Isopeptide bond

An isopeptide bond is an amide bond that is not present on the main chain of a protein. The bond forms between the carboxyl terminus of one protein and the amino group of a lysine residue on another (target) protein.

Isopeptide bonds can occur between the side chain amine of lysine (as one example lysine is not the only one) and the side chain carboxyl groups of either glutamate or aspartate. Bond formation can be either enzyme catalyzed, as in the case for the bond formed between lysine and glutamine catalyzed by transglutaminases, or it can form spontaneously as observed in HK97 bacteriophage capsid formation and Gram-positive bacterial pili. Spontaneous isopeptide bond formation requires the presence of another residue, glutamic acid, which catalyzes bond formation in a proximity induced manner.

An example of a small peptide containing an isopeptide bond is glutathione, which has a bond between the side chain of a glutamate residue and the amino group of a cysteine residue. An example of a protein involved in isopeptide bonding is ubiquitin, which gets attached to other proteins with a bond between the C-terminal glycine residue of ubiquitin and a lysine side chain of the substrate protein.

The function of enzyme generated isopeptide bonds can be roughly divided into two separate categories; signaling and structure. In the case of the former these can be a wide range of functions, influencing protein function, chromatin condensation, or protein half-life. With regard to the latter category, isopeptides can play a role in a variety of structural aspects, from helping to form the clots in wound healing, roles in extra cellular matrix upkeep & apoptosis pathway, roles in the formation of pathogenic pilin, restructuring of the actin skeleton of a host cell to help in the pathogenecity of V. cholerae, and modifying the properties micro-tubilin to influence its role in the structure of a cell.

The chemistry involved in the formation of these isopeptide bonds also tend to fall into these two categories. In the case of ubiquitin and ubiquitin-like proteins, tend to have a structured pathway of continuously passing along the peptide with a series of reactions, using multiple intermediate enzymes to reach the target protein for the conjugation reaction. The structural enzymes while varying from bacterial and eukaryotic domains, tend to be single enzymes that generally in a single step, fuse the two substrates together for a larger repetitive process of linking and inter-linking the said substrates to form and influence large macromolecular structures.

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