Human sulfatases: A structural perspective to catalysis

Abstract

The sulfatase family of enzymes catalyzes hydrolysis of sulfate ester bonds of a wide variety of substrates. Seventeen genes have been identified in this class of sulfatases, many of which are associated with genetic disorders leading to reduction or loss of function of the corresponding enzymes. Amino acid sequence homology suggests that the enzymes have similar overall folds, mechanisms of action, and bivalent metal ion-binding sites. A catalytic cysteine residue, strictly conserved in prokaryotic and eukaryotic sulfatases, is post-translationally modified into a formylglycine. Hydroxylation of the formylglycine residue by a water molecule forming the activated hydroxylformylglycine (a formylglycine hydrate or a gem-diol) is a necessary step for the enzyme's sulfatase activity. Crystal structures of three human sulfatases, arylsulfatases A and B(ARSA and ARSB), and estrone/dehydroepiandrosterone sulfatase or steroid sulfatase (STS), also known as arylsulfatase C, have been determined. While ARSA and ARSB are water-soluble enzymes, STS has a hydrophobic domain and is an integral membrane protein of the endoplasmic reticulum. In this article, we compare and contrast sulfatase structures and revisit the proposed catalytic mechanism in light of available structural and functional data. Examination of the STS active site reveals substrate-specific interactions previously identified as the estrogen-recognition motif. Because of the proximity of the catalytic cleft of STS to the membrane surface, the lipid bilayer has a critical role in the constitution of the active site, unlike other sulfatases.

Structure-based mechanism of lipoteichoic acid synthesis by Staphylococcus aureus LtaS

“…The structure revealed that the overall fold of eLtaS is indeed sulfatase-like and shows striking similarity to human sulfatases and the prokaryotic Pseudomonas aeruginosa arylsulfatase (Fig. 2) (16,17). eLtaS folds into 1 hemispheric unit made up of an ␣/␤ core and a C-terminal part composed of 4 anti-parallel ␤-strands and a long ␣-helix ( Fig.…”

“…For PGM and sulfatases, high-resolution structures with bound substrate or substrate analogues made it possible to propose catalytic mechanisms for these enzymes (16,17). To gain similar insight into the eLtaS reaction mechanism, we cocrystallized eLtaS and an inactive eLtaS-T300A variant with glycerol-phosphate (mimicking the head group of PG) and refined the structures to 1.6-and 1.7-Å resolution, respectively [ Fig.…”

Arylsulfatase B Mediates the Sulfonation-Transport Interplay in Human Embryonic Kidney 293 Cells Overexpressing Sulfotransferase 1A3

“…They are located in lysosome [arylsulfatase A (ARSA), ARSB, iduronate 2-sulfatase, heparan N-sulfatase, N-acetylglucosamine-6-sulfatase, N-acetyl-galactosamine-6-sulfatase, and telethon sulfatase], endoplasmic reticulum [ARSC, ARSD, ARSF, ARSG, ARSH, ARSJ, and ARSK], Golgi apparatus (ARSE), or cell surface (sulfatase 1 and sulfatase 2) (Diez-Roux and Ballabio, 2005). Sulfatases use the formylglycine (derived from a cysteine) as the catalytic residue that attacks the sulfur atom upon activation by a water molecule (Ghosh, 2007). Due to their roles in the regulation of cell metabolism and signaling, genetic deficiencies of sulfatases result in various pathophysiological conditions such as hormone-dependent cancers, lysosomal storage disorders, and developmental abnormalities Buono and Cosma, 2010).…”

X-ray structure of an AdoMet radical activase reveals an anaerobic solution for formylglycine posttranslational modification

“…Arylsulfatases, for example, require the co-or posttranslational formation of a catalytically essential formylglycine (FGly) moiety to perform their hydrolysis function, removing sulfate groups from a wide array of substrates (e.g., sulfated polysaccharides, sulfolipids, and steroid sulfates) (1)(2)(3). In humans, lack of sulfatase activity can lead to disease (4), while in bacteria, inhibition impairs colonizing the mucosal layer of the host's gut (5).…”