Two amino acids, cysteine and methionine, contain sulfur. Cysteine, with its –SH group, isn't too hydrophilic, since the sulfhydryl group doesn't form hydrogen bonds readily. You may recall the difference between the boiling points for H₂S and H₂O: -62 vs. 100°C.

Cys is present in the active site of various enzymes. The –SH group can dissociate to an anionic species, which is an exceptional nucleophile (pK 8 to 9).

Two cysteine residues which are in close proximity in the three-dimensional structure of a protein can be oxidized to form a disulfide bond.

Cys–SH + HS–Cys → Cys–S–S–Cys + 2H⁺ + 2e^-

The covalent S–S bond may be cleaved by reduction with thiols. Such covalent bonds usually contribute to the stabilization of the folded conformation. The addition of reducing agents will unfold the protein. No denaturing agents, such as urea or guanidinium chloride, are required.

Many extracellular proteins contain disulfide cross-bridges. This either creates intrachain links in the main polypeptide chain or links different chains together. The multiply linked chains are generally derived from a single-chain precursor that has been cleaved by proteolysis, as in the conversion of proinsulin to insulin.

Endothelin-1. This 21-amino-acid peptide, discovered in 1989, is the most potent vasoconstrictor yet identified. It is released by vascular endothelial cells. The conformation of this hormone is stabilized by two disulfide bonds between four Cys residues (the CPK color for sulfur is yellow). The α carbons are colored dark gray.

Let's perform some molecular surgery to see how a covalent disulfide bond ties two parts of the peptide chain together. We'll start by pairing Cys 3 and Cys 11 to form the S–S bridge nearest the N-terminus. two tripeptides: Ser-Cys-Ser (residues 2-4), followed by Glu-Cys-Val (residues 10-12). The oxidation of the two thiols forms a S–S bond.

spacefill. You may also find it helpful to the model by displaying it as a backbone trace (a tube drawn through the α carbons).

Cross-linking the polypeptide chain with two covalent disulfide bonds stabilizes the folded conformation of this important signal molecule.

Methionine is a nonpolar amino acid. The side chain resembles an n-butyl group (sulfur is about the size of a methylene group). However, the relatively long, flexible chain means that the Met side chain can adopt a large number of conformations, making it difficult to fit into a definite compact structure. Consequently, Met is rare in proteins. Since it is rare, Met is assigned one codon, AUG, which is also used to specify the initiation site for protein synthesis. N-formylmethionine in eubacteria or methionine in other organisms is the first amino acid incorporated into proteins. After protein synthesis is underway, however, the N-terminal Met of many proteins is either deformylated or removed from the polypeptide chain.

This concludes our in-depth look at each of the 20 essential amino acids. You can compare molecules and practice memorizing the names, abbreviations and structures of the amino acids by using the flash cards.