Menu

Close

Glutamic acid is a carrier for hydrazine during the biosyntheses of fosfazinomycin and kinamycin

Kwo-Kwang Abraham Wang, Tai L. Ng, Peng Wang, Zedu Huang, Emily P. Balskus, Wilfred van der Donk

Preprint posted on July 09, 2018 https://www.biorxiv.org/content/early/2018/07/09/365031

Adding rocket fuel to antibiotics – a new way hydrazine is incorporated into natural products.

Selected by Ellis O'Neill

Background

Nitrogen-nitrogen bonds are rare in nature but are found in certain very potent natural products, including the antibiotic valanimycin and streptozotocin, used in the treatment of cancer. The strategy for the formation of this hydrazine bond has been shown in a few cases to be the addition of the second nitrogen from nitrous acid onto a nitrogen on the nearly completed product, towards the end of biosynthesis. However, for many natural products we do not yet know the biosynthetic routes to their N-N bonds.

 

Overview

In this paper, the authors looked at the biosynthetic gene clusters for two totally unrelated natural products, fosfazinomycin and kinamycin, and noticed that they encode a similar set of five enzymes. They used extensive isotope labelling studies and feeding intermediates in the biosynthesis to demonstrate that both these natural products have a novel hydrazine donor. This is made via the addition of nitrous acid to aspartate, acetylation and then formation of glutamylhydrazine, as the donor. Various steps were performed in vitro to show the exact reaction carried out by each of these enzymes. The hydrazine is then transferred from the newly discovered donor onto hydroxyls of either the almost complete product, for kinamycin, or a building block arginine, for fosfazinomycin.

 

The hydrazine group is rare in nature and I was drawn to this paper because of the unusual chemistry. Understanding how nature can make these odd groups can allow us to modify known compounds to improve their efficacy, but it can also be used to perform reactions that are currently done using harsh chemicals.

 

Future Outlook

The chemistry carried out by these enzymes is very interesting and the structures of the proteins involved would provide great insight into how they perform these specific reactions. Searching for other gene clusters that contain these five enzymes, with the prediction that they are likely to add hydrazine, can be used to find new pathways that make N-N bond containing molecules. These hydrazine-transferring enzymes may represent an ingenious way of installing hydrazine moieties during chemical synthesis from relatively stable precursors. One way to realise this would be to screen many compounds, including known drugs, with these enzymes to see what products can be made. This would show the substrate specificity of the enzymes, which could then be engineered, and allow them to be used for specific biotransformations.

Further Reading

A review of hydrazine containing natural products

(https://www.sciencedirect.com/science/article/pii/S096808961400724X?via%3Dihub)

 

Posted on: 19th July 2018

Read preprint (No Ratings Yet)




  • Have your say

    Your email address will not be published. Required fields are marked *

    This site uses Akismet to reduce spam. Learn how your comment data is processed.

    Sign up to customise the site to your preferences and to receive alerts

    Register here

    Also in the biochemistry category:

    A DNA-based voltmeter for organelles

    Anand Saminathan, John Devany, Kavya S Pillai, et al.



    Selected by Robert Mahen

    Structures of the Otopetrin Proton Channels Otop1 and Otop3

    Kei Saotome, Bochuan Teng, Che Chun (Alex) Tsui, et al.



    Selected by David Wright

    Inactive USP14 and inactive UCHL5 cause accumulation of distinct ubiquitinated proteins in mammalian cells

    Jayashree Chadchankar, Victoria Korboukh, Peter Doig, et al.



    Selected by Mila Basic

    S-acylated Golga7b stabilises DHHC5 at the plasma membrane to regulate desmosome assembly and cell adhesion.

    Keith T Woodley, Mark O Collins



    Selected by Abagael Lasseigne

    3

    A complex containing lysine-acetylated actin inhibits the formin INF2

    Mu A, Tak Shun Fung, Arminja N. Kettenbach, et al.



    Selected by Laura McCormick

    1

    Super-resolution Molecular Map of Basal Foot Reveals Novel Cilium in Airway Multiciliated Cells

    Quynh Nguyen, Zhen Liu, Rashmi Nanjundappa, et al.



    Selected by Robert Mahen

    Atlas of Subcellular RNA Localization Revealed by APEX-seq

    Furqan M Fazal, Shuo Han, Pornchai Kaewsapsak, et al.

    AND

    Proximity RNA labeling by APEX-Seq Reveals the Organization of Translation Initiation Complexes and Repressive RNA Granules

    Alejandro Padron, Shintaro Iwasaki, Nicholas Ingolia



    Selected by Christian Bates

    Applications, Promises, and Pitfalls of Deep Learning for Fluorescence Image Reconstruction

    Chinmay Belthangady , Loic A. Royer



    Selected by Romain F. Laine

    Activation of intracellular transport by relieving KIF1C autoinhibition

    Nida Siddiqui, Alice Bachmann, Alexander J Zwetsloot, et al.



    Selected by Ben Craske, Thibault Legal and Toni McHugh

    1

    Reduced mitochondrial lipid oxidation leads to fat accumulation in myosteatosis

    Jonathan P Gumucio, Austin H Qasawa, Patrick J Ferrara, et al.



