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

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: 19 July 2018

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