Asparagine, Aspartate, Glutamine and Glutamate

There are four amino acids that are intrinsically linked by the similarity in their structures, and unsurprisingly, the stories behind their names are just as intertwined. I am of course referring to the compounds with the carboxylic acid and primary amide side chains: asparagine, aspartic acid, glutamine and glutamic acid.

Acid and amide structures

Asparagine

Asparagine was the first amino acid to be discovered, but it’s unclear if it was the first to be named. Asparagine was first reported in 1806 by the French chemists Vaquilin and Robiquet, who found a large number of crystals had formed in an extraction from asparagus shoots that they had left to stand.1 Robiquet commented that two of these crystals belonged to an as yet unknown substance, which he surmised from the shape and transparency of the crystals…and their flavour! I know this was over 200 years ago, and they’d got the stuff from asparagus, but the lab safety part of my brain is still horrified that a taste-test was pretty common practice.

However, in this report from 1806 the new compound is not given a name. The first use of the word ‘asparagine’, that we know of, comes from an analysis of the chemistry of asparagus roots by Pierre Louis Dulong in 1826.2 Dulong explains that one of his objectives had been to see if he could isolate the substance Vaquilin and Robiquet had found in the shoots, which “they had designated under the name of asparagine”. It seems that by 1826 this name was in reasonably common usage, and was clearly allocated by the discoverers, but the exact point in the previous 20 years that the name was decided upon is currently a mystery. The reason I find this noteworthy is that it throws into doubt the identity of the first amino acid to be named. Asparagine is one candidate, but the other is leucine. Leucine was discovered in 1819 and a year later was allocated its (initially provisional) name after the Greek word leukos, meaning ‘white’.3 Incidentally, anyone who has spent any time in an organic chemistry lab will tell you that naming a compound after the fact that it is a white powder is never going to be a sustainable system! Nevertheless, even without the original source for the naming of asparagine, I think we can safely say that the root of the word (weak pun very much intended) is ‘asparagus’.

Aspartic Acid

The year after Dulong’s delvings into asparagus roots, another French chemist, Auguste-Arthur Plisson, was busying himself disproving the work of a colleague. This other chemist had isolated a compound from the root of the marshmallow plant, believed it to be novel, given it a new name, and then Plisson showed that it was actually asparagine.4 After doing this he was left with a sample of asparagine, and what else was he going to do other than boil it up with lead hydroxide? From this he isolated a new, acidic compound, and noted the loss of ammonia during the reaction (and also the lack of flavour of the product). In one paper he rather helpfully described his rationale for naming the compound, and while I was unable to locate that particular paper, the paragraph in question was helpfully transcribed in a review.5 He initially considered assigning the name ‘l’acide asparagique’, which makes complete sense given it is an acid derived from asparagine. This would presumably have us calling it asparagic acid in English. However, he was concerned that this name would suggest that the compound occurred naturally; it would be another forty years before this amino acid was observed to be a component of proteins.5 Therefore, he decided that it would be better to adopt the name ‘l’acide asparartique’ to remind everyone that it was artificial in origin. Note the double ‘ar’ in this name, which isn’t present in the modern form: either it was decided that it was a bit of a mouthful, it was assumed to be a misprint, or it was transcribed incorrectly, but by 1842 (if not earlier, I haven’t researched this bit extensively) it was described as “l’acide aspartique”, with just the one ‘ar’.6

Glutamic Acid

While the story of asparagine and aspartic acid was very much a French one, the knowledge of glutamine and glutamic acid is of German origin. Glutamic acid, or ‘glutaminsäure’ as it is known in German, was discovered and named in 1866 by Karl Henrich Ritthausen.7,8 Within this word, ‘säure’ means acid in German, the ‘amin’ is presumed to refer to the compound being an amine, and the commonly stated etymology for ‘glut’ is that the compound was isolated from gluten, as obtained from wheat flour. However, my reading of Ritthausen’s work suggests that there may be a subtle error in the final part of this explanation.8

Ritthausen states that he gave the compound the name glutaminsäure “with regard to the material from which it is derived”.7 This material is described by the name “Kleber”. In modern German (i.e. according to Google Translate) ‘kleber’ mainly means glue but can also mean gluten…so far, so good. However, in a German dictionary from 1854 (which I was excited to discover was compiled by the Brothers Grimm) the definition of Kleber in the field of chemistry was given as “the gluey substance which, for example, remains in the preparation of starch from wheat flour”.9 Ritthausen separated various fractions from this ‘Kleber’ which included ‘mucedin’ and ‘glutenfibrin’, but the latter was only mentioned once in the paper, and this was to explain that he was unable to determine if glutamic acid was present in it due to a lack of sufficient material. He actually isolated glutamic acid from the ‘mucedin’ fraction.

