Cysteine (and Cystine)

The “Cystine-Cysteine Problem” was a phrase used in 1972 by chroniclers of the history of the discovery of the amino acids to describe the puzzle surrounding these two species, and how they are incorporated into proteins.1 Cysteine is the name given the monomeric amino acid with a free thiol group, whereas cystine is the name used for the dimer, generated by the formation of a disulphide bond.

Historically, this was a difficult conundrum. When proteins were being hydrolysed in the 19th century to isolate the amino acid constituents, the propensity of cysteine to exist as dimers meant that it was the dimer that was most commonly isolated; any free cystine that was produced was often lost during the work-up, largely by bad luck.2 Following the first isolation of the monomer in 1884, it wasn’t until the 1950s that is became reasonably clear that it was in fact this species that was incorporated into proteins, and that disulphide bridges, within or between peptide chains, were formed afterwards.1

In fact, while I may default to thinking of cysteine as the ‘main’ species, with cystine perhaps being thought of “di-cysteine”, there are frequent references around the 1960s and 70s to cysteine as “half-cystine”.

Google Ngram trace of the use of the terms cystine, cysteine and half-cystine in the Google books archive by year published3

Nowadays I would suggest that the more pertinent “cystine-cysteine” problem is one of pronunciation. What idiot would give two such similar species near identical names that a practically impossible to distinguish when said out loud?! His name was Eugen Baumann, and other than his poor linguistic choices, it should be stated that he was very much not an idiot.4 But before getting to Baumann’s isolation of cysteine in 1884, let’s skip back to the discovery and naming of the dimer, cystine.

Cystine was first discovered by the English chemist William Hyde Wollaston in 1810, as the principal component of a new type of urinary calculus (stone in the urinary tract).5 Wollaston had samples of two calculi which did not match the properties of those he had previously studied, of which there appear to have been many (“I have omitted no opportunity of paying attention to any urinary concretions to which I could have access”…it’s good to have a hobby!).

Wollaston named the compound “cystic oxide”, and over 200 years later his reasoning, while not perfect based on our current understanding, is still so clear that it bears repeating verbatim:

“From the ready disposition of this substance to unite with both acids and alkalies, it would appear to be an oxide; and that it does, in fact, contain oxygen, is proved by the formation of carbonic acid in distillation. The quantity of oxygen present in the calculus is not, however, sufficient to give it acid properties, for it has no effect on paper coloured with litmus.
               I am therefore inclined to consider it an oxide; and since both the calculi that have yet been observed have been taken from the bladder, it may be convenient to give it the name of cystic oxide5

In this name, the word “cystic” is derived from the Greek word for the bladder, kustis.

By 1832 it appears that the French chemist Berzelius has taken it upon himself to rename this compound. He explains in the 1833 edition of his textbook that although cystic oxide resembles certain metallic oxides in terms of solubility, most organic compounds contain oxygen, so oxide is not an appropriate designation –  “so I took the liberty of changing the name proposed by this distinguished man”. With this, he provided us with the alternative name, cystine.2

By 1884, the idea that cystine was a dimer (or a “double molecule”) had already been suggested, and it was Baumann who managed to demonstrating this by reducing a sample of cystine to isolate the monomer.2,4  At this point the concept of disulphide bonds was already understood, so he correctly explained the relationship between these two compounds. He chose the name cysteine for this compound by the seemingly arbitrary addition of an e into the name (and putting an umlaut on the i, but that isn’t retained in English or in modern German):

“To denote the relationship of this substance to cystine, I call this reduction product of cystines: cysteine”.4

Great work. Well done. That’s not going to cause any confusion whatsoever!

References

1.          Bradford Vickery H. The History of the Discovery of the Amino Acids II. A Review of Amino Acids Described Since 1931 as Components of Native Proteins. Adv Protein Chem. 1972;26:81-171. doi:10.1016/S0065-3233(08)60140-0.

2.          Vickery HB, Schmidt CLA. The History of the Discovery of the Amino Acids. Chem Rev. 1931;9(2):169-318. doi:10.1021/cr60033a001.

3.          Google Ngram Viewer trace: cysteine, cystine, half-cystine. Available at https://books.google.com/ngrams/graph?content=cystine%2C+cysteine%2C+half-cystine&year_start=1800&year_end=2019&corpus=26&smoothing=3&direct_url=t1%3B%2Ccystine%3B%2Cc0%3B.t1%3B%2Cc.

4.          Baumann E. Ueber Cystin und Cystein. Zeitschrift für Physiol Chemie. 1884;8(4):299-305. doi:10.1515/bchm1.1884.8.4.299.

5.          Wollaston WH. On Cystic Oxide, a New Species of Urinary Calculus. Philos Trans R Soc London. 1810;100:223-230. doi:10.1098/rstl.1810.0015. URL:https://www.jstor.org/stable/107222

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google photo

You are commenting using your Google account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s