Many biologically important molecules exist as tautomer pairs, in which the major tautomer (tantotautomer) is so favored energetically over the minor tautomer (tenutautomer) that the latter species cannot even be detected by any spectroscopic means in the equilibrium mixture. 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 living systems, namely, that the tenutautomers of various metabolites may be the """"""""true"""""""" ligands for some enzymes and receptors. This theory leads to the critical consequence that potential inhibitors and antagonists should be designed as analogues of thE tenutautomers, not of the tantotautomers as is common practice. Our first effort to support the theory has met with highly gratifying success. Stable analogues of the indolenine tenutautomer of tryptophan with a tetrahedral carbon at C-3, 2,3-dihydro-L-tryptophan, oxindolyl-L-alanine and dioxindolyl-Lalanine, are potent competitive inhibitors of tryptophan synthase and tryptophanase, enzymes involved in the biosynthesis and degradation of tryptophan. Furthermore, the two enzymes show """"""""mirror-image"""""""" specificity, in that the 3R diastereoisomer of the analogues inhibits only tryptophanase while the 3S diastereoisomer inhibits only tryptophan synthase. The diastereoisomers of 3-azido-oxindolyl-L-alanine have been prepared as potential specific photoaffinity labels for these enzymes. A similar approach is now being used with tyrosine phenol-lyase: methods have been developed to synthesize stable p-dienone analogues of tyrosine and these analogues will soon be evaluated with the enzyme.
