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The CNRGH is the French national research center which enables a response to scientific questions necessitating high throughput sequencing and genotyping thanks to the development and deployment of innovative integrated technologies. The organization of the CNRGH enables optimization of genetic and genomic research on human diseases by creating indispensable links between cohort constitution (DNA samples), identification of the responsible genes, and study of the transcriptome and epigenome.
List of the main projects of the Institut de Génomique
This work has been performed in the context of the GENOZYME ANR project involving two other partners (ICCF/UBP-CNRS, UMR 6296 and ISTHMUS).
Nature provides various enzymes which form or cleave C–C bonds. These enzymes have attracted chemists' interest for industrial synthesis operations. In particular, monosaccharides are in many cases prepared by traditional organic synthesis, which requires many protection and deprotection steps.
Aldolases (ALD) and transketolases (TK) are two of the most important groups of asymmetric C–C bond forming enzymes and this project proposed to open up the field of their industrial applications by screening for novel C-C bond formation biocatalysts.
A total of 732 ALD and 874 TK representing the phylogenetic diversity of these two enzyme families were selected, overexpressed in E. coli and screened for new chemical reactions using the Genoscope cloning and screening platform. TK and ALD were assayed respectively on ten and five chemical reactions. Candidate TK were found for six out of the ten tested reactions, while candidate ALD were found for all the reactions tested. This screening led to the discovery of several new biocatalysts including aldolases using hydroxypyruvate (HP) as the donor. Until now, no HP aldolase has been described in the literature and this discovery represents a ground-breaking in biocatalysis enabling biosynthesis of novel α-ketoacids (Lemaire M, Hélaine, V, De Beradinis V, Salanoubat M, in prep). In addition, only enzymes catalyzing the aldolisation of glyceraldehyde-3P with dihydroxyacetone phosphate generating fructose-6P are currently known.
The screening strategy we used by selecting enzymes catalyzing the formation of hexose-6P by Mass Spectrometry identified putative aldolase candidates for sugar phosphate with a stereochemistry different from the one of fructose. Work is currently in progress to determine the stereochemistry of these aldoses and surprisingly led to the characterisation of an unreported enzymatic reaction which is being characterized. In addition, this work allowed the experimental annotation of hundreds of proteins representing the natural diversity of ALD and TK enzyme families. Beside the discovery of new biocatalysts, this study is useful to improve function annotation by adding experimental knowledge to the sequence homology based annotation. Nowadays, aldolases are largely established as efficient and versatile tools for biocatalysis and are used in organic synthesis for the preparation of biologically active molecules (Clapés and Garrabou, 2011). This project promises major breakthroughs for aldolase applications in industry.
Laboratories involved : Laboratory for Cloning and Screening Bioconversion Activities, Laboratory of Genomics and Biochemistry of Metabolism.
CEA is a French government-funded technological research organisation in four main areas: low-carbon energies, defense and security, information technologies and health technologies. A prominent player in the European Research Area, it is involved in setting up collaborative projects with many partners around the world.