Welcome to the Alanine World! Computational design takes over! Painting protein translation blue

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Believe it or not, but this was the first amino acid ever discovered by chemists.* Cysteine is most famous for the disulfide bridges it creates. Oxidative conditions allow proximal cysteine residues to form S-S bond, thus ensuring a more stable fold. A classic example is human insulin, where a disulfide bond links together the A- and B-chains making a dimer structure. Linkage to cysteine is also an easiest way to link non-native chemical moieties to a protein. This can be done simply by adding an excess of a thiol reagent that bears the function of interest.

Was disulfide bond the original reason, why cysteine was recruited to the genetic code? Most probably, not. Consider that originally the conditions on the planet were reductive until the great oxygenation event happened after the emergence of photosystem II around 2.5 billion years ago. In the genetic code formation phase the conditions were reductive, therefore disulfide bridges would hardly be possible.

But what’s about metal coordination? Cysteine has the best metal coordinating side chain, especially for transition metals. For example, iron-sulfur clusters are coordinated by cysteines side-chains to form very stable protein-cluster complexes, while other side-chains are involved into a loose coordination to form permissive sites.

One can easily speculate that cysteine-transition metal and direct cysteine-iron complexes played important role under the reductive conditions of the initial life evolution process. Importantly, it is a well-known fact that pre-oxygenated oceans contained a fairly high concentration of dissolved iron (II). Thus, Cys-Fe coupling was probably inevitable, and there are many uses one can imagine for this motif.

Other than this, cysteine is involved in numerous post-translational modification processes, for example, formation of lantionine (thioether bridge) with a dehydroalanine counterpart, or backbone cyclization into a thiazole and more. Glutathione, the second most abundant metabolite in E. coli (after glutamate being the 1st), contains cysteine residue and this maintains the redox potential in the cells. Therefore, after the biosynthesis, a large amount of cysteine is directed towards glutathione synthesis, especially under oxidative stress conditions.

Last fun fact about cysteine, this is the only (R)-amino acid in the canonical repertoire. Below is the figure, which illustrates this. Usually, carboxyl-group has a higher priority than a side chain moiety, because there are three oxygen atoms in the second layer. However, sulfur has a higher atomic number than oxygen, therefore, it swaps the priority, and this changes the name of the configuration:

Interesting readings:
  • Chalker. J. M., et al. Methods for converting cysteine to dehydroalanine on peptides and proteins. Chem. Sci., 2, 2011, 1666-1676, doi: 10.1039/C1SC00185J

    Convert cysteine to dehydroalanine and then attach whatever you want.

  • Maio, N. and Rouault, T. A. Iron–sulfur cluster biogenesis in mammalian cells: New insights into the molecular mechanisms of cluster delivery. Biochim. Biophys. Acta, 1853, 2015, 1493-1512, doi: 10.1016/j.bbamcr.2014.09.009

    A recent review about the iron-sulfur clusters.

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