse der Substanz ergibt Werthe, welche den vom Cystin (C6H12N2S2O4) verlangten sich nähern, […] nenne ich dieses Reduktionsprodukt des Cystins: Cysteïn." (Analysis of the substance [cysteine] reveals values which approximate those [that are] required by cystine (C6H12N2S2O4), however the new base [cysteine] can clearly be recognized as a reduction product of cystine, to which the [empirical] formula C3H7NSO2, [which had] previously [been] ascribed to cystine, is [now] ascribed. In order to indicate the relationships of this substance to cystine, I name this reduction product of cystine: "cysteïne".) Note: Baumann's proposed structures for cysteine and cystine (see p.302) are incorrect: for cysteine, he proposed CH3CNH2(SH)COOH .
^Bradford Vickery, Hubert (1972).The History of the Discovery of the Amino Acids II. A Review of Amino Acids Described Since 1931 as Components of Native Proteins. Advances in Protein Chemistry. Vol. 26. pp. 81–171.doi:10.1016/S0065-3233(08)60140-0.ISBN978-0-12-034226-6.
