IDEAS home Printed from https://ideas.repec.org/a/nat/nature/v566y2019i7742d10.1038_s41586-019-0894-z.html
   My bibliography  Save this article

An N-nitrosating metalloenzyme constructs the pharmacophore of streptozotocin

Author

Listed:
  • Tai L. Ng

    (Harvard University)

  • Roman Rohac

    (The Pennsylvania State University)

  • Andrew J. Mitchell

    (The Pennsylvania State University)

  • Amie K. Boal

    (The Pennsylvania State University
    The Pennsylvania State University)

  • Emily P. Balskus

    (Harvard University)

Abstract

Small molecules containing the N-nitroso group, such as the bacterial natural product streptozotocin, are prominent carcinogens1,2 and important cancer chemotherapeutics3,4. 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 Nω-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.

Suggested Citation

  • Tai L. Ng & Roman Rohac & Andrew J. Mitchell & Amie K. Boal & Emily P. Balskus, 2019. "An N-nitrosating metalloenzyme constructs the pharmacophore of streptozotocin," Nature, Nature, vol. 566(7742), pages 94-99, February.
  • Handle: RePEc:nat:nature:v:566:y:2019:i:7742:d:10.1038_s41586-019-0894-z
    DOI: 10.1038/s41586-019-0894-z
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41586-019-0894-z
    File Function: Abstract
    Download Restriction: Access to the full text of the articles in this series is restricted.

    File URL: https://libkey.io/10.1038/s41586-019-0894-z?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    As the access to this document is restricted, you may want to search for a different version of it.

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Elwood A. Mullins & Jonathan Dorival & Gong-Li Tang & Dale L. Boger & Brandt F. Eichman, 2021. "Structural evolution of a DNA repair self-resistance mechanism targeting genotoxic secondary metabolites," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    2. Hao Li & Jian-Wen Huang & Longhai Dai & Haibin Zheng & Si Dai & Qishan Zhang & Licheng Yao & Yunyun Yang & Yu Yang & Jian Min & Rey-Ting Guo & Chun-Chi Chen, 2023. "The structural and functional investigation into an unusual nitrile synthase," Nature Communications, Nature, vol. 14(1), pages 1-9, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:nature:v:566:y:2019:i:7742:d:10.1038_s41586-019-0894-z. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.