A large variety of metabolically important molecules exist as pairs of tautomers, in which the major tautomer (Tantotautomer) is so favored energetically over the minor tautomer (Tenutautomer) that the latter species cannot even be detected in the equilibrium mixture by any available spectroscopic means. Nevertheless, mechanistic studies have revealed that the tenutautomer is very often the "true" reactant in various chemical transformations. We have proposed that the same phenomenon may exist in biological systems, namely, that the tenutautomers of various metabolite may be the "true" ligands for some enzymes and receptors. This theory provides a new pathway for substrate activation; it also leads to the critical consequence that potential inhibitors and drugs should be designed as analogues of the tenutautomers, rather than the standard practice of mimicking the tantotautomers. We were very successful in using this approach in designing inhibitors of tryptophan synthase and tryptophanase, and are now applying the principle to indole- 2,3-dioxygenase. Some years ago, we discovered a synthetic route to the p-hydroxydienone analogue of tyrosine by electrolytic oxidation. Unfortunately, this compound is rather unstable, and we have been exploring routes to more stable analogues of the dienone tautomer of tyrosine. Several stable dienones have been synthesized and are being tested as inhibitors of tyrosine-phenol lyase. Even more important applications of the principle involve the synthesis and testing of dienone analogues of the catecholamines and dihydroxyphenylalanine; the synthesis of such analogues presents a novel and unprecedented challenge. Studies have also been initiated to explore the synthesis of stable CH tautomers of histidine and histamine, for which we have already established a role in test-tube reactions and which we believe to be the true substrates in certain enzymatic processes. Recent results with histidine-ammonia lyase confirm our proposal for the involvement of a histidine CH-tautomer as the "true" substrate for this enzyme.