IsoleucineIsoleucine is among the most neglected amino acids in the genetic code repertoire. Often people say: why there is iso-leucine, when there is alsready leucine, isn’t isomeric amino acid obsolete? We certainly cannot agree with this kind of argument, and here is why. Isoleicine and leucine are common names for the amino acids, but these are not what is called systematic names. Systematic names are usually given in organic chemistry in order to designate a chemical structure with its unique and unambiguous textual equivalent. According to these rules isoleucine should be called (2S,3S)-2-amino-3-methylpentanoic acid, whereas leucine’s name will be (2S)-2-amino-4-methylpentanoic acid. Both structures have almost identical names; although they are actually isomeric to each other, there is no more ‘iso’, both names are just different. It is thus fully ambiguous which amino acid is considered the ‘original’, and which one is the ‘other isomer’. We could also say, that isoleucine is isoisoleucine.
In fact, both amino acids have equal rights to be fully competent in fulfilling usual tasks of hydrophobic amino acids: cause hydrophobic collapse in globular proteins, and form hydrophobic exterior of membrane immersed sections in membrane proteins.
Let’s look at another example. There are two main toxins from death cap mushroom, amanitin and phalloidin. Both are bicyclic short peptides with very similar type of structures. There is one interesting difference though. Phalloidin structure has dihydroxy-leucine as one of the residues, while amanitin has dihydroxy-iso-leucine. These peptides are very nasty toxins, which cause much troubles for people and animals, who get poisoned by this deadly mushroom. There is derivative of one amino acid in one case, and another - in the other. Interestingly, it has been found that dihydroxy-leucine moiety is not very critical in the activity mode of phalloidin toxin, whereas the dihydroxy-iso-leucine is involved in the mode of action of amanitin.
This example illustrates how nature manipulates with these amino acid residues in order to create desired activity and selectivity of the specific natural products. Leucine and isoleucine are both important, and their choice in one or another structural context can have a difference in fine tuning of the interaction with the surrounding. After all, we should face the fact that almost all types of side-chain functions are not unique: there are two positively charged amino acids (Arg, Lys), negatively charged - also two (Asp, Glu), aromatic - three (Phe, Tyr, Trp), two - with hydroxyl-groups (Ser, Thr), two amides (Asn, Gln) etc. Thus, it should not surprise us that there are few aliphatic hydrophobic amino acids in the genetic code set.
There is no general rule, how to choose between Leu and Ile for better performance in a protein structure. However, there are arguments which indicate that Leu may be slightly better hydrophobic amino acid for making hydrophobic face in water-exposed -helices, whereas, Ile - may be slightly better doing the same job in lipid-exposed transmembrane helices. This is due to the fact that Ile side-chain is closed to the backbone, and may shield it better from the lipid. In contrast, Leu has a better -helical propensity in water, and there it may be critical for the stability of the helix.
Another peculiarity of isoleucine is the fact that the amino acid has a second chiral center, a chiral center in the side chain. Hydrophobic surfaces formed by isoleucine should be highly chiral. Perhaps, in the future, we’ll get more information, how to make use of this feature.
- Deber, C. M. and Stone, T. A. Relative role(s) of leucine versus isoleucine in the folding of membrane proteins. Peptide Sci., 111, 2019, e24075, doi: 10.1002/pep2.24075
- Li, S.-C. and Deber, C. M. A measure of helical propensity for amino acids in membrane environments. Nat. Struct. Mol. Biol., 1, 1994, 368-373, doi: 10.1038/nsb0694-368
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