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Peptide bonds are formed as such: img

Aspartic acid, glutamic acid and lysine all contain either one extra $\ce{-COOH}$ or $\ce{-NH2}$ group in them. Why does that extra group not participate in peptide bond formation? For reference, the structure are given below:

enter image description here enter image description here enter image description here

It should be possible for the $\ce{-COOH}$ group attached to $\ce{C}$3 in aspartic acid and $\ce{C}$4 in Glutamic acid to form a peptide bond with $\ce{-NH2}$ of another amino acid. Do these bonds occur in any peptide linkage? If they do, what is the nomenclature associated with them and how do their chemical properties differ?

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Equilibrium in aqueous solution

In aqueous solution (such as our digestive tract), the equilibrium of the reaction as written is on the side of the reactants. Digestive enzymes catalyze the hydrolysis of peptide bonds, showing that they are not thermodynamically stable in water. However, in the absence of catalysts at neutral $\mathrm{pH}$, the peptide bond is very stable against hydrolysis, explaining how it is possible for proteins to fulfill their biological role.

Peptide formation in the cell

In the cell, amino acids form a mixed phosphoric acid anhydride by reacting with ATP, which then reacts with hydroxyl groups of tRNA to form an ester. This ester reacts with the growing peptide chain, catalyzed by ribosomes using mRNA as a template to make a specific polypeptide rather than a random one. All steps are enzyme-catalyzed, ensuring that only the main chain carboxylate reacts while the side chain carboxylate does not.

Peptide solid state synthesis

In a peptide synthesizer, amino acid building blocks start out as esters and amides with suitable protecting groups on the side chains. Only when the entire polypeptide has been synthesized are the side chain protecting groups removed. Below is a schematic of the process:

enter image description here

Source: https://www.biosyn.com/images/userfiles/image/general-scheme-solid-phase.jpg

Why does that extra group not participate in peptide bond formation?

It depends on the context but it does not react because

  • it is not activated (carboxylic acid in water does not form amide)

  • it is protected

  • enzymes are selective for specific functional groups on a molecule

It should be possible for the $\ce{-COOH}$ group attached to $\ce{C}$3 in aspartic acid and $\ce{C}$4 in Glutamic acid to form a peptide bond with $\ce{−NH2}$ of another amino acid. Do these bonds occur in any peptide linkage? If they do, what is the nomenclature associated with them and how do their chemical properties differ?

For side chains with amino groups, there are cases of peptide formation, for example in ubiquitination reactions where the protein ubiquitin is attached to a lysine via its carboxy-terminus. Other side chains are glycosylated, methylated, or attached to lipids. Together, these reactions are described as post-translational modifications. There is a report of glutamate methylation (https://www.ncbi.nlm.nih.gov/pubmed/16707700).

Some cyclic peptide antibiotics form peptide bonds with the glutamate side chain called gamma peptides (instead of alpha peptides). Here is an example:

enter image description here

Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1176672/?page=7

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    $\begingroup$ Actually, as far as I am aware the amide bond is the ‘bottom of the thermodynamic well’, i.e. the most stable possible carboxyl derivative. Digestive enzymes (as all enzymes) have a couple of tricks to influence kinetics and make the reaction work. $\endgroup$ – Jan Dec 17 '19 at 13:56
  • $\begingroup$ @Jan Yes, that is why reactions from anhydride to amide (or from amide to carboxylate) work without being coupled to the hydrolysis of ATP or some other source of free energy. $\endgroup$ – Karsten Theis Dec 17 '19 at 14:22
  • $\begingroup$ Let me rephrase that: afaik, the equilibrium $\ce{RCO-NHR' + H2O<=>RCOOH + H2NR'}$ favours the reactant side thermodynamically at neutral pH which would be in contradiction to your first paragraph. $\endgroup$ – Jan Dec 17 '19 at 14:27
  • $\begingroup$ @Jan That depends on the concentration of water (just like esters). If you run this in organic solvent, reactants may be favored, certainly when you continuously remove the water. With water as a solvent, the products are favored (enzymes can't change the equilibrium constant, and there is no ATP in the digestive tract for a coupled reaction - we would be unable to digest protein if the products weren't favored). $\endgroup$ – Karsten Theis Dec 17 '19 at 14:39
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Regarding the second question, post-translational modification is not the only way. https://en.wikipedia.org/wiki/Isopeptide_bond, and the references therein, answer your questions quite nicely. These are relatively uncommon (compared to the usual peptide bond) because enzymes are capable of exerting control over which carboxylic acid / amine reacts: you will see that the example given, glutathione, requires (different) specialised enzymes to make and to break the isopeptide bond. But it is still sufficiently common that you should not be too surprised to see it.

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  • $\begingroup$ Thank you very much for the reference. Will read more on these bonds. $\endgroup$ – Aniruddha Deb Dec 18 '19 at 3:17

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