Email updates

Keep up to date with the latest news and content from Genome Biology and BioMed Central.

Open Access Research

The alpha/beta fold uracil DNA glycosylases: a common origin with diverse fates

L Aravind* and Eugene V Koonin

Author Affiliations

National Center for Biotechnology Information, National Institutes of Health, Bethesda, MD 20894, USA

For all author emails, please log on.

Genome Biology 2000, 1:research0007-research0007.8  doi:10.1186/gb-2000-1-4-research0007

Published: 13 October 2000

Abstract

Background

Uracil DNA glycosylases (UDGs) are major repair enzymes that protect DNA from mutational damage caused by uracil incorporated as a result of a polymerase error or deamination of cytosine. Four distinct families of UDGs have been identified, which show very limited sequence similarity to each other, although two of them have been shown to possess the same structural fold. The structural and evolutionary relationships between the rest of the UDGs remain uncertain.

Results

Using sequence profile searches, multiple alignment analysis and protein structure comparisons, we show here that all known UDGs possess the same fold and must have evolved from a common ancestor. Although all UDGs catalyze essentially the same reaction, significant changes in the configuration of the catalytic residues were detected within their common fold, which probably results in differences in the biochemistry of these enzymes. The extreme sequence divergence of the UDGs, which is unusual for enzymes with the same principal activity, is probably due to the major role of the uracil-flipping caused by the conformational strain enacted by the enzyme on uracil-containing DNA, as compared with the catalytic action of individual polar residues. We predict two previously undetected families of UDGs and delineate a hypothetical scenario for their evolution.

Conclusions

UDGs form a single protein superfamily with a distinct structural fold and a common evolutionary origin. Differences in the catalytic mechanism of the different families combined with the construction of the catalytic pocket have, however, resulted in extreme sequence divergence of these enzymes.