Descripción del proyecto
Una manera sostenible de producir nuevos antibióticos
Los policétidos son una gran clase de metabolitos secundarios de bacterias, hongos y plantas con actividades valiosas e interesantes. Se emplean como antibióticos, antimicóticos y fármacos, además de producirse o sintetizarse químicamente a partir de fuentes biológicas. El proyecto PrediKSion, financiado con fondos europeos, propone aprovechar las enzimas del dominio aciltransferasa de la policétido sintasa (AT PKS, por sus siglas en inglés) de bacterias como una manera sostenible para producir policétidos. A fin de desvelar las características biosintéticas de la AT PKS, los investigadores desarrollarán un proceso computacional que evaluará la funcionalidad de las enzimas sin caracterizar. A largo plazo, eso llevará al descubrimiento de nuevas entidades farmacéuticas.
Objetivo
Many of the most valuable, yet complex chemicals in society are obtained from bacteria, who use giant, multimodular acyltransferase polyketide synthase (AT PKS) enzyme complexes to make these products. The modular nature of these enzymes holds the promise to engineer biosynthetic assembly lines to produce new, societally relevant products in a benign and sustainable manner. However, the chemical functionalities installed by the textbook cis-AT PKSs is mostly limited to several basic moieties.
In contrast, in a second class of PKSs, trans-AT PKSs, over 150 different module types have been identified, yet with many more still uncharacterized. Initial results show that bioinformatically-guided approaches can be effective ways to assign the functionality of these uncharacterized modules, but only individual examples have been studied. To catalyze the discovery of new functionality in trans-AT PKSs, I propose PrediKSion: a comprehensive, evolution-guided and experimentally validated computational pipeline to unravel the hidden chemical functionality of unassigned trans-AT PKS modules.
PrediKSion will facilitate unbiased discovery of new module functionalities by looking at the phylogeny of ketosynthases (KSs) in the PKS sequences. The high substrate selectivity in KSs reveals crucial information on chemistry installed by upstream modules and can thereby lead to the discovery of new and unexpected biosynthetic features in uncharacterized PKS modules and elusive trans-acting components. PrediKSion will be applied on the complete bacterial tree of life and achieve great impact by providing the community with a global mapping of predicted chemical functionality in trans-AT PKSs. The computational suggestions will finally be validated experimentally and the substrate scope of new PKS modules will be studied. In this way, PrediKSion will accelerate the mapping of uncharacterized PKSs and the discovery of new metabolites and potentially interesting pharmaceutical platforms.
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MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinador
8092 Zuerich
Suiza