Our analyses on the basis of antibody recognition as a result of incompatible epitopes just after processing. Further research on this issue will demand expression of larger amounts of ARSK and/or availability of other ARSKspecific antibodies. ARSK is expressed in all tissues examined within this study and was also identified in eight tissues from rat in M6P glycoproteome analyses (33). Its ubiquitous expression pattern may well suggest a typical and widespread sulfated substrate and indicates that ARSK deficiency probably results in a lysosomal storage disorder, as shown for all other lysosomal sulfatases. At present, we’re producing an ARSK-deficient mouse model that really should pave the approach to identify the physiological substrate of this sulfatase and its general pathophysiological relevance. Ultimately, the mouse model could enable us to draw conclusions on ARSKdeficient human patients who so far escaped diagnosis and may possibly be accessible for enzyme replacement therapy. The presence of M6P on ARSK qualifies this sulfatase for such a therapy, which has verified PLD Inhibitor MedChemExpress beneficial for therapy of various other lysosomal storage problems.Acknowledgments–We thank Bernhard 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 assistance; 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 in the course of the initial phase of this project.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 that may be defective in many 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 complicated supplies insight in to 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 within 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 multiple sulfatase deficiency and mechanism for formylglycine generation with the human mGluR1 Activator Biological Activity 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) Multiple sulfatase deficiency is brought on by mutations within the gene encoding the human C( )-formylglycine generating enzyme. Cell 113, 435?444 Dierks, T., Schlotawa, L., Frese, M. A., Radhakrishnan, K., von Figura, K., and Schmidt, B. (2009) Molecular basis of a number of 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,.