Cysteine (symbol CysorC;[4]/ˈsɪstɪiːn/)[5] is a semiessential[6]proteinogenic amino acid with the formulaHOOC−CH(−NH2)−CH2−SH. The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile. Cysteine is chiral, but interestingly, both D and L-cysteine are found in nature with D-cysteine having been found in developing brain (see Semenza et al., 2021). Cysteine is named after its discovery in urine, which comes from the urinary bladder or cyst, from kystis "bladder".[7]
The thiol is susceptible to oxidation to give the disulfide derivative cystine, which serves an important structural role in many proteins. In this case, the symbol Cyx is sometimes used.[8][9] The deprotonated form can generally be described by the symbol Cym as well.[9][10]
When used as a food additive, cysteine has the E number E920.
Like other amino acids (not as a residue of a protein), cysteine exists as a zwitterion. Cysteine has lchirality in the older d/l notation based on homology to d- and l-glyceraldehyde. In the newer R/S system of designating chirality, based on the atomic numbers of atoms near the asymmetric carbon, cysteine (and selenocysteine) have R 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, have S chirality. Replacing sulfur with selenium gives selenocysteine.
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.[11] Although classified as a nonessential amino acid,[12] in rare cases, cysteine may be essential for infants, the elderly, and individuals with certain metabolic diseases or who suffer from malabsorptionsyndromes. Cysteine can usually be synthesized by the human body under normal physiological conditions if a sufficient quantity of methionine is available.
The majority of l-cysteine is obtained industrially by hydrolysis of animal materials, such as poultry feathers or hog hair. Despite widespread belief otherwise, little evidence shows that human hair is used as a source material and its use is explicitly banned for food additives and cosmetic products in the European Union.[13][14][why?] Synthetically produced l-cysteine, compliant with Jewish kosher and Muslim halal laws, is also available, albeit at a higher price.[15] The synthetic route involves fermentation using a mutant of E. coli. Evonik (formerly Degussa) introduced a route from substituted thiazolines.[16] Following this technology, l-cysteine is produced by the hydrolysis of racemic 2-amino-Δ2-thiazoline-4-carboxylic acid using Pseudomonas thiazolinophilum.[17]
The cysteine sulfhydryl group is nucleophilic and easily oxidized. The reactivity is enhanced when the thiol is ionized, and cysteine residues in proteins have pKa values close to neutrality, so are often in their reactive thiolate form in the cell.[19] 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 have antioxidant properties. Its antioxidant properties are typically expressed in the tripeptide glutathione, 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, and glutamic 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.[20]
In the translation of messenger RNA molecules to produce polypeptides, cysteine is coded for by the UGU and UGC codons.
Cysteine has traditionally been considered to be a hydrophilic amino acid, based largely on the chemical parallel between its sulfhydryl group and the hydroxyl 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.[24] 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 as methionine and tyrosine (tyrosine is polar aromatic but also hydrophobic[25]), those of which were much greater than that of known polar amino acids such as serine and threonine.[26]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,[27][28] though it is sometimes also classified as slightly polar,[29] or polar.[6]
Most cysteine residues are covalently bonded to other cysteine residues to form disulfide bonds, which play an important role in the folding and stability of some proteins, usually proteins secreted to the extracellular medium.[30] Since most cellular compartments are reducing environments, disulfide bonds are generally unstable in the cytosol with some exceptions as noted below.
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 corresponding sulfinic acid and sulfonic 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 numerous post-translational modifications. The nucleophilic sulfhydryl group allows cysteine to conjugate to other groups, e.g., in prenylation. Ubiquitinligases transfer ubiquitin to its pendant, proteins, and caspases, 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, mainly the l-enantiomer, is a precursor 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 a Maillard reaction yields meat flavors.[31]l-Cysteine is also used as a processing aid for baking.[32]
In the field of personal care, cysteine is used for permanent-wave applications, predominantly in Asia. Again, the cysteine is used for breaking up the disulfide bonds in the hair's keratin.
Cysteine is a very popular target for site-directed labeling experiments to investigate biomolecular structure and dynamics. Maleimides selectively attach to cysteine using a covalent Michael 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 and hangover. It counteracts the poisonous effects of acetaldehyde.[33] Cysteine supports the next step in metabolism, which turns acetaldehyde into acetic acid.[citation needed]
In a rat study, test animals received an LD90 dose of acetaldehyde. Those that received cysteine had an 80% survival rate; when both cysteine and thiamine were administered, all animals survived. The control group had a 10% survival rate.[34]
In 2020 an article was published that suggests L-cysteine might also work in humans.[35]
Cysteine is required by sheep 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.[37]
Being multifunctional, cysteine undergoes a variety of reactions. Much attention has focused on protecting the sulfhydryl group.[38]Methylation of cysteine gives S-methylcysteine. Treatment with formaldehyde gives the thiazolidinethioproline. Cysteine forms a variety of coordination complexes upon treatment with metal ions.[39]
The animal-originating sources of l-cysteine as a food additive are a point of contention for people following dietary restrictions such as kosher, halal, vegan, or vegetarian.[41] To avoid this problem, l-cysteine can also be sourced from microbial or other synthetic processes.
In 1884 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".[42]
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^Weast, Robert C., ed. (1981). CRC Handbook of Chemistry and Physics (62nd ed.). Boca Raton, FL: CRC Press. p. C-259. ISBN0-8493-0462-8..
^"Nomenclature and symbolism for amino acids and peptides (IUPAC-IUB Recommendations 1983)", Pure Appl. Chem., 56 (5): 595–624, 1984, doi:10.1351/pac198456050595
^"EU Chemical Requirements". Retrieved May 24, 2020. ...L-cysteine hydrochloride or hydrochloride monohydrate. Human hair may not be used as a source for this substance
^Lippard, Stephen J.; Berg, Jeremy M. (1994). Principles of Bioinorganic Chemistry. Mill Valley, CA: University Science Books. ISBN978-0-935702-73-6.[page needed]
^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 .