We summarize the currently available information regarding the state of ionization and tautomerization of the 4¢-aminopyrimidine ring of the thia-mine diphosphate on enzymes requiring this coenzyme. This coenzyme forms a series of covalent intermediates with its substrates as an electro-philic catalyst, and the coenzyme itself also carries out intramolecular pro-ton transfers, which is virtually unprecedented in coenzyme chemistry.