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Evolution of Cyclic Amidohydrolases: A Highly Diversified Superfamily

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Abstract

Dihydroorotases are universal proteins catalyzing the third step of pyrimidine biosynthesis. These zinc metalloenzymes belong to the superfamily of cyclic amidohydrolases, comprising also other enzymes that are involved in degradation of either purines (allantoinases), pyrimidines (dihydropyrimidinases) or hydantoins (hydantoinases). The evolutionary relationships between these mechanistically related enzymes were estimated after designing a method to build an accurate multiple sequence alignment. The amino acid sequences that have been crystallized were used to build a seed alignment. All the remaining homologues were progressively added by aligning their HMM profiles to the seed HMM profile, allowing to obtain a reliable phylogeny of the superfamily. This helped us to propose a new evolutionary classification of dihydroorotases into three major types, while at the same time disentangling an important part of the history of their complex structure–function relationships. Although differing in their substrate specificity, allantoinases, hydantoinases and dihydropyrimidinases are found to be phylogenetically closer to DHOase Type I than the proximity of the three DHOase types to each other. This suggests that the primordial cyclic amidohydrolase was a multifunctional, highly evolvable generalist, with high conformational diversity allowing for promiscuous activities. Then, successive gene duplications allowed resolving the primordial substrate ambiguity in various substrate specificities. The present-day superfamily of cyclic amidohydrolases is the result of the progressive divergence of these ancestral paralogous copies by descent with modification.

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Acknowledgments

We are very indebted to Barry Holland for his invaluable help in critically reading our manuscript and improving the English. The constructive comments of the two reviewers and of the associate editor were very helpful to improve our manuscript at the revision stage. This work, funded by the CNRS (UMR 8621), forms part of the PhD thesis of Matthieu Barba who was supported by a doctoral grant from the French Ministère de la Recherche.

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  1. Matthieu Barba

    Present address: Laboratoire de Biométrie et Biologie Évolutive.CNRS UMR 5558, Université Claude, Bernard Lyon 1, 69622, Villeurbanne Cedex, France

  2. Bernard Labedan

    Present address: Bioinformatique, Laboratoire de Recherche en Informatique CNRS UMR 8623, Université Paris Sud, Bâtiment 650, 91405, Orsay Cedex, France

Authors and Affiliations

  1. Institut de Génétique et Microbiologie, CNRS UMR 8621, Université Paris Sud, Bâtiment 400, 91405, Orsay Cedex, France

    Matthieu Barba & Bernard Labedan

  2. Microbiology, Free University of Brussels (VUB) and J.M. Wiame Research Institute, 1, ave E. Gryzon, 1070, Brussels, Belgium

    Nicolas Glansdorff

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  1. Matthieu Barba
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  3. Bernard Labedan
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Correspondence to Bernard Labedan.

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Nicolas Glansdorff—Deceased in July 2009.

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Barba, M., Glansdorff, N. & Labedan, B. Evolution of Cyclic Amidohydrolases: A Highly Diversified Superfamily. J Mol Evol 77, 70–80 (2013). https://doi.org/10.1007/s00239-013-9580-1

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