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Human Molecular Genetics Advance Access published online on September 20, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi351
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received June 30, 2005
Revised September 14, 2005
Accepted September 14, 2005

Article

Sulfatases and sulfatase modifying factors: an exclusive and promiscuous relationship

Marco Sardiello 1, Ida Annunziata 1, Guglielmo Roma 1, and Andrea Ballabio 2*

1 Telethon Institute of Genetics and Medicine, Via Pietro Castellino 111, 80131 Naples, Italy
2 Telethon Institute of Genetics and Medicine, Via Pietro Castellino 111, 80131 Naples, Italy; Medical Genetics, Department of Pediatrics, Federico II University, Via Sergio Pansini 5, 80131 Naples, Italy

* To whom correspondence should be addressed.
Andrea Ballabio, E-mail: ballabio{at}tigem.it


  Abstract

Sulfatases catalyze the hydrolysis of sulfate ester bonds from a wide variety of substrates. Several human inherited diseases are caused by the deficiency of individual sulfatases, while in patients with multiple sulfatase deficiency mutations in the Sulfatase Modifying Factor 1 (SUMF1) gene cause a defect in the post-translational modification of a cysteine residue into C{alpha}-formylglycine (FGly) at the active site of all sulfatases. This unique modification mechanism, which is required for catalytic activity, has been highly conserved during evolution. Here we used a genomic approach to investigate the relationship between sulfatases and their modifying factors in humans and several model systems. Firstly, we determined the complete catalogue of human sulfatases, which is comprised of 17 members (vs. 14 in rodents), including four novel ones (ARSH, ARSI, ARSJ, and ARSK). Secondly, we showed that the active site, which is the target of the post-translational modification, is the most evolutionarily constrained region of sulfatases and shows intraspecies sequence convergence. Exhaustive sequence analyses of available proteomes indicate that sulfatases are the only likely targets of their modifying factors. Thirdly, we showed that sulfatases and ectonucleotide pyrophosphatases share significant homology at their active sites, suggesting a common evolutionary origin as well as similar catalytic mechanisms. Most importantly, gene association studies performed on prokaryotes suggested the presence of at least two additional mechanisms of cysteine-to-FGly conversion that do not require SUMF1. These results may have important implications in the study of diseases caused by sulfatase deficiencies and in the development of therapeutic strategies.


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