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Biosynthesis of pharmaceutically useful compounds: an original reaction in bacteria

Researchers from INRA have discovered a novel mechanism for a key reaction in the biosynthetic pathway for a pharmaceutically useful compound, Thiostrepton A. These results reveal the existence of a new type of enzymatic reaction in bacteria, thus opening the way towards promising prospects for the synthesis of pharmaceutical useful compounds.

Antibiogramme par diffusion en gélose (méthode des disques).,Les diamètres d'inhibition sont mesurés (cercles transparents) et sont comparés à des valeurs critiques proposées par le Comité de l'Antibiogramme de la Société Française de Microbiologie. L'interprétation des résultats de ces mesures permet de classer la souche bactérienne dans les catégories sensible, résistante ou intermédiaire. © CARRERAS Florence
Updated on 04/22/2013
Published on 04/12/2013

Researchers from INRA, working in collaboration with teams at the Max Planck Institute in Heidelberg and the Swedish University of Agricultural Sciences in Uppsala, have discovered a novel mechanism for a key reaction in the biosynthetic pathway for a pharmaceutically useful compound, Thiostrepton A.  

Thiostrepton A is a natural antibiotic which is active against a broad panel of multi-resistant bacteria, such as Staphylococcus aureus.  Some studies have demonstrated its potential activity versus malaria, but the most promising prospects concern the fight against cancer.  Indeed, Thiostrepton A targets a so-called proto-oncogene and inhibits its expression; this halts the cell cycle and hence the proliferation of cancer cells, particularly in the setting of breast cancer.

Although Thiostrepton A and its antibiotic activity have been known for 50 years, the genes involved in its biosynthesis were only described in 2009.  This substance is produced naturally by Streptomyces bacteria from two base elements, a peptide and the amino acid tryptophane (Trp).  To obtain Thiostrepton A, these two elements must undergo a cascade of modifications involving some twenty enzymes, most of whose functions remain unknown.

The INRA scientists focused on the mechanism of action of one of these enzymes, belonging to the family of methyl-transferases and involved in an early and crucial step in the biosynthetic pathway for Thiostrepton A.  This step consists in the grafting of a methyl group (CH3) onto tryptophane.  During their study, the INRA researchers managed not only to identify the enzyme responsible for the transfer of this methyl group onto tryptophane (called TsrM), but also showed that this reaction occurred thanks to a hitherto wholly unknown enzymatic mechanism.

This transfer reaction is particularly difficult to simulate because it involves replacing the target hydrogen atom present on tryptophane with a methyl group.  The bond between this hydrogen atom and a carbon atom thus needs to be broken, but this bond with the cyclical part of the tryptophane molecule is highly stable, as it is reinforced by a neighbouring double bond.

To achieve this transfer, the scientists showed that the enzyme was assisted not by a single co-factor – as is generally the case in a reaction operated by this family of enzymes – but by two co-factors.  Instead of being transferred directly to tryptophane, the methyl group is first of all added to another co-factor, probably to enable its activation.  It can then replace the target hydrogen atom on tryptophane.

The researchers were thus able to establish the precise function of this enzyme, which will enable the performance of studies to improve the properties of this anticancer agent and produce new, pharmaceutically useful compounds.  This work has also shown that the enzyme thus involved functions according to a mechanism that is entirely new in enzymology, and contrasts with previous predictions.  But because this enzymatic architecture is very widespread, this study clarifies the operation of a large number of enzymes, notably those which are coded by the intestinal metagenome, or in other words, by the genes of our digestive system, the role of which remains unknown.

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  • Stéphane Pierre, Alain Guillot, Alhosna Benjdia, Corine Sandström, Philippe Langella, Olivier Berteau. Thiostrepton tryptophan methyltransferase expands the chemistry of radical SAM enzymes. Nature Chemical Biology, 14 octobre 2012, DOI : 10.1038/NChemBio.1091