Comparative and Evolutionary Studies of the Lysosomal 2-Sulfoglucuronate Sulfatase


Arylsulfatase K (ARSK) is one of 17 sulfatase gene family members encoded on the human genome for which a role has been recently identified as a lysosomal 2-sulfoglucuronate sulfatase. Vertebrate ARSK sequences shared 60-82%identity but only <27% identities with other arylsulfatase family members. Comparative enzyme structures were studied,including residues with predicted roles in forming N-glycosylation sites, Ca2+ binding and active site residues. VertebrateARSK genes usually contained 8 coding exons. A human ARSK gene promoter comprised CpG61 and multiple TFBS,which may be involved in signal transduction, transcription activation or regulating entry into cell division. Phylogeneticanalyses examined evolutionary changes for the vertebrate ARSK and the invertebrate SUL1 genes. In summary,a major role for this enzyme as a 2-sulfoglucuronate sulfatase is supported which has been conserved throughout vertebrate evolution.

Seventeen human sulfatase gene families and fourteen mousesulfatase gene families encode sulfates which catalyze the hydrolysis of a range of biological sulfate esters in the body. The gene encoding arylsulfatase K (ARSK; EC (AR Skin vertebrates; Arks in rodents) was initially identified using bioinformatic methods through its conserved sulfates active site signature sequence and subsequently cloned, expressed in human cells, purified and biochemically characterized as anarylsulfatase, recently identified as catalyzing the hydrolysis of the 2-O-sulfate group from 2-sulfoglucuronat. Kinetic properties for human ARSK were similar to those of several otherlysosomal sulfates and an established role in the degradation of sulfated glycosaminoglycan’s has been identified. In addition, low sequence identities with other human sulfatases have been reported, indicating that this gene and enzyme represents a distinct form of human sulfatase. Broad ARSK mRNA expression in human tissues has been reported which suggested that a ubiquitous biological aryl sulfate substrate was the target for ARSK physiologically .Previous studies have shown that it comprises several domains: anN-terminus signal peptide (residues 1-22); five Ca2+ binding sites (1Ca2+ per subunit); two active site residues (313Asp and 314His); and multiple N-glycosylation sites.

Vertebrate ARSK genes and encoded proteins represent a distinct gene and protein arylsulfatase family which share key conserved sequences and domains reported for other arylsulfatase proteins previously studied. The metabolic role for ARSK has recently been established and the natural substrate for this enzyme described as lysosomal 2-sulfoglucuronate, a key enzyme in the catabolism ofheparin sulfate and dermatan sulfate . A single gene (ARSK/Arsk)encodes this enzyme among the vertebrate genomes studied , which is moderately expressed in a wide range of human tissues, but with highest levels of expression in fibroblasts. ARSK usually contained 8 coding exons on the negative or positive strands, depending on the vertebrate genome. The human ARSK gene contained a large CpG island within the promoter region, with several transcription factor binding sites collocated within the ARSK gene promoter region (Figure 4). Predicted secondary and tertiary structures for human ARSK showed similarities with reported 3Dstructures for other aryl sulfates.

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Alex Stewart