Transglutaminase-mediated cross-linking of proteins and cell ageing: the erythrocyte and lens models.

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The illustration in Fig. 1, reproduced from a publication of Heinrich Waelsch in 19621, might be the best starting point for discussing the biological functions of transglutaminases. Waelsch, the discoverer of this interesting family of protein-remodelling enzymes, was clearly aware of the possibility — which is the main topic of my presentation — that they may be involved in the cross-linking of proteins by Ne-(γ-glutamyl) lysine bridges, marked as reaction (3) in Fig. 1. For lack of an adequate test system, however, he was unable to prove this hypothesis. Rather, he focused on reaction (1), i.e. the incorporation of naturally occurring and synthetic amines into proteins, and devoted particular attention to the coupling of histamine to proteins in endotoxin-related biological phenomena. He theorized that the transglutaminase-mediated incorporation of amines “could produce modified body proteins which might interfere with enzymatic activities.....or might possess antigenic properties”2. The latter suggestion gains some support from the high incidence of autoimmune diseases following treatment with isoniazid and hydralazine, two drugs which — similarly to histamine — can serve as amine substrates for transglutaminases3,4. An enzymatic, “hit and run” type of accidental modification of proteins by drugs such as these could conceivably provoke a breakdown of immune tolerance against the parent protein itself.