Sulfatases and sulfatase modifying factors: an exclusive and promiscuous relationship

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. 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.

Molecular analysis ofSUMF1 mutations: stability and residual activity of mutant formylglycine-generating enzyme determine disease severity in multiple sulfatase deficiency

“…So far, 17 human genes encoding sulfatases have been identified and eight of them are associated with human diseases presenting with clearly defined clinical pictures [Diez-Roux and Ballabio, 2005]. All sulfatases share amino acid homology in their active sites including a cysteine residue in the core-motif [Dierks et al, 1999;Sardiello et al, 2005]. This so-called sulfatase signature determines the cysteine to be posttranslationally modified to FGly by FGE in the endoplasmic reticulum (ER) [Dierks et al, 1997;Dierks et al, 1999], which is a strict precondition to become a catalytically active sulfatase [Schmidt et al, 1995].…”

A non-conserved miRNA regulates lysosomal function and impacts on a human lysosomal storage disorder

“…Thus, sulfate homeostasis is highly dynamic and tightly regulated by multiple enzymes including a large family of sulfatase enzymes that hydrolyse sulfate esters from many substrates, including sulfolipids, steroid sulfates and glycosaminoglycans (GAGs) 6 . To date, 17 human sulfatases are known, broadly categorized into two main groups, exerting their enzymatic activity either at a neutral or an acidic pH.…”

Systemic inflammation and neurodegeneration in a mouse model of multiple sulfatase deficiency

“…Seventeen sulfatase genes are present in the human genome (2). Based on current knowledge, two main functional categories can be identified.…”