    Selected by Pablo Ranea Robles

    Integrated NMR and cryo-EM atomic-resolution structure determination of a half-megadalton enzyme complex

    Diego Gauto, Leandro Estrozi, Charles Schwieters, et al.



    Selected by Reid Alderson

    1

    Disrupting Transcriptional Feedback Yields an Escape-Resistant Antiviral

    Sonali Chaturvedi, Marie Wolf, Noam Vardi, et al.



    Selected by Pavithran Ravindran

    1

    Structure of a cytochrome-based bacterial nanowire

    David J Filman, Stephen F Marino, Joy E Ward, et al.



    Selected by Amberley Stephens

    Multi-color single molecule imaging uncovers extensive heterogeneity in mRNA decoding

    Sanne Boersma, Deepak Khuperkar, Bram M.P. Verhagen, et al.

    AND

    Live-cell single RNA imaging reveals bursts of translational frameshifting

    Kenneth R Lyon Jr, Luis U Aguilera, Tatsuya Morisaki, et al.



    Selected by Nicola Stevenson

    Retrieving High-Resolution Information from Disordered 2D Crystals by Single Particle Cryo-EM

    Ricardo Righetto, Nikhil Biyani, Julia Kowal, et al.



    Selected by David Wright

    Structural venomics: evolution of a complex chemical arsenal by massive duplication and neofunctionalization of a single ancestral fold

    Sandy Steffany Pineda, Yanni K-Y Chin, Eivind A.B. Undheim, et al.



    Selected by Tessa Sinnige

    Also in the molecular biology category:

    A DNA-based voltmeter for organelles

    Anand Saminathan, John Devany, Kavya S Pillai, et al.



    Selected by Robert Mahen

    Structures of the Otopetrin Proton Channels Otop1 and Otop3

    Kei Saotome, Bochuan Teng, Che Chun (Alex) Tsui, et al.



    Selected by David Wright

    Central spindle microtubules are strongly coupled to chromosomes during both anaphase A and anaphase B

    Che-Hang Yu, Stefanie Redemann, Hai-Yin Wu, et al.



    Selected by Federico Pelisch

    1

    Cell growth dilutes the cell cycle inhibitor Rb to trigger cell division

    Evgeny Zatulovskiy, Daniel F. Berenson, Benjamin R. Topacio, et al.



    Selected by Zaki Ahmad

    1

    Distinct ROPGEFs successively drive polarization and outgrowth of root hairs

    Philipp Denninger, Anna Reichelt, Vanessa Aphaia Fiona Schmidt, et al.



    Selected by Marc Somssich

    Inactive USP14 and inactive UCHL5 cause accumulation of distinct ubiquitinated proteins in mammalian cells

    Jayashree Chadchankar, Victoria Korboukh, Peter Doig, et al.



    Selected by Mila Basic

    Bacteriophage resistance alters antibiotic mediated intestinal expansion of enterococci

    Anushila Chatterjee, Cydney N Johnson, Phat Luong, et al.



    Selected by Yasmin Lau

    On-site ribosome remodeling by locally synthesized ribosomal proteins in axons

    Toshiaki Shigeoka, Max Koppers, Hovy Ho-Wai Wong, et al.



    Selected by Srivats Venkataramanan

    MRE11-RAD50-NBS1 activates Fanconi Anemia R-loop suppression at transcription-replication conflicts

    Emily Yun-Chia Chang, James P Wells, Shu-Huei Tsai, et al.



    Selected by Katie Weiner

    1

    Super-resolution Molecular Map of Basal Foot Reveals Novel Cilium in Airway Multiciliated Cells

    Quynh Nguyen, Zhen Liu, Rashmi Nanjundappa, et al.



    Selected by Robert Mahen

    Atlas of Subcellular RNA Localization Revealed by APEX-seq

    Furqan M Fazal, Shuo Han, Pornchai Kaewsapsak, et al.

    AND

    Proximity RNA labeling by APEX-Seq Reveals the Organization of Translation Initiation Complexes and Repressive RNA Granules

    Alejandro Padron, Shintaro Iwasaki, Nicholas Ingolia



    Selected by Christian Bates

    Unlimited genetic switches for cell-type specific manipulation

    Jorge Garcia-Marques, Ching-Po Yang, Isabel Espinosa-Medina, et al.



    Selected by Rafael Almeida

    1

    Stable knockout and complementation of receptor expression using in vitro cell line derived reticulocytes for dissection of host malaria invasion requirements

    Timothy J Satchwell, Katherine E Wright, Katy L Haydn-Smith, et al.



    Selected by Alyson Smith

    The coordination of terminal differentiation and cell cycle exit is mediated through the regulation of chromatin accessibility

    Yiqin Ma, Daniel J McKay, Laura Buttitta



    Selected by Gabriel Aughey

    1

    Disrupting Transcriptional Feedback Yields an Escape-Resistant Antiviral

    Sonali Chaturvedi, Marie Wolf, Noam Vardi, et al.



    Selected by Pavithran Ravindran

    1

    Multi-color single molecule imaging uncovers extensive heterogeneity in mRNA decoding

    Sanne Boersma, Deepak Khuperkar, Bram M.P. Verhagen, et al.



    Selected by Lorenzo Lafranchi

    Also in the synthetic biology category:

    Close