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Comparative genomic analysis of the DUF71/COG2102 family predicts roles in diphthamide biosynthesis and B12 salvage

Valérie de Crécy-Lagard1*, Farhad Forouhar2, Céline Brochier-Armanet3, Liang Tong2 and John F Hunt2

Author Affiliations

1 Department of Microbiology and Cell Science, University of Florida, Gainesville, FL, 32611, USA

2 Department of Biological Sciences, Columbia University, Northeast Structural Genomics Consortium, 1212 Amsterdam Ave, New York, NY, 10027, USA

3 Université de Lyon; Université Lyon 1; CNRS; UMR5558, Laboratoire de Biométrie et Biologie Evolutive, 43 boulevard du 11 Novembre 1918, Lyon, Villeurbanne, F-69622, France

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Biology Direct 2012, 7:32  doi:10.1186/1745-6150-7-32

Published: 26 September 2012

Abstract

Background

The availability of over 3000 published genome sequences has enabled the use of comparative genomic approaches to drive the biological function discovery process. Classically, one used to link gene with function by genetic or biochemical approaches, a lengthy process that often took years. Phylogenetic distribution profiles, physical clustering, gene fusion, co-expression profiles, structural information and other genomic or post-genomic derived associations can be now used to make very strong functional hypotheses. Here, we illustrate this shift with the analysis of the DUF71/COG2102 family, a subgroup of the PP-loop ATPase family.

Results

The DUF71 family contains at least two subfamilies, one of which was predicted to be the missing diphthine-ammonia ligase (EC 6.3.1.14), Dph6. This enzyme catalyzes the last ATP-dependent step in the synthesis of diphthamide, a complex modification of Elongation Factor 2 that can be ADP-ribosylated by bacterial toxins. Dph6 orthologs are found in nearly all sequenced Archaea and Eucarya, as expected from the distribution of the diphthamide modification. The DUF71 family appears to have originated in the Archaea/Eucarya ancestor and to have been subsequently horizontally transferred to Bacteria. Bacterial DUF71 members likely acquired a different function because the diphthamide modification is absent in this Domain of Life. In-depth investigations suggest that some archaeal and bacterial DUF71 proteins participate in B12 salvage.

Conclusions

This detailed analysis of the DUF71 family members provides an example of the power of integrated data-miming for solving important “missing genes” or “missing function” cases and illustrates the danger of functional annotation of protein families by homology alone.

Reviewers’ names

This article was reviewed by Arcady Mushegian, Michael Galperin and L. Aravind.

Keywords:
Diphthamide; Vitamin B12; Amidotransferase; Comparative genomics