Human Molecular Genetics Advance Access originally published online on September 20, 2005
Human Molecular Genetics 2005 14(21):3203-3217; doi:10.1093/hmg/ddi351
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Sulfatases and sulfatase modifying factors: an exclusive and promiscuous relationship
1Telethon Institute of Genetics and Medicine (TIGEM), Via Pietro Castellino 111, 80131 Naples, Italy and 2Medical Genetics, Department of Pediatrics, Federico II University, Via Sergio Pansini 5, 80131 Naples, Italy
* To whom correspondence should be addressed. Tel: +39 816132207; Fax: +39 815790919; Email: ballabio{at}tigem.it
Received June 30, 2005; Accepted September 14, 2005
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
-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. First, we determined the complete catalog of human sulfatases, which comprises 17 members (versus 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, which 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.
AY875937–AY875940; BN000735–BN000767
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