Zinc is the modulator of the calcium-dependent activation of post-translationally acting thiol-enzymes in autoimmune diseases.

UNLABELLED: Post-translational modifications of proteins can generate antigenic conformations that may cause autoimmune diseases in persons with specific HLA-haplotypes. Monocytes and macrophages, attracted to an inflamed site, can release post-translationally acting enzymes, such as transglutaminases and peptidylarginine deiminases. In vivo, the activation of these enzymes is crucial for the further course of event. Our hypothesis is that zinc modulates the activation of these calcium-dependent thiol-enzymes. Persons with celiac disease carry antibodies against deamidated dietary gluten and against transglutaminase type 2. Similarly, antibodies against citrulline-containing peptides and against peptidylarginine deiminase are detected in patients with rheumatoid arthritis. Thus, in two major autoimmune diseases, antibodies are detected against post-translationally modified proteins and against the thiol-enzymes responsible for catalyzing the modifications. In vitro, physiological concentrations of zinc reversibly inhibit the calcium-dependent activation of transglutaminases. Zinc attenuates the calcium-induced increase in affinity between transglutaminase 2 and serum from patients with celiac disease. Peptidylarginine deiminases are also inhibited by zinc. Moreover, zinc is rapidly redistributed in animals when an infection is induced. This pathway starting with an unspecific inflammation and ending up with an immune reaction against a specific tissue constitutes a theme with variations in other autoimmune diseases, such as dermatitis herpetiformis, multiple sclerosis, and type 1 diabetes. Inhibitors against transglutaminases and peptidylarginine deiminases have a great pharmacological potential. Interestingly, a large portion of the population may have been exposed to such an inhibitor. The primary metabolite of ethanol, acetaldehyde, can probably function as an irreversible inhibitor of these enzymes by forming a hemithioacetal with the thiol group of the active site. Not surprisingly, epidemiological studies have shown that alcohol is beneficial in rheumatoid arthritis. We predict that a similar situation will be observed in multiple sclerosis. The affinity of chelators such as EDTA and EGTA for Zn(2+) is three orders of magnitude greater than that for Ca(2+). This frequently overlooked complication imposes problems in biomedical research since a restoration of the zinc level can never be achieved in a blood sample which has been anti-coagulated by calcium chelators. The new synthetic direct thrombin inhibitors may offer a better way of preventing coagulation in vitro.

CONCLUSIONS: Post-translational modifications are of potential interest in autoimmune diseases. The in vivo activation of calcium-dependent thiol-enzymes catalyzing these alterations, such as the transglutaminases and the peptidylarginine deiminases, is crucial for this pathway. According to our hypothesis, zinc is the modulator of this key function.