The Cremeomycin Biosynthetic Gene Cluster Encodes a Pathway for Diazo Formation.
Diazo groups are found in a range of natural products that possess potent biological activities. Despite longstanding interest in these metabolites, diazo group biosynthesis is not well understood, in part because of difficulties in identifying specific genes linked to diazo formation. Here we describe the discovery of the gene cluster that produces the o-diazoquinone natural product cremeomycin and its heterologous expression in Streptomyces lividans. We used stable isotope feeding experiments and in vitro characterization of biosynthetic enzymes to decipher the order of events in this pathway and establish that diazo construction involves late-stage N-N bond formation. This work represents the first successful production of a diazo-containing metabolite in a heterologous host, experimentally linking a set of genes with diazo formation.
Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA, 02138, USA.
Abraham J
AJ
Waldman
Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA, 02138, USA.
Yakov
Y
Pechersky
Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA, 02138, USA.
Peng
P
Wang
Small Molecule Mass Spectrometry Facility, Faculty of Arts and Sciences Division of Science, Harvard University, 52 Oxford Street, Cambridge, MA, 02138, USA.
Jennifer X
JX
Wang
Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA, 02138, USA. balskus@chemistry.harvard.edu.
Emily P
EP
Balskus
D001391:Azo Compounds / Q000737:chemistry / Q000378:metabolism*; D053898:Biosynthetic Pathways / Q000235:genetics*; D003512:Cyclohexanones / Q000737:chemistry / Q000378:metabolism; D015394:Molecular Structure; D005810:Multigene Family; D048170:Streptomyces lividans / Q000737:chemistry / Q000378:metabolism
D001391:Azo Compounds; D003512:Cyclohexanones; C094831:cremeomycin
biosynthesis; diazo compounds; enzymes; heterologous expression; natural products