Our analyses on the basis of antibody recognition because of incompatible epitopes immediately after processing. Further research on this problem will demand expression of bigger amounts of ARSK and/or availability of other ARSKspecific antibodies. ARSK is expressed in all tissues examined in this study and was also identified in eight tissues from rat in M6P glycoproteome analyses (33). Its ubiquitous expression pattern may possibly suggest a popular and widespread sulfated substrate and indicates that ARSK deficiency in all probability leads to a lysosomal storage disorder, as shown for all other lysosomal sulfatases. Presently, we’re generating an ARSK-deficient mouse model that really should pave the solution to determine the physiological substrate of this sulfatase and its general pathophysiological relevance. Ultimately, the mouse model could allow us to draw conclusions on ARSKdeficient human individuals who so far escaped diagnosis and could possibly be accessible for enzyme replacement therapy. The presence of M6P on ARSK qualifies this sulfatase for such a therapy, which has proven useful for treatment of quite a few other lysosomal storage issues.Acknowledgments–We thank Bernhard TLR7 Agonist Storage & Stability Schmidt and Olaf Bernhard for mass spectrometry; Nicole Tasch, Annegret Schneemann, Britta Dreier, Martina Balleininger (all from G tingen), William C. Lamanna, Jaqueline Alonso Lunar, Kerstin B er, and Claudia Prange for technical help; Markus Damme for initial evaluation of subcellular localization; and Jeffrey Esko (San Diego) for critically reading the manuscript. We also thank Kurt von Figura for help throughout the initial phase of this project.SIRT1 Activator custom synthesis Dierks, T. (2007) The heparanome. The enigma of encoding and decoding heparan sulfate sulfation. J. Biotechnol. 129, 290 ?07 Schmidt, B., Selmer, T., Ingendoh, A., and von Figura, K. (1995) A novel amino acid modification in sulfatases which is defective in a number of sulfatase deficiency. Cell 82, 271?78 von B ow, R., Schmidt, B., Dierks, T., von Figura, K., and Us , I. (2001) Crystal structure of an enzyme-substrate complex gives insight into the interaction amongst human arylsulfatase A and its substrates for the duration of catalysis. J. Mol. Biol. 305, 269 ?77 Dierks, T., Lecca, M. R., Schlotterhose, P., Schmidt, B., and von Figura, K. (1999) Sequence determinants directing conversion of cysteine to formylglycine in eukaryotic sulfatases. EMBO J. 18, 2084 ?091 Dierks, T., Schmidt, B., and von Figura, K. (1997) Conversion of cysteine to formylglycine. A protein modification inside the endoplasmic reticulum. Proc. Natl. Acad. Sci. U.S.A. 94, 11963?1968 Dierks, T., Dickmanns, A., Preusser-Kunze, A., Schmidt, B., Mariappan, M., von Figura, K., Ficner, R., and Rudolph, M. G. (2005) Molecular basis for many sulfatase deficiency and mechanism for formylglycine generation of the human formylglycine-generating enzyme. Cell 121, 541?52 Dierks, T., Schmidt, B., Borissenko, L. V., Peng, J., Preusser, A., Mariappan, M., and von Figura, K. (2003) Several sulfatase deficiency is caused by mutations inside the gene encoding the human C( )-formylglycine producing enzyme. Cell 113, 435?444 Dierks, T., Schlotawa, L., Frese, M. A., Radhakrishnan, K., von Figura, K., and Schmidt, B. (2009) Molecular basis of many sulfatase deficiency, mucolipidosis II/III and Niemann-Pick C1 disease. Lysosomal storage problems triggered by defects of non-lysosomal proteins. Biochim. Biophys. Acta 1793, 710 ?25 Cosma, M. P., Pepe, S., Annunziata, I., Newbold, R. F., Grompe, M., Parenti, G., and Ballabio,.