The tryptophan in your Thanksgiving turkey was not made by the turkey, it was made by tryptophan synthase, an enzyme found only in microbes and plants. The beta-subunit of tryptophan synthase catalyzes the condensation reaction of indole with L-serine to give L-tryptophan. In 1984, I discovered that oxindolyl-L-alanine (OIA), an oxidation product of L-tryptophan, is a potent competitive inhibitor of tryptophan synthase that binds about 10-fold more tightly than L-tryptophan (1). However, OIA exists as a mixture of diastereoisomers, and it was not known which isomer is the inhibitory one, since they rapidly interconvert in aqueous solution. We have now obtained the X-ray crystal structure of OIA bound to tryptophan synthase, and the structure shows clearly that (3S)-oxindolyl-L-alanine is the inhibitory isomer bound covalently to the pyridoxal-5’-phosphate cofactor (2). This result suggests that the reaction mechanism of tryptophan synthase proceeds via a (3S)-indolenine intermediate. Phillips, R. S., Miles, E. W. and Cohen, L. A. (1984) Interactions of tryptophan synthase, tryptophanase, and pyridoxal phosphate with oxindolyl-L-alanine and 2,3-dihydro-L-tryptophan: Support for an indolenine intermediate in tryptophan metabolism, Biochemistry 23, 6228-6234. Phillips, R. S., and Harris, A. P. (2020) Structural basis of the stereochemistry of inhibition of tryptophan synthase by tryptophan and derivatives, Biochemistry, revision submitted.
