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Nat Chem Biol. 2014 Jan;10(1):42-9. doi: 10.1038/nchembio.1387. Epub 2013 Nov 17.

Revealing the hidden functional diversity of an enzyme family.

Author information

1
1] Direction des Sciences du Vivant, Commissariat à l'energie atomique et aux énergies alternatives (CEA), Institut de Génomique, Evry, France. [2] CNRS-UMR8030, Evry, France. [3] Université d'Evry Val d'Essonne, Evry, France. [4].
2
1] Direction des Sciences du Vivant, Commissariat à l'energie atomique et aux énergies alternatives (CEA), Institut de Génomique, Evry, France. [2] CNRS-UMR8030, Evry, France. [3] Université d'Evry Val d'Essonne, Evry, France. [4] [5].
3
1] Direction des Sciences du Vivant, Commissariat à l'energie atomique et aux énergies alternatives (CEA), Institut de Génomique, Evry, France. [2] CNRS-UMR8030, Evry, France. [3] Université d'Evry Val d'Essonne, Evry, France.
4
1] Direction des Sciences du Vivant, Commissariat à l'energie atomique et aux énergies alternatives (CEA), Institut de Génomique, Evry, France. [2] CNRS-UMR8030, Evry, France. [3] Université d'Evry Val d'Essonne, Evry, France. [4] Department of Computer Science, Federal University of Minas Gerais, Belo Horizonte, Brazil.

Abstract

Millions of protein database entries are not assigned reliable functions, preventing the full understanding of chemical diversity in living organisms. Here, we describe an integrated strategy for the discovery of various enzymatic activities catalyzed within protein families of unknown or little known function. This approach relies on the definition of a generic reaction conserved within the family, high-throughput enzymatic screening on representatives, structural and modeling investigations and analysis of genomic and metabolic context. As a proof of principle, we investigated the DUF849 Pfam family and unearthed 14 potential new enzymatic activities, leading to the designation of these proteins as β-keto acid cleavage enzymes. We propose an in vivo role for four enzymatic activities and suggest key residues for guiding further functional annotation. Our results show that the functional diversity within a family may be largely underestimated. The extension of this strategy to other families will improve our knowledge of the enzymatic landscape.

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PMID:
24240508
DOI:
10.1038/nchembio.1387
[Indexed for MEDLINE]

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