Structure and function of the geldanamycin amide synthase from Streptomyces hygroscopicus

Abstract

Amide synthases catalyze the formation of macrolactam rings from aniline-containing polyketide-derived seco-acids as found in the important class of ansamycin antibiotics. One of these structurally and functionally hitherto undescribed amide synthases is the geldanamycin amide synthase ShGdmF, which we isolated for the first time and studied in detail both functionally as well as structurally. Here we show that purified ShGdmF catalyzes the amide formation using synthetically derived simplified substrates. The atomic structures of the apo enzyme and in complex with simplified substrates reveal distinct structural features of the substrate binding site and a putative role of the flexible interdomain region for the catalysis reaction.