The Latin word for glue, and therefore the Latin word for ‘Kleber’, is gluten. I therefore propose that Ritthausen did not name glutamic acid after gluten (the mixture of proteins found in wheat) but after gluten (the Latin word for glue) due to the gluey nature of the material he started with. I acknowledge that this is a petty distinction, especially as said gluey substance would almost certainly have contained actual gluten, and it is likely that the ‘mucedin’ fraction also contained gluten, but my aim here is to determine the original rationale for these etymologies and try to avoid applying a back-rationalisation biased by modern knowledge and word usage. Also, I’m a big fan of petty distinctions!

Glutamine

And finally: glutamine. Alongside tryptophan, glutamine was one of the two amino acids to be named before it was first isolated, and before it was first reported in 1883 its existence had been suspected for a number of years.5,10 The issue that led to the elusiveness of this compound was the way in which amino acids were being isolated from proteins at the time: acid hydrolysis. While this method successfully cleaved the amide bonds in the peptide backbones, it also had the habit of hydrolysing the amide bonds in the side chains of glutamine and asparagine, forming glutamic acid and aspartic acid. Luckily it was noticed that the acid hydrolysis of some proteins was accompanied by the evolution of ammonia.

A paper published by Hlasiwetz and Haberman in 1873 describes how the hydrolysis of casein with hydrochloric acid, in the presence of stannous chloride, yielded exclusively glutamic acid, aspartic acid, leucine, tyrosine, and ammonia.11 Equipped with the prior knowledge of the ammonia release that occurs when asparagine is hydrolysed to aspartic acid (‘asparagin’ and ‘asparaginsäure’ in German; they avoided retaining the ‘artificial’ artefact in their name for the acid), the two authors discuss the idea of “loosely bound nitrogen”, and an “NH2 group” that exits the compound when aspartic acid is formed. They suggest that this may also be true of glutamic acid, and thus propose the possible existence of a precursor of ‘glutaminsäure’, which they refer to by simple analogy as ‘glutamin’.

And thus the quartet was complete. It wasn’t until 1932, at Imperial College, that chemists were able to succesfully use enzymatic digestion to prove that asparagine and glutamine were actually present in polypeptides, without hydrolysing them to the acids in the process.13 And to this day, we’re still referring to one of the key molecules that we code for in our DNA with a name that’s supposed to imply it’s artificial: is it too late to switch to asparagic acid?

References

  1. Vauquelin & Robiquet. Découverte d’un nouveau principe végétal dans les Asperges (asparagus sativus. LINN.). Ann. Chim. 57, 88–93 (1806).
  2. Dulong. Analyse chimique de la racine d’asperge. J. Pharm. 12, 278–284 (1826).
  3. Braconnot, H. Sur la conversion des matieres animales en nouvelles substances par le moyen de l’acide sulfurique. Ann. Chim. Phys. 13, 113–125 (1820).
  4. Plisson, A. Sur l’Identite du Malate acide d’altheine avec l’Asparagine. Ann. Chim. Phys. 36, 175–184 (1827).
  5. Vickery, H. B. & Schmidt, C. L. A. The History of the Discovery of the Amino Acids. Chem. Rev. 9, 169–318 (1931).
  6. Liebig, J. Traité de chimie organique: Volume 2. https://books.google.fr/books?id=1uWKAzHORU8C. (1842).
  7. Werther, G. Ueber Glutaminsäure. J. für Prakt. Chemie 99, 6–7 (1866).
  8. Ritthausen, H. Ueber die Glutaminsäure. J. für Prakt. Chemie 99, 454–462 (1866).
  9. Grimm, J. & Grimm, W. Deutsches Worterbuch. Available at http://woerterbuchnetz.de/cgi-bin/WBNetz/wbgui_py?sigle=DWB&mode=Vernetzung&lemid=GK06739#XGK06739. (1854).
  10. Schulze, E. & Bosshard, E. Ueber das Glutamin. Berichte der Dtsch. Chem. Gesellschaft 16, 312–315 (1883).
  11. Hlasiwetz, H. & Habermann, J. Ueber die Proteinstoffe. J. für Prakt. Chemie 7, 397–412 (1873).
  12. Proust. Sur le Principe qui assaisonne les Fromages. Ann. Chim. Phys. 10, 29–49 (1819).
  13. 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. 26, 81–171 (1972).

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