P118: The unusual biosynthetic origins of lymphostin and the ammosamides, pyrroloquinoline alkaloids derived from marine bacteria

The pyrroloquinoline alkaloids are a diverse class of biologically active secondary metabolites produced by a wide range of organisms.  Little is known about pyrroloquinoline alkaloid biosynthesis, beyond speculation that the heterocyclic core derives from a tryptophan precursor.  Through bioinformatics, heterologous expression and genetic manipulations we have interrogated the biosynthetic gene clusters for the marine bacteria derived antitumor compounds ammosamides A and B, and the immunosuppressant lymphostin.  These studies have begun to reveal that these seemingly simple small molecule metabolites derive from a highly unusual biosynthetic process that begins with a tryptophan embedded ribosomal peptide, which undergoes extensive remodeling by posttranslational processing enzymes encoded within the biosynthetic gene cluster. This unusual mechanism may prove to be general for many pyrroloquinoline alkaloids and expands our basic understanding of the chemical diversity afforded through the ribosome.