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There are 'acidic' and 'basic' amino acids like aspartate and histidine.

When protein is synthesized with those amino acids, what ensures that the to-be-assembled amino acids will not bond to the amine groups or acidic groups in the functional groups of the amino acids in the polypeptide?

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2 Answers 2

When the amino acid comes to the ribosome it is in the form of an aminoacyl tRNA in which the carboxyl group of the amino acid is esterified with the 3' OH group of the ribose moiety at the 3' end of the tRNA.

There is already a growing peptide bound in the P site of the ribosome with a free -COOH group which will react with the -NH2 group of the incoming amino acid in the A site to form the next peptide bond. This reaction takes place in the context of what is essentially an enzymic active site. The reactants will be held in the correct positions for catalysis to take place (in this case the catalysis is carried out by the ribozyme activity of the small ribosomal RNA).

So the answer is that the selectivity of this reaction is just another example of the way in which enzymes are able to carry out highly-specific reactions. So, for example, the enzyme hexokinase, which phosphorylates glucose at the 6 position has, potentially, four other -OH groups that, chemically speaking, could be phosphorylated.

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I think it does happen that peptide linkages can happen to side chains. For the reasons that @AlanBoyd lays out, this won't happen in conventional peptide synthesis and is in principle the answer to the question here.

To add a note though:

Non ribosomal peptide synthases can produce peptides with many subsequent unorthodox modifications. If you look at the structure of bacitracin, I believe the large ring is closed by condensation between a lysine amine and the carboxylate of the amino acid on the other end of the ring. There should be plenty of other examples.


So called secondary metabolism pathways create many diverse compounds - nearly anything seems to be possible.

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Yes, agreed. A classic example of this is the tripeptide glutathione, a key molecule in controlling redox potential in cells. Glutathione is gamma-glutamyl-cysteinyl-methionine. The bond between the Cys and the Met is a classical peptide bond, but the one between the Glu and the Cys involves the side chain (gamma) carboxyl group of the Glu. This is referred to as an isopeptide bond. But glutathione isn't made by ribosomes, it's made by specific enzymes, so it's the exception that proves the rule. –  Alan Boyd Oct 12 '13 at 16:02
thanks @AlanBoyd secondary metabolites are a corner case for sure but hopefully useful. –  shigeta Oct 12 '13 at 18:12
I think Glutathione is gamma-ECG, or gamma-glutamyl-cysteine-glycine –  TomD Oct 13 '13 at 14:31
@TomD thanks - was doing the answer from memory. Can't edit the original comment however. –  Alan Boyd Oct 19 '13 at 12:24

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