Download MendeleyAn N-nitrosating metalloenzyme constructs the pharmacophore of streptozotocin.
Ng, T.L., Rohac, R., Mitchell, A.J., Boal, A.K., Balskus, E.P.(2019) Nature 566: 94-99
- PubMed: 30728519
- DOI: https://doi.org/10.1038/s41586-019-0894-z
- Primary Citation of Related Structures:
6M9R, 6M9S - PubMed Abstract:
Small molecules containing the N-nitroso group, such as the bacterial natural product streptozotocin, are prominent carcinogens 1,2 and important cancer chemotherapeutics 3,4 . Despite the considerable importance of this functional group to human health, enzymes dedicated to the assembly of the N-nitroso unit have not been identified. Here we show that SznF, a metalloenzyme from the biosynthesis of streptozotocin, catalyses an oxidative rearrangement of the guanidine group of N ω -methyl-L-arginine to generate an N-nitrosourea product. Structural characterization and mutagenesis of SznF reveal two separate active sites that promote distinct steps in this transformation using different iron-containing metallocofactors. This biosynthetic reaction, which has little precedent in enzymology or organic synthesis, expands the catalytic capabilities of non-haem-iron-dependent enzymes to include N-N bond formation. We find that biosynthetic gene clusters that encode SznF homologues are widely distributed among bacteria-including environmental organisms, plant symbionts and human pathogens-which suggests an unexpectedly diverse and uncharacterized microbial reservoir of bioactive N-nitroso metabolites.
Organizational Affiliation:
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA.
