An N-nitrosating metalloenzyme constructs the pharmacophore of streptozotocin

Ng, Tai L.; Rohac, Roman; Mitchell, Andrew J.; Boal, Amie K.; Balskus, Emily P.

doi:10.1038/s41586-019-0894-z

Title: An N-nitrosating metalloenzyme constructs the pharmacophore of streptozotocin

Journal Article · 06 February 2019 · Nature (London)

DOI: https://doi.org/10.1038/s41586-019-0894-z · OSTI ID:1497172

Ng, Tai L. ^[1]; Rohac, Roman ^[2]; Mitchell, Andrew J. ^[2]; Boal, Amie K. ^[2]; Balskus, Emily P. ^[1]

Harvard Univ., Cambridge, MA (United States)
Pennsylvania State Univ., University Park, PA (United States)

Small molecules containing the N-nitroso group, such as the bacterial natural product streptozotocin, are prominent carcinogens and important cancer chemotherapeutics. 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. In this work, 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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: Camille Dreyfus Teacher-Scholar Award; Cottrell Scholar Award; Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor; National Cancer Institute (NCI); National Institute of General Medical Sciences (NIGMS); National Institutes of Health (NIH); Searle Scholars Program; USDOE Office of Science (SC)

OSTI ID:: 1497172

Journal Information:: Nature (London), Journal Name: Nature (London) Journal Issue: 7742 Vol. 566; ISSN 0028-0836

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Genomics‐Driven Discovery of NO‐Donating Diazeniumdiolate Siderophores in Diverse Plant‐Associated Bacteria Hermenau, Ron; Mehl, Jule L.; Ishida, Keishi Angewandte Chemie International Edition, Vol. 58, Issue 37 https://doi.org/10.1002/anie.201906326	journal	August 2019
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