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If polypeptides are synthesized by acid-base reactions between the carboxyl group of one amino acid and the amine group of another amino acid, what stops the formation of a peptide bond between the alpha amine group of one amino acid and the carboxyl group (that's in the side chain) of another amino acid?

For example, why doesn't the side chain of glutamic acid bond to the alpha amine of another amino acid (essentially creating a new branch at which polypeptide synthesis can occur)?

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  • $\begingroup$ It can happen, but it's hardly the norm. See, for example, glutathione. As you may anticipate this reaction is catalysed by a different enzyme, not the ribosome. $\endgroup$ – orthocresol Mar 7 '17 at 18:14
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Chemically

If you were making a small polypeptide you'd have a protecting group on the side-chain of glutamic acid, and preferably also an activating group on the carboxyl where you want to attach it. If you're just mixing glutamate with another amino acid you'll get a mixture as you expect (including all kinds of possible oligomers).

Biologically

Protein synthesis in the ribosome actually works the other way around (the amine-end is in the ribosome, tRNAs are attached to residues at the carboxyl side). So your expected error would be the continuation of protein synthesis at another alpha amine: the lysine sidechain. Apparently the ribosome is quite good at distinguishing this 4-carbon difference.

My 2 minute hypothesis is that this is one of the reasons why there are residues with shorter acid sidechains (glutamate and aspartate) while a shorter version of lysine is not used in biological protein synthesis.

How the tRNA synthases are so specific that they don't load the amino acid with the wrong carboxyl group is a different question, but tRNAs are extremely specific enzymes in many ways (they have no problem recognizing the difference between a methyl and a hydroxyl group).

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