Tryptophan synthase is a bifunctional α2β2 complex catalyzing the last two steps of L-tryptophan biosynthesis. The natural substrates of the α-subunit indole-3-glycerolphosphate and glyceraldehyde-3-phosphate, and the substrate analogs indole-3-propanolphosphate and DL-α-glycerol-3-phosphate are allosteric effectors of the β-subunit activity. It has been shown recently, that the indole-3-acetyl amino acids indole-3-acetylglycine and indole-3-acetyl-L-aspartic acid are both α-subunit inhibitors and β-subunit allosteric effectors, whereas indole-3-acetyl-L-valine is only an α-subunit inhibitor (Marabotti, A., Cozzini, P., and Mozzarelli, A. (2000) Biochim. Biophys. Acta 1476, 287-299). The crystal structures of tryptophan synthase complexed with indole-3-acetylglycine and indole-3-acetyl-L-aspartic acid show that both ligands bind to the active site such that the carboxylate moiety is positioned similarly as the phosphate group of the natural substrates. As a consequence, the residues of the α-active site that interact with the ligands are the same as observed in the indole 3-glycerolphosphate-enzyme complex. Ligand binding leads to closure of loop αL6 of the α-subunit, a key structural element of intersubunit communication. This is in keeping with the allosteric role played by these compounds. The structure of the enzyme complex with indole-3-acetyl-L-valine is quite different. Due to the hydrophobic lateral chain, this molecule adopts a new orientation in the α-active site. In this case, closure of loop αL6 is no longer observed, in agreement with its functioning only as an inhibitor of the α-subunit reaction.
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