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. Because of its high reactivity, the sulfhydryl group of cysteine has numerous biological functions.
Precursor to the antioxidant glutathione 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.
Precursor to iron-sulfur clusters Cysteine is an important source of
sulfide in human
metabolism. The sulfide in
iron-sulfur clusters and in
nitrogenase is extracted from cysteine, which is converted to
alanine in the process.
Metal ion binding Beyond the iron-sulfur proteins, many other metal cofactors in enzymes are bound to the thiolate substituent of cysteinyl residues. Examples include zinc in
zinc fingers and
alcohol dehydrogenase, copper in the
blue copper proteins, iron in
cytochrome P450, and nickel in the [NiFe]-
hydrogenases. The sulfhydryl group also has a high
affinity for
heavy metals, so that proteins containing cysteine, such as
metallothionein, will
bind metals such as mercury, lead, and cadmium tightly.
Roles in protein structure 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. 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), those of which were much greater than that of known polar amino acids such as serine and
threonine.
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, though it is sometimes also classified as slightly polar, or polar. Since most cellular compartments are
reducing environments, disulfide bonds are generally unstable in the
cytosol with some exceptions as noted below. (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 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.
Protein disulfide isomerases catalyze the proper formation of
disulfide bonds; the cell transfers
dehydroascorbic acid to the
endoplasmic reticulum, which oxidizes the environment. In this environment, cysteines are, in general, oxidized to cystine and are no longer functional as a nucleophiles. 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.
Ubiquitin ligases 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. == Evolutionary role of cysteine ==