Non-ribosomal peptide synthesis: why Glutathione cannot be produced by the ribosome?

Question

**Case**: I am writing a summary for a class in protein structure and function, and was asked to describe some different ways that peptides are synthesized (that does not involve the ribosome). I understand that glutathione is a tri-peptide consisting of L-cystine with a "gamma" bond to L-glycine which is then bound to glutamic acid.**Problem**: Why is it that the ribosome cannot produce this peptide? What is special about the peptide-gamma-bond?**My reasoning:** The peptide is too short, meaning that the large ribosome complex cannot bind to mRNA of this length as it need many different binding spots in order for the large and small subunit to come together. Also, the "gamma" bond is very special, and the ribosome can only produce peptides with the "Standard" peptide bonds.- Is this correct, and is there something else I am missing? - Does the "gamma" bond relate to the fact the glutathione is not that easily degraded by peptidases in the cytosol?

Answer 1

I am not sure your reasoning concerning the mRNA is correct, since mRNAs can contain non-translated regulatory regions. A better but potentially still flawed argument might be that glutathione does not contain the an N terminal methionine (however, consider that a protease could theoretically be used to cleave a methionine). You are correct in your reasoning that the gamma peptide bond is the main reason why a ribosome could not synthesize glutathione. Recall that a gamma peptide bond refers to a bond between a carboxyl group and an amino group. Since ribosomes exclusively synthesize peptide bonds between the hydroxyl group and the amino group of amino acids, they would be unable to synthesize glutathione. As for stability, consider what sites proteases generally cleave, and whether or not glutathione has those sites.