(A) Transglutaminase-catalyzed N^ε (γ-glutamyl)lysine isodipeptide formation: transglutaminases catalyze an acyl transfer reaction that proceeds by a Bi-Molecular or Ping-Pong mechanism. Activated transglutaminases first act to form a thioester bond between the active site Cys²⁷⁷ and the carboxamide moiety of glutaminyl residues. Formation of this intermediate involves the release of the amide nitrogen as ammonia, which powers the subsequent catalysis. The thioester bond then undergoes a nucleophilic attack by the ε amine of lysine to complete the acyl transfer and produce N^ε (γ-glutamyl)lysine isodipeptide linkage. These dipeptides can then be released from the protein by hydrolysis of the peptide linkages. (B) Oxidative inactivation of transglutaminase 2 by cystamine by the mechanism of Lorand and Conrad [46]: in this model, the thiol moiety of Cys²⁷⁷ participates in thiol-disulphide interchange with cystamine to produce cysteamine–Cys²⁷⁷ mixed disulphide. (C) Oxidative inactivation of transglutaminase 2 by cysteamine by our interpretation of the mechanism of Palanski and Khosla [48]: in this model, cystamine first forms mixed disulphides with Cys³⁷⁰ and Cys³⁷¹. Cys²³⁰ then undergoes thiol–disulphide interchange with cysteamine–Cys²³⁰ mixed disulphide. The newly reduced Cys³⁷¹ then reduces the mixed disulphide of cysteamine–Cys³⁷⁰ while being oxidized to the Cys³⁷⁰–Cys³⁷¹ disulphide. It is also possible that the Cys²³⁰ undergoes thiol–disulphide interchange with the cysteamine–Cys³⁷⁰ mixed disulphide rather than the cysteamine–Cys³⁷¹ mixed disulphide. In either case, the Cys³⁷⁰–Cys³⁷¹ disulphide would form and allosterically regulate the enzyme. (D) Thiol–disulphide interchange of cysteamine and cystine: cysteamine interacts with cystine by thiol–disulphide interchange to from the cysteamine–cysteine mixed disulphide. Note that the latter resembles the lysyl residue depicted in (A). (E) Transglutaminase-catalyzed N-(γ-glutamyl)cysteamine formation: a mechanism for the competitive inhibition of transglutaminase by cysteamine. This mechanism is analogous to that shown in (A) and for the sake of brevity begins with thioester bound intermediate. The thio–ester bond is attacked by the amine nitrogen of cysteamine to complete the acyl transfer and produce N-(γ-glutamyl)cysteamine. We propose that N-(γ-glutamyl)cysteamine is released from the protein by proteolysis, as is the case for other N-(γ-glutamyl)amines.